Current Problems in Diagnostic Radiology 44 (2015) 449–461

Current Problems in Diagnostic Radiology journal homepage: www.cpdrjournal.com

Neurologic Manifestations of Chronic Liver Disease and Liver Cirrhosis Binit Sureka, MD, DNB, MBA-HCA, MNAMS, PGDHA, Kalpana Bansal, MD, Yashwant Patidar, MD, S. Rajesh, MD, PDCC, Amar Mukund, MD, Ankur Arora, MD, DNB, FRCR, EdiRn Department of Radiology/Interventional Radiology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, India

The normal functioning of brain is intimately as well as intricately interrelated with normal functioning of the liver. Liver plays a critical role of not only providing vital nutrients to the brain but also of detoxifying the splanchnic blood. Compromised liver function leads to insufficient detoxification thus allowing neurotoxins (such as ammonia, manganese, and other chemicals) to enter the cerebral circulation. In addition, portosystemic shunts, which are common accompaniments of advanced liver disease, facilitate free passage of neurotoxins into the cerebral circulation. The problem is compounded further by additional variables such as gastrointestinal tract bleeding, malnutrition, and concurrent renal failure, which are often associated with liver cirrhosis. Neurologic damage in chronic liver disease and liver cirrhosis seems to be multifactorial primarily attributable to the following: brain accumulation of ammonia, manganese, and lactate; altered permeability of the blood-brain barrier; recruitment of monocytes after microglial activation; and neuroinflammation, that is, direct effects of circulating systemic proinflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-6. Radiologist should be aware of the conundrum of neurologic complications that can be encountered in liver disease, which include hepatic encephalopathy, hepatocerebral degeneration, hepatic myelopathy, cirrhosis-related parkinsonism, cerebral infections, hemorrhage, and osmotic demyelination. In addition, neurologic complications can be exclusive to certain disorders, for example, Wilson disease, alcoholism (Wernicke encephalopathy, alcoholic cerebellar degeneration, Marchiafava-Bignami disease, etc). Radiologist should be aware of their varied clinical presentation and radiological appearances as the diagnosis is not always straightforward. & 2015 Mosby, Inc. All rights reserved.

Introduction Globally, chronic liver disease (CLD) and liver cirrhosis (LC) constitute a leading cause of morbidity and mortality primarily attributable to wide prevalence of alcoholism, viral hepatitides, and nonalcoholic fatty liver disease.1,2 Chronic injury to the liver, regardless of the underlying cause, results in ongoing liver fibrosis and architectural distortion ultimately ending in cirrhosis.3 Currently, it is the 12th leading cause of death in the United States, and the national cost for treatment ranges from $14 million to $2 billion, depending on disease etiology.1,2 And, this burden is expected to double by next 20 years.1 Cirrhosis is associated with various comorbidities and complications, which can virtually involve any system in the human body.2 The complications further add to the burden of health care costs; thus, affecting the health care providers as well as the working families at large. Patients with CLD and LC are at increased risk for a wide spectrum of neurologic complications.4-10 These neurologic complaints can range from subtle neuropsychiatric symptoms such as behavioral changes and abnormality of movements to overt hepatic encephalopathy (HE). Cirrhosis-associated neurologic

n Reprint requests: Ankur Arora, MD, DNB, FRCR, EdiR, Department of Radiology/ Interventional Radiology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi-110070, India E-mail address: [email protected] (A. Arora).

http://dx.doi.org/10.1067/j.cpradiol.2015.03.004 0363-0188/& 2015 Mosby, Inc. All rights reserved.

comorbidities also include depression, bipolar disorder, schizophrenia, substance abuse, and suicidal tendencies. Broadly, from a neuroradiological perspective, the neurologic complications associated with CLD can be divided into direct effects of cirrhosis on the nervous system and neurologic complications related to specific etiologies of liver disease (eg, alcohol, hepatitis C infection, and Wilson disease).6-10 The various entities associated are highlighted in Table 1.

