The Nervous Liver: Neurological complications ...

The Nervous Liver: Neurological complications associated with 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

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Learning objectives That there is a relationship between the brain and the liver has been known for many years, and patients with chronic liver disease frequently experience a wide spectrum of neurological problems that can adversely affect patient's neurocognitive functioning [1-3]. These neurological problems range from neurological complications such as hepatic myelopathy, acquired hepatocerebral degeneration, cognitive and mental status changes such as hepatic encephalopathy to metabolic, infective and hemorrhagic complications of liver cirrhosis; and, can severely restrict the patient's functioning and also result in significant 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

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The present exhibit aims: 1. To appraise the wide array of neurological syndromes and disorderes that can be associated with liver cirrhosis, highlighting their most pertinent neuroimaging manifestations and providing an up-to-date information on these relatively understudied entities. 2. To study and illustrate perioperative neurological complications which may originate before, during or after orthotopic liver transplantation.

Background LIVER-BRAIN AXIS Normal brain functioning depends on several aspects of normal liver functioning. For example, the liver supplies certain nutrients to the brain that the brain itself cannot produce. 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 toxic substances 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 for cleansing is diverted directly into the general circulation without first passing through the liver, a phenomenon known as portal-systemic shunting. As a result, the shunted blood is not detoxified and blood levels of toxic substances rise. Persistently elevated neurotoxin levels 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, the peripheral nervous system, or both; and, could represent a direct complication of the disease, or part of spectrum of pathologies that affect the brain and liver concurrently [1-6]. Boradly, neurological disorders in cirrhosis can be attributed to:

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(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 the highest incidence of neurological complications. Neurological complications following liver transplantation have an overall incidence of 13 - 47%. These complications can be broadly classified into:

(1) Immunosuppressive neurotoxicity (2) Opportunistic infections

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(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 and bilateral signal intensities of various extents involving the basal ganglia and the hypothalamus on T1WI [1, 7, 8].

•

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

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Fig. 2: Symmetrical T1-hyperintensity involving the bilateral globus pallidus (arrows) in an 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 internal capsule of the hypothalamus, putamen, caudate, substantia nigra, and mesencephalic tegmentum (Fig 3) [8].

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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). 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 remain indefinite, however several hypotheses have been proposed. Deposition of paramagnetic substances, particularly manganese (Mn), is speculated to be responsible 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 adaptive process designed to improve the efficacy of ammonia detoxification by astrocytes [10, 11].

•

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

•

The pituitary gland is another commonly affected site shown on the MR images; and when involved appears homogeneously bright on spin echo T1-weighted images. The hyperintense signal of the pituitary gland makes it impossible to distinguish between the normal isointense anterior pituitary signal and the posterior pituitary hyperintensity [8].

•

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

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

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

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Fig. 5: A 40-year old male with alcoholic liver cirrhosis and grade-I hepatic encephalopathy. Fast-FLAIR MR images reveal diffuse high-signal intensity in the hemispheric 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 the periventricular white, thalami, and basal ganglia in studies of patients with cirrhosis with hepatic encephalopathy [9, 10].

•

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

•

Another common neuroimaging manifestation in cirrhotic patients is the presence 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].

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Fig. 6: Cerebral atrophy accompanying typical intracranial signal intensity changes in a 36-year old patient with long standing cryptogenic cirrhosis. Axial T1-WI shows symmetrical T1-prolongation of the basal ganglia (asterisk) representing manganese deposition. Attendant widening of the sylvian fissures (thick arrows) and ventricular enlargement (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 have revealed ventricular enlargement, cisternal and sulcal prominence, selective loss of subcortical white matter, and prominent subarachnoid CSF spaces.

•

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

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Fig. 7: Ventricular enlargement (white arrow) and subarachnoid CSF-space (sylvian fissure) widening represent cerebral involutional changes in a 30-year old male with alcohol 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 associated with a poor psychometric performance and both brain atrophy and EEG alterations 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 on proton MRS [17].

HEPATIC ENCEPHALOPATHY •

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

•

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

•

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

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to manganese, but this only variably correlates with the plasma ammonia levels 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 chronic phase, there is a thin cortex and cortical laminar necrosis [18].

•

The proposed cytotoxic edema mechanism in HE is hyperammonia inducing intracerebral accumulation of glutamine, resulting in astrocyte swelling and brain edema [18].

•

On MR imaging, presence of extensive cortical edema including the deep gray matter, with symmetric involvement of the cingulate gyrus and insular cortex on DWI or FLAIR imaging, associated with sparing of the perirolandic and 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 symmetrical cortical 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

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•

Thus, the cingulate gyrus and insular cortex appear to be particularly vulnerable to hyperammonemic-hyperglutaminergic encephalopathy, while the perirolandic and occipital cortex seem relatively resistant. These MR manifestations therefore should alert the radiologist to the possibility of acute hyperammonemic encephalopathy in appropriate clinical settings (Fig 9) [19, 20].

Fig. 9: Acute HE. DWI displaying extensive symmetrical gyral edema which characteristically 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

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•

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

•

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

•

On proton MR spectroscopy: an elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals, representing disturbances in cell-volume homeostasis secondary to brain hyperammonemia, constitute the characteristic imaging manifestations of HE.

•

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

Fig. 10: Chronic HE. Axial T1-WI showing cortical atrophy with gyriform T1hyperintensity representing cortical laminar necrosis in a follow-up case of liver cirrhosis 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 laminar necrosis of hypoxic brain damage preferentially involves the watershed

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

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

•

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

ACQUIRED HEPATOCEREBRAL DEGENERATION •

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

•

The pathophysiology and the locations of the cerebral injuries are incompletely understood and are not necessarily related to hyperammonaemia. However, cerebral deposition of manganese may have a pathogenetic role [25, 26].