I. Direct Effects of Cirrhosis on the Nervous System Hepatic Encephalopathy HE is a known complication of advanced cirrhosis. Between 30% and 50% of hospitalization cases of cirrhosis are related to HE.11 HE is a syndrome of spectrum of neuropsychiatric abnormalities caused by portosystemic venous shunting, with or without intrinsic liver disease.12 The 3 types of known HE are the following: type A—due to acute liver failure; type B—portosystemic shunting, without intrinsic liver disease; and type C—cirrhosis associated with portosystemic shunting.12 Pathophysiological basis for the neurologic manifestations in HE is because of shunting of blood from the portal venous bed into the systemic circulation, resulting in elevated plasma levels of manganese and ammonia, which then enter the brain where they induce disturbances in astrocyte and neuron function.13 Manganese induces selective neuronal loss in basal ganglia (particularly globus pallidus and substantia nigra

450

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

Table 1 Neurologic manifestations in chronic liver disease I. Direct effects of cirrhosis on the nervous system Hepatic encephalopathy Acquired hepatocerebral degeneration Cirrhosis-related parkinsonism Cirrhotic myelopathy Intracranial hemorrhage Infections Diffuse cerebral edema II. Neurologic complications specific to a. Chronic alcohol use Osmotic Demyelination Syndromes Wernicke encephalopathy Marchiafava-Bignami disease Alcohol Withdrawal Syndrome Alcoholic cognitive decline and cerebral atrophy Alcoholic cerebellar degeneration b. Wilson disease c. HCV-related CNS complications CNS, central nervous system.

reticulata). Hyperammonemia results in activation of glutamine synthetase in brain, leading to increased ammonia detoxification and thus excessive generation of osmolytes, mainly glutamine. Increased glutamine levels cause abnormalities in intracellular pH and membrane potential leading to disruption in ion homeostasis and ultimately cause astrocyte swelling, cytotoxic brain edema, intracranial hypertension, and cerebral hypoperfusion.13 Although the diagnosis of HE is essentially clinical, neuroimaging may be helpful in reaching a definitive diagnosis in patients presenting with marginally deranged liver function tests or atypical neurologic symptoms. Moreover, it helps to exclude other etiologies that might account for the patient's symptoms.14 In addition, advancements in magnetic resonance imaging (MRI) technology and growing experience in patients with different

types of liver disease have provided new insight into the pathogenesis of HE, particularly with respect to the substrates that are responsible for causing the neurochemical changes in HE and the associated clinical symptoms.14-16 Clinically, HE can be episodic, chronic, or minimal. Episodic HE is characterized by rapid onset of a confusional syndrome including neuromuscular abnormalities and impaired mental state. Diagnosis is clinical and requires demonstration of persistent neurologic manifestations in a patient with severe liver failure or portosystemic shunt or both. Chronic HE may be recurrent, manifesting as frequent episodes of acute HE similar to the ones seen in episodic HE, which may be spontaneous or secondary to a precipitating factor. However, in contrast to episodic HE, patients with recurrent chronic HE demonstrate subtle neurologic abnormalities between the acute episodes. Persistent chronic HE refers to manifestations that do not reverse despite adequate treatment and affect daily activities. Minimal HE refers to patients with cirrhosis or portosystemic shunts who have subtle abnormalities in cognitive functions that cannot be detected by standard clinical examination and manifest only while performing complex tasks.15 Imaging findings in the various clinical types of HE reflect the different neuroanatomical changes that are occurring in the disease process. During an acute episode, there is diffuse brain edema, which can progress to cortical thinning with cortical laminar necrosis in chronic stages.17,18 On MRI, acute HE also known as acute hyperammonemic encephalopathy manifests as extensive cortical edema involving the deep gray matter. Symmetric involvement of the cingulate gyrus and insular cortex on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) imaging with sparing of the perirolandic and occipital cortex, has been suggested to be a unique imaging feature of acute HE (Fig 1).15 Follow-up MRI in chronic phase may show diffuse cortical atrophy T1 hyperintensity involving both basal ganglia and temporal lobe cortex (Fig 2).15

Fig. 1. Typical manifestations of acute HE. Axial T2W (A) and DW (B) MR images displaying extensive bilateral symmetrical gyral edema characteristically involving the cingulate gyrus (thin arrow) and insular cortex (thick arrow). Note the characteristic sparing of perirolandic and occipital cortex.

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

451

Fig. 2. Chronic HE. Axial T1W (A and B) MR image showing cortical atrophy with gyriform T1 hyperintensity representing cortical laminar necrosis in a follow-up case of liver cirrhosis with recurrent episodes of hepatic encephalopathy in the past. (Reproduced with permission from Arora et al.4)

Other nonspecific findings that may be encountered are bilateral, symmetric high signal intensity of the globus pallidus and substantia nigra on T1-weighted images; diffuse white matter high signal intensities involving predominantly the hemispheric corticospinal tract; focal high signal intensity T2 lesions in subcortical hemispheric white matter, basal ganglia, thalami, and brain stem involvement suggests more severe injury on T2/FLAIR sequences.14,15 On 1H-MR spectroscopy (MRS), there is increase in glutamine or glutamate signal, depletion of myoinositol signal, decrease in choline signal, and presence of a normal Nacetylaspartate (NAA) signal.19-21 On DWI, increased mean diffusivity is seen in hemispheric white matter with normal fractional anisotropy. It is important to know at this stage that patients with cirrhosis and no clinical, neuropsychological, or neurophysiological signs of HE can also show severe signal intensity alterations, whereas others who manifest HE may present only slight signal intensity alterations.14-16 Acquired Hepatocerebral Degeneration Acquired hepatocerebral degeneration (AHD) is a clinically distinct entity from HE seen in nearly 1% of patients with LC.22,23 It was first reported by van Woerkem in 1919 and is postulated to occur because of intracerebral deposition of manganese owing to the presence of portosystemic shunts. Clinically, patients present with extrapyramidal signs, ataxia, and cognitive dysfunction (parkinsonian features combined with cerebellar signs).24 It is also known as non-Wilson or pseudo-Wilson hepatocerebral degeneration as the clinical symptoms, neuropathologic features, and MRI appearance are similar to those seen in Wilson disease. The insult is usually irreversible. Distinction from true Wilson disease (hepatolenticular degeneration) depends on age of presentation— although Wilson disease is a genetic disease, which rarely starts after the age of 30 years, AHD occurs in those with severe liver disease and can manifest at any age. Disordered copper metabolism in Wilson disease leads to copper overload, which deposits in the liver, brain, kidney, cornea, etc, whereas copper metabolism is

normal in patients with AHD. Also, Wilson’ disease is characterized by Kayser-Fleischer ring in the cornea, which is not a feature of AHD. Classically, the MRI findings reveal increased signal intensities on T2-weighted images involving the lenticular nuclei and the brachium pontis or dentate nucleus of cerebellum (Fig 3). Other findings include increased signal on T1-weighted images in basal ganglia, pituitary gland, quadrigeminal plate, caudate nucleus, subthalamic region, and red nucleus, probably reflecting intracerebral deposits of manganese.22,25 Cirrhosis-Related Parkinsonism Cirrhosis-related Parkinsonism is defined as rapidly progressing parkinsonian symptoms (bradykinesia, rigidity, and dystonia), which are unresponsive to treatment of HE.26,27 It presumably represents a unique and common subset of AHD with prevalence as high as 21% in patients with LC (Butterworth). The mechanism proposed behind this syndrome is increased manganese deposition in the basal ganglia owing to the presence of significant portosystemic shunts resulting in dysfunction of the dopaminergic neurotransmitter system.26-28 Another postulated theory is the alteration of presynaptic and postsynaptic striatal dopaminergic neurotransmission limiting the effects of dopaminergic therapy.26 Cirrhosis-related parkinsonism is a distinct and separate entity from idiopathic Parkinson disease. Clinically, cirrhosis-related parkinsonism presents by early gait and balance dysfunction, relative absence of resting tremor, presence of mild cognitive impairment at the time of presentation, elevated serum manganese levels, and little or no response to levodopa therapy. Manganese deposition preferentially produces pallidal degeneration, while sparing the nigrostriatal system, in contrast to Parkinson disease, which preferentially damages dopaminergic neurons in the substantia nigra pars compacta. On MRI, bilateral symmetric high T1 signal intensity changes are seen involving the globus pallidus, substantia nigra, dorsal pons, striatum, and subthalamic and dentate nuclei with sparing of