•

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

•

Clinically, it is characterized by a combination of parkinsonism and cerebellar signs, with neuropsychiatric changes and movement disorders usually 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-weighted hyperintensities involving the brachium pontis (middle cerebellar peduncles) and subcortical white matter (Fig 11) [23, 24].

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Fig. 11: A 50-year old liver cirrhosis patient developed cognitive deficits, ataxia, dysarthria, movement disorders, and features of parkinsonism. MR images reveal symmetrical T1-hyperintensity of the basal ganglia (A) with attendant T2-hyperintense changes involving the bilateral middle cerebellar peduncles (B). Imaging findings in the light 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 dentate nuclei bilaterally on T2-weighted images is often indistinguishable from Wilson disease [23-27].

•

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

•

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

CIRRHOSIS-RELATED PARKINSONISM

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•

Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment 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 Parkinsonism was associated with hepatic myelopathy [28].

•

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

•

The aforementioned hypothesis is supported by the observation that cirrhosis-related Parkinsonism and dystonia could be effectively treated with chelating agents, and by reports which have shown an improvement of extrapyramidal symptoms after successful liver transplantation in parallel to the disappearance of cerebral MRI signal alterations ascribed to manganese deposition [28-32].

•

MR T1-weighted images show characteristic hyperintensity of the basal ganglia including the globus pallidus, putamen, and caudate, subthalamic, and dentate nuclei with sparing of the thalamus and ventral pons (Fig 12). When the disease is extensive, white matter and anterior pituitary involvement can be present [32].

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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 cirrhosis presenting 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 a much lesser extent. More often than not they are reported as normal on T2WI [32].

•

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

CIRRHOTIC or HEPATIC MYELOPATHY

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•

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

•

The main clinical feature of hepatic myelopathy is progressive spastic paraparesis in the absence of sensory or sphincter impairment. Typically, a patient with underlying chronic liver disease, develops progressive pure motor spastic paraparesis with minimal or no sensory deficit and without bowel and bladder involvement [34].

•

The exact pathogenesis of HM is still unclear. However, it has been hypothesized that the hepatocerebral dysfunction secondary to recurrent episodes of hepatic encephalopathy, and prolonged exposure to bypassed nitrogenous waste (ammonia, fatty acids, indoles, and mercaptans) cause myelin damage resulting in the pathological white matter demyelination in the brain and the spinal cord (Fig 13) [35].

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Fig. 13: A 50-year old male patient with hepatic myelopathy. MR spine failed to depict any overt intramedullary signal alteration; however, screening of brain revealed symmetrical 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 with varying degrees of axonal loss. The selective predisposition for the motor system has been demonstrated by involvement of the lateral corticospinal tracts in autopsy studies [35].

•

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

•

Early and accurate diagnosis of hepatic myelopathy is important because patients with early stages of the disease can fully recover following liver transplantation [34-36].

•

Hepatic myelopathy remains a default diagnosis assigned only after the exclusion of other causes of spastic paraparesis and partial transverse myelopathy. Accordingly, a detailed and accurate history along with appropriate imaging and laboratory findings remain crucial for establishing the diagnosis [37].

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

•

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

•

In contrast to hepatic encephalopathy, hepatic myelopathy does not respond to blood ammonia lowering therapies but must be considered as an indication for urgent liver transplantation [6].

CIRRHOSIS-RELATED INTRACEREBRAL HEMORRHAGE •

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

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•

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

•

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

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

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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 obstructive ventriculomegaly (arrowhead). The cerebral sulci are effaced and the cortico-medullary junction 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 retrospective study of 4515 patients with liver cirrhosis. The incidence in the alcoholrelated group was 1.9% whereas the virus-related group had an incidence of 0.3%. A combined group (patients with both virus- and alcohol-related cirrhosis) had an incidence of 3% [39].

•

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

INFECTIVE COMPLICATIONS OF CIRRHOSIS •

Cirrhosis has been characterized as the commonest acquired immunodeficiency syndrome worldwide (exceeding even AIDS) and infectious complications in cirrhotic patients can cause severe morbidity and mortality [45, 46].

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•

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

•

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

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

•

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

•

Compared to the general population, the mortality of infections is more than 20 times increased in cirrhosis. The incidence of bacteremia, peritonitis, urinary tract infection, pneumonia, meningitis, and tuberculosis is increased more than tenfold, and the mortality of each episode 3-10 times higher [48].

•

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

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

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Fig. 16: Pyogenic meningitis and ventriculitis in a 42-year old patient with NASH related liver cirrhosis. Post gadolinium T1-WI reveals inflammation, thickening and abnormal enhancement of the right lateral ventricle ependyma (A, B) and choroid plexus (C) in keeping with ventriculitis and choroid plexitis. In addition, abnormal leptomeningeal enhancement can be seen along the right mesial temporal lobe (D) in keeping 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, but focal neurologic deficits [49-51].

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•

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 of longstanding alcohol abuse. Contrast enhanced T1-WI shows multiple pinhead sized enhancing 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 confronted with brain space-occupying lesions in the immunocompromised or malnutritional hosts such as liver cirrhosis (Fig 17) [52].

DIFFUSE CEREBRAL EDEMA IN ACUTE or ACUTE-ON-CHRONIC LIVER FAILURE Page 25 of 110

•

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

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

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

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

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

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Ranjan et al have demonstrated significantly lower apparent diffusion coefficient 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].

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The most accurate method of diagnosing cerebral edema is intracranial pressure monitoring [54].