452

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

Fig. 3. Acquired hepatocerebral degeneration. Axial T1W (A) and T2W (B) MR images reveal symmetrical T1 hyperintensity of bilateral lentiform nuclei (black arrows) with T2 hyperintensity involving bilateral middle cerebellar peduncles (white arrow) in a patient with cirrhosis presenting with features of parkinsonism and cerebellar signs. (Reproduced with permission from Arora et al.4)

thalamus and ventral pons (Fig 4). MRI findings are reversible when manganese blood levels returns to normal levels.26-28 Cirrhotic Myelopathy Cirrhotic or hepatic myelopathy (HM) or portosystemic myelopathy is a rare neurologic complication of chronic liver disease

characterized by insidious-onset progressive pure motor spastic paraparesis without sensory or bladder or bowel involvement.29,30 It is usually seen in adult patients with overt liver failure or a spontaneous or surgical portosystemic shunt (especially portocaval shunt) or presence of both.29 Neuropathologic and autopsy studies have revealed demyelination in the lateral corticospinal tracts with varying degrees of axonal loss. Apart from cirrhosis,

Fig. 4. Cirrhosis-related parkinsonism. Axial T1W MR images reveal bilateral symmetrical T1 hyperintensity (thick white arrows) involving the basal ganglia (A) and cerebral peduncles (B).

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

HM has also been reported in post–liver transplant patients, congenital hepatic fibrosis, childhood portal vein thrombosis, and acute hepatitis E.29 Motor-evoked potential studies can help attain an early diagnosis, which can be even during the preclinical stages of the disease.30 A timely diagnosis of HM is crucial as patients with early stages of the disease can recover following liver transplantation.30 Diagnosis is by exclusion and relatively commoner conditions that need to be excluded include amyotrophic lateral sclerosis, demyelination syndromes like multiple sclerosis and neuromyelitis optica, toxic myelopathy, paraneoplastic syndromes, radiation myelopathy, HTLV-I-associated myelopathy, and spinal cord disease like myelitis and compressive myelopathy.29 On MRI, symmetrical hyperintensity is seen along the bilateral lateral pyramidal tracts (corticospinal tracts) on T2/FLAIR images, involving the perirolandic cortex, centrum semiovale, corona radiata (lateral to the posterior half of the lateral ventricle), posterior limb of internal capsule, cerebral peduncles of midbrain, and anterior part of pons and medulla, and in severe cases, changes in the corticospinal tracts in spinal cord can be seen.30 Intracranial Hemorrhage Spontaneous intracranial hemorrhage (Fig 5) is a well-known complication of cirrhosis as these patients usually have hematologic complications especially thrombocytopenia and coagulation disorders (vitamin K deficiency, decreased production of coagulation and inhibitor factors, synthesis of abnormal clotting factors, decreased clearance of activated factors by the reticuloendothelial system, hyperfibrinolysis, and disseminated intravascular coagulation).31,32 Recently, Huang et al32 reported an overall incidence of 0.8% in their study and found intracerebral bleeds to be much more prevalent in young males with mild-to-moderate alcoholic cirrhosis. The incidence in the alcohol-related group was 1.9%,