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

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

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Fig. 19: Fulminant hepatic failure. T2W MR imaging reveals effaced cerebral sulci with slit-like ventricles (A, B) and diffuse gyral swelling (C, D) in keeping with diffuse ceerbral edema. The cisternal spaces are also effaced suggesting impending herniation (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 unreliable for the diagnosis of intracranial hypertension (owing to their poor correlation with intracranial pressure); nonetheless, if interpreted carefully they can provide pivotal information [53, 58, 59].

•

Also, cross sectional imaging is effective at establishing the diagnosis of cerebral herniation, which will guide important decisions regarding therapeutic options and prognosis (Fig 20).

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Fig. 20: (A, B) Sagittal and axial T2-WI show bilateral medial part of the temporal lobes protruding over the tentorial edge in keeping with uncal herniation (black arrows). In addition, there is downward cerebellar herniation (tonsillar herniation or coning) seen in this patient of fulminant hepatic failure. The patient was subsequently declared brain dead 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 liver failure 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 been considered 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 related liver disease may range from Wernicke's encephalopathy, hepatocerebral degeneration, head trauma, central pontine myelinolysis, MarchiafavaBignami syndrome to ethanol neurotoxicity [61, 62].

OSMOTIC DEMYELINATION SYNDROMES

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•

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

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The concept was extended from 1962 with the recognition that lesions can occur outside the pons, so-called extrapontine myelinolysis (EPM). In 1976 a link between these disorders and the rapid correction of sodium in hyponatraemic patients was suggested, and by 1982 substantially established [64].

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

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

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

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Radiological confirmation is necessary to exclude other diagnosis and to determine the exact extension of the demyelination. Since CT can underestimate the real extension MRI plays a pivotal role in the determination of the presence, number and extension of the lesions [65].

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

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

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Fig. 22: (A, B) Axial Fast FLAIR and T2-WI of the aforementioned patient shows hyperintensity involving the central pons with characteristic sparing of the periphery. Careful evaluation suggests that there is predominant involvement of the transverse pontine 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].

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Fig. 23: Extra-pontine myelinolysis. Axial FLAIR images showing extra-pontine areas of signal alteration (demyelination) involving the left thalamus (white arrow) and the right cerebellar hemisphere (black arrow) in a malnourished chronic alcoholic male patient 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 affects the cerebellum but may also affect parts of the cerebrum. In up to 25% of patients the demyelination is exclusively extrapontine [67].

WERNICKE ENCEPHALOPATHY •

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

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If untreated, irreversible brain damage may ensue and could even lead to coma, death, or Korsakoff syndrome, a permanent brain injury that results in antegrade amnesia and confabulation. The classic triad of WE includes ataxia, global confusion, and opthalmoplegia.

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

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

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Fig. 25: Coronal T2-WI showing bilateral areas of increased intensity surrounding the aqueduct 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

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Fig. 26: Fast FLAIR images of the same patient showing symmetrical signal alterations 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 T2and FLAIR signal intensity surrounding the aqueduct and the third ventricle, at the floor of fourth ventricle, in the medial thalami, and in the capita of caudate nuclei (Fig 24-26) [66].

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MR spectroscopy (MRS) may depict lactate peak and low levels of Nacetylaspartate (N-NAA)/creatine (Cr) in the affected areas but does not have a clinical prognostic impact [66].

MARCHIAFAVA-BIGNAMI DISEASE (MBD) •

MBD is a rare disorder that results in progressive demyelination and necrosis of the corpus collosum. MBD is generally associated with chronic alcohol abuse but is occasionally seen in nonalcoholic patients. MBD is most prevalent in men between 40 and 60 years of age [66].

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

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

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CT shows diffuse periventricular low density and focal areas of low density in the genu and splenium of the corpus callosum. On MRI, there is high T2-and FLAIR signal intensity changes involving the body of the corpus callosum, genu, splenium, and adjacent white matter. These appear hypointense on T1-WI and during the acute phase, may show peripheral contrast enhancement [66].

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Fig. 27: Sagittal T2-WI in a chronic alcoholic male showing relatively atrophic posterior body of the corpus callosum (white arrow) with focal area of signal alteration within the splenium (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, but residual atrophy of the corpus callosum is usually observed (Fig 27). MBD may be found in association with other alcohol-related diseases, including WE, Korsakoff syndrome, and central pontine myelinolysis [66].

ALCOHOL WITHDRAWAL SYNDROME (AWS) •

Alcohol withdrawal syndrome (AWS) is a constellation of symptoms observed in a person who stops drinking alcohol after a period of continuous and heavy alcohol consumption [66].

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In AWS, disturbances in cognition, perception hallucinations, visual impairment, nausea, and tinnitus are thought to relate to cortical dysfunction. Tremor, sweating, depression, and anxiety are related to effects on the limbic system. Changes in consciousness and gait disorders are associated with brainstem involvement.

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Fig. 28: Axial FAST FLAIR image in a liver cirrhosis patient with auditory hallucinations following 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 in temporal regions during the acute and subacute phases and significant volume loss (Fig 28). It could therefore be deduced that epileptic seizures affect alcoholic subjects similarly to temporal epilepsy, in which reversible edema with some volume loss and consequent hippocampus atrophy is observed [66].

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

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

ALCOHOLIC COGNITIVE DECLINE AND CEREBRAL ATROPHY •

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

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

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CT and MRI show enlargement of the cerebral ventricles and sulci in the majority of alcohol abusers. There is evidence for regional vulnerability in the brains of alcohol abusers with frontal lobe changes being the most pronounced (Fig 29).

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

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Fig. 29: Axial FLAIR and T2WI showing selective bi-frontal cerebral atrophy in a 36year 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, including those with liver disease and Wernicke encephalopathy (WE), lose a disproportionate amount of subcortical white matter compared with cortical gray matter [68, 69].

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

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MRI imaging of alcohol abusers shows an increase in white matter volume following three months of abstinence, suggesting that a component of the white 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].