453

whereas in the virus-related group was 0.3%. This incidence further increased to 3% in the combined group (patients with both virus- and alcohol-related cirrhosis). Huang et al advocated that patients with cirrhosis should undergo prompt radiologic workup when any new neurologic signs are seen. Infections Patients with cirrhosis are at increased risk to septicemia, spontaneous bacterial peritonitis, pneumonia, tuberculosis, urinary tract infection, and meningitis.33-36 Compared with the general population, incidence of infections is increased more than 10-fold, and the mortality of each episode is 3-10 times higher. Cirrhosis presumably is one of the most common forms of acquired immunodeficiency superseding even AIDS, and bacterial infections have been incriminated to be responsible for up to 25% of deaths in patients with cirrhosis.34 Clinically, in patients with cirrhosis, it is not easy to distinguish HE from intracranial infection. Compromised humoral and cellmediated immunity in patients with cirrhosis permits hematogenous translocation of enteric bacteria leading to bacteremia. In addition, the cirrhotic liver is ineffective at detoxifying the blood and clearing bacteria and associated endotoxins (Ghassemi). The main bacterial pathogens include Streptococcus pneumoniae, Escherichia coli, Listeria, and unspecified bacteria. Klebsiella pneumoniae, which can colonize the gastrointestinal tract, is another pathogen of brain abscess in patients with cirrhosis (Figs 6 and 7).33-36 Often, the patients manifest focal neurologic deficits, which may not be accompanied with fever or leukocytosis.33 Furthermore, patients with cirrhosis are also at high-risk of developing invasive fungal infections (Candida, Aspergillus, Mucor, and Cryptococcus neoformans) primarily owing to depressed immunity, concurrent renal failure, indwelling vascular catheters, total parenteral nutrition, hemodialysis, and transplantation.

Fig. 5. Intracranial hemorrhage. Noncontrast axial CT images (A and B) reveal a large intraparenchymal hematoma (thick white arrow) in left basal ganglia region with contiguous extension into bilateral lateral ventricles (asterisk). In addition, there is diffuse subarachnoid hemorrhage that can be seen along cortical sulci (thin white arrow) and interhemispheric fissures with attendant diffuse cerebral edema.

454

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

Fig. 6. Intracranial abscess. Contrast-enhanced axial CT images (A and B) showing a well-defined round peripherally enhancing central hypoattenuating lesion consistent with abscess in left peritrigonal region with attendant thickening and abnormal enhancement of left lateral ventricle ependymal lining (thin white arrow) in keeping with ventriculitis.

Fig. 7. Multiple intracranial tuberculomas. Axial T2W (A) and contrast-enhanced MT T1W (B) MR images reveal multiple discrete as well as conglomerated, T2 hypointense, nodular (thin white arrow) and rim-enhancing (thick white arrow) lesions with attendant marked perilesional edema in right frontal lobe. MT, magnetization transfer.

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

455

Diffuse Cerebral Edema

IIa. Neurologic complications related to chronic alcohol use

Diffuse cerebral edema is usually seen in the setting of acute or acute-on-chronic liver failure and if not timely attended to can rapidly progress to delirium, seizures, coma, and brain death.37-39 By definition, cerebral edema is the excess accumulation of fluid in the intracellular and extracellular spaces of the brain. Moreover, cerebral edema can be of 3 types: cytotoxic, vasogenic, and interstitial. Cytotoxic edema predominantly affects the gray matter and is caused by swelling of glia, neurons, and endothelial cells. It usually begins within minutes after an insult. Although vasogenic edema involves the white matter and is secondary to incompetent blood-brain barrier, interstitial edema is seen in the setting of hydrocephalus when there is increase in resistance to outflow of cerebrospinal fluid. Brain edema in liver failure is cytotoxic, and ammonia is considered to be the main precipitating culprit. Although the mechanism(s) by which ammonia induces astrocyte swelling, which is the most common neuropathologic finding, is dubious, increase in glutamine within astrocytes is considered to be the primarily cause. Additionally, there is an alternate “Trojan horse” hypothesis, which suggests that glutamine serves as a carrier of ammonia into mitochondria, where its accumulation results in oxidative stress, energy failure, and ultimately astrocyte swelling.40 Clinically, patients have altered level of consciousness, bradycardia, hypertension, abnormal breathing patterns and extraocular movements, unequal papillary size, and extensor plantar response. On imaging, there is decreased attenuation of brain parenchyma, sulcal and cisternal effacement (particularly the suprasellar and perimesencephalic cistern), loss of distinction between the graywhite matter, indistinct boundaries of the lenticular nucleus, and small or compressed cerebral ventricles (Fig 8). “White cerebellum sign” and “reversal sign” is also described in cerebral edema on computed tomography (CT). However, MR is undoubtedly superior to CT for detecting early cerebral edema. Additionally, MRI also plays a pivotal role in recognizing complications of cerebral edema like herniation, ischemia, and secondary hemorrhage.39