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Alcoholic cerebellar degeneration typically occurs after 10 or more years of alcohol abuse. These chronic ethanol abusers develop a chronic cerebellar syndrome related to the degeneration of Purkinje cells in the cerebellar cortex.

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

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Symptoms, primarily related to gait disturbance, usually develop gradually over weeks to months, but it may also evolve over years or commence abruptly.

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Fig. 30: Alcoholic cerebellar degeneration. DIffuse cerebellar atrophy is seen in the form of cerebellar foliar prominence, ventricular enlargement and prominence of the infratentorial subarachnoid CSF spaces in a 44-year old male cirrhotic with history of chronic 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, onehalf of alcoholic patients with this finding may not be ataxic on examination. In addition, a structural imaging study is also required to exclude mass lesions or other diagnoses (Fig 30) [71, 72].

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

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

WILSON DISEASE-RELATED NEUROIMAGING MANIFESTATIONS •

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

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In Wilson disease, ceruloplasmin, the serum transport protein for copper, is deficient. Copper accumulates in the tissues of patients primarily in the liver and later in the brain.

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Despite the ubiquitous presence of toxic copper within the brain, pathologic findings are limited primarily to the basal ganglia, thalamus, and brain stem. The initial neurological presentations frequently include dysarthria and tremors, with later manifestations of neuropsychiatric problems, and Parkinsonian tremors, ataxia, dystonia, and chorea.

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The most frequently identified abnormality on MR imaging was bilateral symmetric high signal intensity in the putamen on T2-weighted images, followed by the caudate nucleus, globus pallidus, thalamus, midbrain (Fig 31) [73, 74].

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Fig. 31: Axial T2-WI in a patient with Wilson disease depicting symmetrical increased signal intensity of the bilateral lentiform nuclei (ahite arrow), thalami (black arrow) and caudate nuclei (arrowhead). References: Image reproduced from: Arora A et al. Intracranial MR manifestations of 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 the disease process due to cytotoxic edema or inflammation due to excessive copper deposition (Fig 32). However, this restricted diffusion is not seen in chronic cases [73].

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Fig. 32: DWI in a patient with Wilson disease depicting diffusion restriction involving the lentiform and caudate nuclei (hepatolenticular degeneration) during the acute phase of the disease. References: Image reproduced from: Arora A et al. Intracranial MR manifestations of 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 to copper deposition or iron deposition (Fig 33) [73].

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Fig. 33: Axial T2WI (A) and T2*GRE (B) showing hypointense signal and blooming reflecting 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 images reflects hepatic involvement of Wilson disease-namely, chronic liver disease or 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 a patient of Wilson disease. References: Image reproduced from: Arora A et al. Intracranial MR manifestations of Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/ C-1518 •

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

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

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

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Fig. 36: Giant panda cub. Axial T2WI in a patient of Wilson disease depicting signal alteration in the dorsal pons simulating the face of a giant panda - popularly referred to as 'giant panda cub' sign. References: Image reproduced from: Arora A et al. Intracranial MR manifestations of 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 that the paramagnetic effects of the deposition of heavy metals, such as iron and copper, may be responsible. It is believed that iron is assumed to play a more important role than copper in reducing the signal intensity of the superior colliculi on the T2-weighted scan. At times, signal alteration may also be encountered within the dorsal pons which has been popularly called as 'Giant Panda Cubs' (Fig 36) [74].

HCV-RELATED CNS COMPLICATIONS •

Chronic infection with hepatitis C virus (HCV), a hepatotropic and lymphotropic agent, is a growing global health issue affecting an estimated 170 million people [75].

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Neurological complications occur in a large number of patients and the speculative pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies, immune complexes, and cryoglobulins [75].

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

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ACUTE CEREBROVASCULAR EVENTS: including ischemic stroke, transient ischemic attacks, lacunar syndromes (Fig 37), or rarely Page 48 of 110

hemorrhages (secondary to occlusive vasculopathy and vasculitis), have been 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 (hepatitisC related) liver disease. DWI reveals multiple acute lacunar infarcts involving the left pareito-temporal and right cerebellar hemisphere - possibly secondary to occlusive vasculopathy or vasculitis. References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES, INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN •

ACUTE OR SUBACUTE ENCEPHALOPATHIC SYNDROMES: clinically characterized by cognitive impairment, confusion, altered consciousness,

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dysarthria, dysphagia, and incontinence, have been associated with diffuse involvement of the white matter in HCV chronically infected patients. An ischemic pathogenesis of these rapidly evolving syndromes is supported by MRI findings showing small lesions in subcortical regions and periventricular white matter (Fig 38). Moreover, severe and diffuse infra- and supratentorial white matter alterations, highly suggestive of vasculitis, are observed in subjects with coincidental systemic vasculitis [75].

Fig. 38: A young 36-year old patient of hepatitis-C related liver cirrhosis and progressive neurocognitive decline. Axial FAST FLAIR imaging reveals bilateral multifocal 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, clinically characterized by impairment of attention, executive, visual constructive, and spatial functions, has been correlated to an increased occurrence of periventricular white matter high intensity signals on T2-weighted MRI (Fig 39). White matter hyperinyensities likely reflect the occurrence of small vessel disease, which leads to chronic hypoperfusion of the white matter and local alteration of the blood-brain barrier [75].

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

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

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MYELITIS: is an infrequent neurological complication in patients chronically infected with HCV. HCV-related myelitis occurs acutely or subacutely, the neurological presentation ranging from transverse myelitis to acute partial transverse myelopathy, or spastic paraplegia; many patients present a recurrent 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 other solid-organ transplants primarily due to the poorer clinical condition of liver disease patients due to malnutrition, coagulopathy, electrolyte imbalance, and pre-transplant encephalopathy. In addition, the highly complex and lengthy surgical procedure with

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

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME •

Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized neurological complication after transplantation with an overall incidence of approximately 1% following liver transplantation [82, 83].

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

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The exact pathophysiology is poorly understood but the widespread vasoconstriction 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].

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

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

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

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

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

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Fig. 40: PRES in a post liver-transplant patient. Axial FAST FLAIR sequence exhibiting 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 with PRES (Fig 41).

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

If timely diagnosed, the patients experience a good recovery without sequelae. Nevertheless, when unrecognized, PRES can progress to ischemia or massive infarction with significant morbidity and mortality [82, 83].

IMMUNOSUPPRESSANT-RELATED LEUKOENCEPHALOPATHY Page 54 of 110

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

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Leukoencephalopathy syndrome is a neurologic complication caused primarily by the neurotoxic effects of immunosuppressive agents on cerebral white matter [84].

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Tacrolimus and cyclosporine are lipophilic immunosuppressant agents that cross the blood-brain barrier and are speculated to have a direct neurotoxic effect especially on the lipid-rich white matter [85].

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

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

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

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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 the occipital, parietal, and temporal white matter in a scattered fashion (Fig 42) [84].

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

Clinico-radiological differentiation from progressive multifocal leukoencephalopathy (PML) can be challenging [84, 85]. A biopsy procedure is usually not considered to be necessary to differentiate between the two especially when after cessation or dose reduction of tacrolimus the clinical condition improves.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY •

Progressive multifocal leukoencephalopathy (PML), a progressive demyelinating disease of the brain caused by JC virus (JCV), can be seen following liver transplantation and other conditions associated with immunosuppression [88].

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

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•

In late stages of disease, patients can develop cortical blindness, quadriparesis, severe dementia and even coma. Death usually occurs within 6 months of diagnosis [90].

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MRI is undoubtedly more sensitive than CT in depicting the white matter changes [89].

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On MRI, PML lesions typically appear as hyperintense signal on T2weighted and FLAIR images (corresponding hypointense signal on T1-WI) involving the subcortical white matter, devoid of contrast enhancement or mass effect [88]. The lesions are multifocal albeit most commonly involve the parieto-occipital white matter (Fig 43).

Fig. 43: Suspected PML in a 44 year old post liver transplant patient with neurocognitive decline. Axial FLAIR images showing patchy and conflueent scattered hyperintensities 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 the combination of a recent onset of neurological disease with white matter lesions on MRI and a positive PCR for the JC virus in the CSF can confirm the diagnosis in the absence of a brain biopsy [89].

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PML is distinguished from immunosuppressant neurotoxicity by its rapid radiological and clinical progression [91].

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

CEREBROVASCULAR COMPLICATIONS •

Cerebrovascular complications, including ischemic strokes and intracranial hemorrhage, have been reported to be prevalent in 2-4% of liver transplant recipients [92].

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An increased risk of intracranial hemorrhage has been demonstrated in patients with thrombocytopenia, old age, and overwhelming infections. That risk 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 post liver-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 transplant recipients include Aspergillus angiopathy and mycotic aneurysms.

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•

In addition, hypercholesterolaemia, diabetes, and hypertension secondary to long term use of immunosuppressive therapy may also compound the risk of cerebral bleeds.

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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 with dysregulation 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 the MCA territory. References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES, INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN •

Perioperative events, such as cerebral hypoperfusion and massive transfusion, may also favor cerebrovascular injury.

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Post anoxic cerebral ischemia is most commonly encountered following cardiac arrest or cardiopulmonary resuscitation in which there has been cessation of cerebral blood flow (Fig 46).

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Fig. 46: Anoxic-hypoxic ischemic encephalopathy following liver transplant (day-3). DWI showing diffusion restriction and extensive gyral swelling involving the bilateral cerebral 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 (global hypoperfusion) has a universally poor prognosis with most patients either progressing to brain death or remaining in a persistent vegetative state [92].

POST-TRANSPLANT ENCEPHALOPATHY •

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

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

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

Delayed allograft function can precipitate hepatic encephalopathy with clinical manifestations of ranging from subtle cognitive slowing and memory difficulties, to somnolence, stupor and coma (Fig 47).

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

OPPORTUNISTIC INFECTIONS •

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

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

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

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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 fungal infections, and may also extend locally following fungal sinusitis (Fig 48) [92].

Fig. 48: Post-transplant invasive fungal sinusitis, orbital cellulitis & meningitis in a 26 year old 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). 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, but CNS infections caused by Candida species are rare.

•

Most common fungal CNS infections are caused by Cryptococcus neoformans and Aspergillus species [92].

•

Increased risk of CNS aspergillosis has been reported after liver retransplantation. Vasoinvasive CNS fungal infections (e.g., Aspergillus species) are often associated with hemorrhagic strokes.

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Fig. 49: Invasive mucormycosis. Post liver-transplant patient with invasive fungal sinusitis (asterisk) invading the left orbit (star) and ipsilateral cavernous sinus (white arrow) 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 liver transplantation but the risk may be increased with environmental exposure.

•

Toxoplasmosis is the most common protozoal infection in transplant recipients.

•

Neuroimaging, spinal tap after excluding increased intracranial pressure, and a search for signs of systemic infection are the core of diagnosis. Brain biopsy 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 extrapontine myelinolysis (EPM) in the early period after liver transplantation is probably attributable to large fluid shifts, similarly as in rapid correction of hyponatremia [92].

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Fig. 50: Central pontine myelinolysis in a post liver transplant patient. Axial FLAIR image showing predominant involvement of the transverse pontine fibres (white arrow) with characteristic sparing of the descending corticospinal tracts (asterisk). Note the 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 preoperative hyponatremia and worse liver dysfunction [92, 93].

POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER •

Lymphoma is the commonest cerebral brain tumor seen in transplant recipients; and, the CNS may be the primary site of involvement or associated 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.

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•

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

•

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

•

Differentiation from toxoplasmosis may be challenging. However, an increased uptake on single-photon emission CT (SPECT) may be useful to differentiate the two entities [94].

Images for this section:

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

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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 symmetrical hyperintensity involving the bilateral lentiform nuclei in a young 26-year old lady with liver cirrhosis.

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

Fig. 6: Cerebral atrophy accompanying typical intracranial signal intensity changes in a 36-year old patient with long standing cryptogenic cirrhosis. Axial T1-WI shows symmetrical T1-prolongation of the basal ganglia (asterisk) representing manganese deposition. Attendant widening of the sylvian fissures (thick arrows) and ventricular enlargement (thin arrows) suggest cerebral parenchymal atrophy.

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

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

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

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Fig. 10: Chronic HE. Axial T1-WI showing cortical atrophy with gyriform T1-hyperintensity representing cortical laminar necrosis in a follow-up case of liver cirrhosis with recurrent episodes 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 reveal symmetrical T1-hyperintensity of the basal ganglia (A) with attendant T2-hyperintense changes involving the bilateral middle cerebellar peduncles (B). Imaging findings in the light of the clinical details are in keeping with acquired hepatocerebral degeneration.

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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 cirrhosis presenting with features of parkinsonism.

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

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

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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 obstructive ventriculomegaly (arrowhead). The cerebral sulci are effaced and the cortico-medullary junction indistinct (asterisk) suggesting raised intracranial pressure.

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

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

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

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

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

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

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

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

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

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

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

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

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

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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.

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

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

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

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

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

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

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

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

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

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

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

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Fig. 41: Axial T2*GRE image of the hitherto discussed patient with PRES showing punctate areas of blooming in keeping with petechial hemorrhages in the left occipital lobe.

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Fig. 42: Immunosupressive leukoencephalopathy. A 56-year old post liver transplant patient on tacrolimus complaining of unrelenting headaches and visual disturbances. MR images show multifocal areas of white matter signal alteration involving the parietooccipital lobes and right fronto-parietal region appearing bright on T2WI (A) and dark on T1WI (B).

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

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

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 the MCA territory.

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

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

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Fig. 48: Post-transplant invasive fungal sinusitis, orbital cellulitis & meningitis in a 26 year old 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).

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

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

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Conclusion Only with better understanding of the prevalence, clinical features and imaging manifestations of different neurological complications associated with liver cirrhosis and liver transplanatation, can we hope to aptly & promptly diagnose them and offer appropriate 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: [email protected]

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Fig. 51: Thank you! References: Ankur Arora

References 1. 2.

Lewis M, Howdle PD. The neurology of liver failure. QJM. 2003 Sep;96(9):623-33. 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 103 of 110

3.

4. 5.

6.

7.

8.

9.

10. 11. 12.

13. 14.

15.

16.

17.

Neurological complications of liver cirrhosis and orthotopic liver transplant. Transplant Proc. 2006 Apr;38(3):789-92. Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. Hepatology. 2009 Dec;50(6):2014-21. doi: 10.1002/hep.23216. Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):279-93. Butterworth RF. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol. 2013 Sep;10(9):522-8. doi: 10.1038/nrgastro.2013.99. Weissenborn K, Bokemeyer M, Krause J, Ennen J, Ahl B. Neurological and neuropsychiatric syndromes associated with liver disease. AIDS. 2005 Oct;19 Suppl 3:S93-8. Das K, Singh P, Chawla Y, Duseja A, Dhiman RK, Suri S. Magnetic resonance imaging of brain in patients with cirrhotic and non-cirrhotic portal hypertension. Dig Dis Sci. 2008 Oct;53(10):2793-8. doi: 10.1007/ s10620-008-0383-y. Genovese E, Maghnie M, Maggiore G, Tinelli C, Lizzoli F, De Giacomo C, Pozza S, Campani R. MR imaging of CNS involvement in children affected by chronic liver disease. AJNR Am J Neuroradiol. 2000 May;21(5):845-51. Vymazal J, Babis M, Brooks RA, Filip K, Dezortova M, Hrncarkova H, Hajek M. T1and T2 alterations in the brains of patients with hepatic cirrhosis. AJNR Am J Neuroradiol. 1996 Feb;17(2):333-6. Morgan MY. Cerebral magnetic resonance imaging in patients with chronic liver disease. Metab Brain Dis. 1998 Dec;13(4):273-90. Morgan MY. Noninvasive neuroinvestigation in liver disease. Semin Liver Dis. 1996 Aug;16(3):293-314. 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. Skehan S, Norris S, Hegarty J, Owens A, MacErlaine D. Brain MRI changes in chronic liver disease. Eur Radiol. 1997;7(6):905-9. Zeneroli ML, Cioni G, Vezzelli C, Grandi S, Crisi G, Luzietti R, Ventura E. Prevalence of brain atrophy in liver cirrhosis patients with chronic persistent encephalopathy. Evaluation by computed tomography. J Hepatol. 1987 Jun;4(3):283-92. Kulisevsky J, Pujol J, Junqué C, Deus J, Balanzó J, Capdevila A. MRI pallidal hyperintensity and brain atrophy in cirrhotic patients: two different MRI patterns of clinical deterioration? Neurology. 1993 Dec;43(12):2570-3. Amodio P, Pellegrini A, Amistà P, Luise S, Del Piccolo F, Mapelli D, Montagnese S, Musto C, Valenti P, Gatta A. Neuropsychologicalneurophysiological alterations and brain atrophy in cirrhotic patients. Metab Brain Dis. 2003 Mar;18(1):63-78. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008 Oct;29(9):1612-21. doi: 10.3174/ajnr.A1139.