Wernicke Encephalopathy Wernicke encephalopathy is a neurologic emergency that occurs secondary to thiamine deficiency in chronic alcoholics with a reported incidence of 0.8%-2% (based on autopsy series).31,41 Although the syndrome is characterized by a clinical triad of ataxia, global confusion, and ophthalmoplegia, all the symptoms may not always be present, and the patient may clinically manifest nonspecific mental status changes.31,41,42 On MRI, typical manifestations include symmetrical areas of increased T2- and FLAIR signal intensity surrounding the periaqueductal gray matter, periventricular region, tectal plate, medial thalamic nuclei, third ventricular floor, massa intermedia, and the mamillary bodies (Fig 9). Postcontrast T1-weighted images may show enhancement of mamillary bodies and periaqueductal gray matter in up to 50%-80% of patients. MRS may depict lactate peak and reduced N-acetylaspartate (N-NAA)/creatine (Cr) ratio in the affected areas.31,42 DWI during the acute phase shows diffusion restriction in the aforesaid sites representing cytotoxic edema. In chronic disease, brain atrophy sets in along with the presence of diffuse signal intensity changes in the cerebral white matter accompanying signal alteration of the typically affected areas.31,41,42 Osmotic Demyelination Syndrome The exact etiopathogenesis of osmotic demyelination syndrome (ODS) in alcoholics is contentious. Although changes in the serum sodium levels are considered the most important factor predisposing to ODS, additional pathogenic factors exist, which appear critical in predisposing pontine and extrapontine glia to osmotic stress. Systemic vasodilatation in cirrhosis is believed to lead to activation of antidiuretic hormone, promoting water retention, which leads to decrease in serum sodium level. Alcoholic patients are generally malnourished and deficient in organic osmolytes,

Fig. 8. Diffuse cerebral edema. Axial (A) and sagittal (B) T2W MR images reveal diffuse gyral swelling with effaced cerebral sulci and cisternal spaces in keeping with diffuse cerebral edema with attendant uncal (short white arrow) and tonsillar (long white arrow) herniation in a patient with fulminant hepatic failure.

456

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

Fig. 9. Wernicke encephalopathy. Axial FLAIR (A) and coronal (B) T2W MR images showing bilateral symmetrical confluent areas of hyperintensity surround the third ventricle and aqueduct (white thick arrow) contiguously extending into the mamillary bodies in a debilitated and malnourished patient with alcohol-induced liver cirrhosis complaining of ataxia and ophthalmoplegia. (Reproduced with permission from Arora et al.4

which in addition puts them at risk of developing ODS. Another possible factor is the direct toxic effect of alcohol on the pontine fibers.31,41,42 ODS is often a progressive disorder with clinical features ranging from a mild tremor or dysarthria to progressive quadriparesis. MRI is more sensitive than CT. Central pontine myelinolysis is characterized by trident-shaped hyperintense signal in central pons owing to involvement of transverse pontine fibers with sparing of ventrolateral pons and descending corticospinal tracts on T2-weighted or FLAIR MR images (Fig 10). Concomitant involvement of basal ganglia and pons is fairly specific for osmotic myelinolysis. Extrapontine myelinolysis (EPM) is seen as involvement of extrapontine sites like putamen, caudate nucleus, midbrain, thalami, and subcortical white matter often in a symmetrical

fashion. EPM is seen in as many as 25%-50% of patients with central pontine myelinolysis. This usually affects the cerebellum but may also affect parts of the cerebrum.31,41,42 Marchiafava-Bignami Disease Marchiafava-Bignami disease is a rare disorder associated with chronic alcoholism characterized by progressive demyelination of the corpus callosum.31,41,42 Previously, this syndrome was thought to be associated with consumption of red wine and was seen in malnourished Italian men. Malnutrition and chronic vitamin deficiency have also been proposed to be partly responsible. Clinically, the disease presents in 2 forms: acute form presenting as severe impairment of consciousness, seizures and muscle