Page 104 of 110

18. Toru S, Matumura K, Kawaguchi R, Kobayashi T, Irie T. Widespread cortical lesions on diffusion-weighted imaging in acute portal systemic shunt encephalopathy 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 presenting as cortical laminar necrosis: case report. Korean J Radiol. 2013 MarApr;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 from late-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-weighted and fluid-attenuated inversion recovery findings, and correlation with plasma ammonia level and clinical outcome. AJNR Am J Neuroradiol. 2010 Sep;31(8):1471-9. doi: 10.3174/ajnr.A2112. 22. Arnold SM, Els T, Spreer J, Schumacher M. Acute hepatic encephalopathy with diffuse cortical lesions. Neuroradiology. 2001 Jul;43(7):551-4. 23. Fernández-Rodriguez R, Contreras A, De Villoria JG, Grandas F. Acquired hepatocerebral degeneration: clinical characteristics and MRI findings. Eur J Neurol. 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 hepatocerebral degeneration: MR and pathologic findings. AJNR Am J Neuroradiol. 1998 Mar;19(3):485-7. 25. Stracciari A, Guarino M, Pazzaglia P, Marchesini G, Pisi P. Acquired hepatocerebral degeneration: full recovery after liver transplantation. J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):136-7. 26. Wijdicks EF, Wiesner RH. Acquired (non-Wilsonian) hepatocerebral degeneration:complex management decisions. Liver Transpl. 2003 Sep;9(9):993-4. 27. Chen WX, Wang P, Yan SX, Li YM, Yu CH, Jiang LL. Acquired hepatocerebral degeneration: a case report. World J Gastroenterol. 2005 Feb 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. 2013 Apr;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, Gagliardi RJ. Reversal of parkinsonism and portosystemic encephalopathy following embolization of a congenital intrahepatic venous shunt: brain MR imaging and 1H spectroscopic findings. AJNR Am J Neuroradiol. 2004 Aug;25(7):1247-50. 30. Shulman LM, Minagar A, Weiner WJ. Reversal of parkinsonism following liver transplantation. Neurology. 2003 Feb 11;60(3):519. 31. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999 Sep;117(3):640-4.

Page 105 of 110

32. Tuschl K, Clayton PT, Gospe SM Jr, et al. Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease. 2012 Aug 30 [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 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic 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, Lee YS, Suh DJ. Hepatic myelopathy as a presenting neurological complication in patients with cirrhosis and spontaneous splenorenal shunt. Korean J Hepatol. 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 a Patient 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. Hepatic myelopathy: an unusual neurological complication of advanced hepatic disease. Intern Med. 1994 Nov;33(11):718-22. 37. Ben Amor S, Saied MZ, Harzallah MS, Benammou S. Hepatic myelopathy with spastic paraparesis: report of two cases and review of the literature. Eur Spine J. 2013 Jun 1. [Epub ahead of print] PubMed PMID: 23728397. 38. Kori P, Sahu R, Jaiswal A, Shukla R. Hepatic myelopathy: an unusual neurological complication of chronic liver disease presenting as quadriparesis. 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, Chao YC, Hsieh TY. Spontaneous intracranial hemorrhage in cirrhotic patients. 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 hospitalization for intracerebral haemorrhage: a Danish population-based case-control study. 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 intracerebral hemorrhage: 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, Buge A, Lhermitte F, Castaigne P. Hepatic cirrhosis and intracranial hemorrhage: significance of the association in 53 pathological cases. Ann Neurol. 1980 Aug;8(2):204-5. 43. Niizuma H, Suzuki J, Yonemitsu T, Otsuki T. Spontaneous intracerebral hemorrhage and liver dysfunction. Stroke. 1988 Jul;19(7):852-6.

Page 106 of 110

44. McCormick WF, Rosenfield DB. Massive brain hemorrhage: a review of 144 cases and an examination of their causes. Stroke. 1973 NovDec;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 and mortality in cirrhosis. Am J Gastroenterol. 2007 Jul;102(7):1510-7. 47. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):77-93. 48. Vilstrup H. Cirrhosis and bacterial infections. Rom J Gastroenterol. 2003 Dec;12(4):297-302. 49. Pauwels A, Pinès E, Abboura M, Chiche I, Lévy VG. Bacterial meningitis in cirrhosis: review of 16 cases. J Hepatol. 1997 Nov;27(5):830-4. 50. Mølle I, Thulstrup AM, Svendsen N, Schønheyder HC, Sørensen HT. Risk and case fatality rate of meningitis in patients with liver cirrhosis. Scand J Infect Dis. 2000;32(4):407-10. 51. Chung CL, Lieu AS, Chen IY, Kwan AL, Howng SL. Brain abscess in adult cirrhotic patients: two case reports. Kaohsiung J Med Sci. 2007 Jan;23(1):34-9. 52. Guzel A, Tatli M, Aluclu U, Yalcin K. Intracranial multiple tuberculomas: 2 unusual cases. Surg Neurol. 2005;64 Suppl 2:S109-12. 53. Rabinstein AA. Treatment of brain edema in acute liver failure. Curr Treat Options 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 intracranial hypertension 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 liver failure and impact of novel therapeutic interventions. Neurol Res. 2007 Oct;29(7):683-90. doi: 10.1179/016164107X240099. 56. Thumburu KK, Taneja S, Vasishta RK, Dhiman RK. Neuropathology of acute 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 edema is responsible for raised intracranial pressure in fulminant hepatic failure: in vivo demonstration using diffusion-weighted MRI in human subjects. Metab Brain 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 tomography of the brain in fulminant hepatocellular failure. Hepatology. 1991 Feb;13(2):209-12. 59. Mukherjee KK, Chhabra R, Khosla VK. Raised intracranial pressure in hepatic encephalopathy. Indian J Gastroenterol. 2003 Dec;22 Suppl 2:S62-5. 60. Charness ME. Brain lesions in alcoholics. Alcohol Clin Exp Res. 1993 Feb;17(1):2-11.

Page 107 of 110

61. Nicolás JM, Fernández-Solà J, Robert J, Antúnez E, Cofán M, Cardenal C, Sacanella E, Estruch R, Urbano-Márquez A. High ethanol intake and malnutrition in alcoholic cerebellar shrinkage. QJM. 2000 Jul;93(7):449-56. 62. Nicolás JM, Estruch R, Salamero M, Orteu N, Fernandez-Solà J, Sacanella E, Urbano-Márquez A. Brain impairment in well-nourished chronic alcoholics is related to ethanol intake. Ann Neurol. 1997 May;41(5):590-8. 63. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry. 1959 Feb;81(2):154-72. 64. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. 2004 Sep;75 Suppl 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 only villain? 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 J Roentgenol. 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 patients with alcohol addiction revealed by voxel-based morphometry. J Neurol Neurosurg Psychiatry. 2007 Jun;78(6):610-4. 69. Ratti MT, Soragna D, Sibilla L, Giardini A, Albergati A, Savoldi F, Bo P. Cognitive impairment and cerebral atrophy in "heavy drinkers". Prog Neuropsychopharmacol 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: cerebral atrophy, lifetime alcohol consumption, and cognitive deficits. Alcohol Clin Exp Res. 1989 Aug;13(4):512-8. 71. de la Monte SM, Kril JJ. Human alcohol-related neuropathology. Acta Neuropathol. 2013 Dec 27. [Epub ahead of print] PubMed PMID: 24370929. 72. Jaatinen P, Rintala J. Mechanisms of ethanol-induced degeneration in the developing, 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, Yeon KM. MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. AJNR Am J Neuroradiol. 2006 Jun-Jul;27(6):1373-8. 74. Shivakumar R, Thomas SV. Teaching NeuroImages: face of the giant panda and her cub: MRI correlates of Wilson disease. Neurology. 2009 Mar 17;72(11):e50. 75. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S. HCV-related nervous system disorders. Clin Dev Immunol. 2012;2012:236148. doi: 10.1155/2012/236148.

Page 108 of 110

76. Carvalho-Filho RJ, Narciso-Schiavon JL, Tolentino LH, Schiavon LL, Ferraz ML, Silva AE. Central nervous system vasculitis and polyneuropathy as first manifestations of hepatitis C. World J Gastroenterol. 2012 Jan 14;18(2):188-91. doi: 10.3748/wjg.v18.i2.188. 77. Sacconi S, Salviati L, Merelli E. Acute disseminated encephalomyelitis associated with hepatitis C virus infection. Arch Neurol. 2001 Oct;58(10):1679-81. 78. Sim JE, Lee JB, Cho YN, Suh SH, Kim JK, Lee KY. A case of acute disseminated 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 virus infections. 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 nervous system complications in liver transplant recipients. Liver Transpl. 2011 Nov;17(11):1279-85. doi: 10.1002/lt.22383. 81. Saner FH, Gensicke J, Olde Damink SW, et al. Neurologic complications in adult living donor liver transplant patients: an underestimated factor? J Neurol. 2010 Feb;257(2):253-8. doi: 10.1007/s00415-009-5303-3. 82. Cruz RJ Jr, DiMartini A, Akhavanheidari M, et al. Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management. Am J Transplant. 2012 Aug;12(8):2228-36. doi: 10.1111/j.1600-6143.2012.04048.x. 83. Santos MM, Tannuri AC, Gibelli NE, et al. Posterior reversible encephalopathy syndrome after liver transplantation in children: a rare complication related to calcineurin inhibitor effects. Pediatr Transplant. 2011 Mar;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, Utsumi M, Yagi T, Fujiwara T. Leukoencephalopathy syndrome after living-donor liver transplantation. Exp Clin Transplant. 2011 Apr;9(2):139-44. 85. Schuuring J, Wesseling P, Verrips A. Severe tacrolimus leukoencephalopathy 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, Stavrou G, Nadalin S, Broelsch CE. Late onset of tacrolimus-related posterior leukoencephalopathy after living donor liver transplantation. Liver Transpl. 2003 Sep;9(9):983-5. 87. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation. 2000 Feb 27;69(4):467-72. 88. Lima MA, Hanto DW, Curry MP, Wong MT, Dang X, Koralnik IJ. Atypical radiological presentation of progressive multifocal leukoencephalopathy following 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 109 of 110

90.

91.

92. 93.

94.

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. Mohanty SR, Testa G, Labrecque DR, Mitros FA. Progressive multifocal leukoencephalopathy with peripheral demyelinating neuropathy in a liver transplant patient. Gastroenterol Hepatol (N Y). 2007 Jan;3(1):70-3. Bronster DJ, Lidov MW, Wolfe D, Schwartz ME, Miller CM. Progressive multifocal leukoencephalopathy after orthotopic liver transplantation. Liver Transpl Surg. 1995 Nov;1(6):371-2. Zivkovi# SA. Neurologic complications after liver transplantation. World J Hepatol. 2013 Aug 27;5(8):409-16. doi: 10.4254/wjh.v5.i8.409. Guarino M, Benito-Leon J, Decruyenaere J, et al. Neurological problems in 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. Dhar R, Human T. Central nervous system complications after transplantation. Neurol Clin. 2011 Nov;29(4):943-72. doi: 10.1016/ j.ncl.2011.07.002.

Page 110 of 110