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

457

Fig. 10. Central pontine myelinolysis. Sagittal (A) and axial (B) T2W images depicting T2 hyperintensity involving the central transverse pontine fibers with characteristic sparing of the periphery in a patient alcohol-induced liver cirrhosis. (Reproduced with permission from Arora et al.4).

rigidity often resulting in death and the chronic form presenting as variable degrees of mental confusion, dementia, and gait impairment.31,41 On CT, diffuse hypodensity is seen in periventricular region, genu, and splenium of the corpus callosum. Although on MRI these changes are seen as high T2 or FLAIR signal intensity changes involving the body of the corpus callosum, genu, splenium, and adjacent white matter (Fig 11), during the acute phase, these areas may show diffusion restriction and peripheral contrast enhancement following intravenous contrast administration.42 Chronic form of the disease is associated with cystic changes and atrophy of the corpus callosum.12 MRS reveals progressive reduction of the NAA:Cr ratio and normalization of the choline:Cr ratio, which is initially slightly increased. Subacute phase is characterized by the presence of a lactate peak, which is replaced by lipids in a couple of months.42 Alcohol Withdrawal Syndrome Alcohol withdrawal syndrome is a set of symptoms that can occur when an individual either stops or significantly reduces alcohol consumption after substantial use.41 As alcohol is a neurodepressant, sudden withdrawal leads to neuronal system overactivity.31,42 These symptoms can range from seizures to hallucinations and severe state of delirium tremens, which is a hyperadrenergic state characterized by disorientation, tremors, diaphoresis, impaired attention or consciousness, and visual and auditory hallucinations. In most instances, neuroradiologic examinations in these patients are noncontributory.42 Nonetheless, during the acute phase of the disease cytotoxic (potentially reversible), edema in temporal and hippocampus region has been described on MRI.31,42 Chronic alcoholics with history of withdrawal seizures may also display significant volume decrease in the temporal cortical gray and white matter as well as the anterior hippocampus.31,41,42 Furthermore, reversible vasogenic edema in the cerebellum; thalami; and cortical, subcortical, and deep parietal white matter has also been described in the clinical setting of posterior reversible encephalopathy syndrome complicating alcohol withdrawal.41

Alcoholic Cognitive Decline and Cerebral Atrophy Cerebral atrophy in chronic alcoholics is not uncommon and is believed to be a sequel of direct neurotoxic effects of ethanol.43-45 It is believed that ethanol causes upregulation of N-methyl-Daspartate receptors secondary to abnormal homocysteine catabolism, which causes increased susceptibility to excitatory and cytotoxic effects of glutamate. Additionally, N-methyl-D-aspartate receptors also inhibit the function of cell membrane ionic canals resulting in reduced intracellular Na þ and Cl  levels thus contributing to brain volume loss. Moreover, it has been proposed that binding of acetaldehyde and related products of lipid peroxidation to the brain tissue initiates an immune-mediated response resulting in neuronal and white matter loss.43-46 The dorsolateral frontal cortex shows the most pronounced atrophic changes followed by relatively less pronounced changes involving the temporal cortex, insula, thalami, and cerebellum (Fig 12).43-45 Decreased gene expressions of myelin protein encoding genes in the glia cells in these regions putatively contribute toward early involution. On imaging, these changes are seen as loss of frontal and temporal white matter and thinning of gray matter, leading to prominent sulci and widening of the frontal and temporal horns.31,41,42 In the final stages, global volume loss results in generalized ventricular enlargement and prominence of the basal cisterns and subarachnoid cerebrospinal fluid spaces along the bilateral cerebral convexities.31,41-45 Early changes may not be discernible using conventional imaging techniques and may only be detectable with quantitative techniques such as voxel-based morphometry or diffusion tensor imaging, which can detect the degradation of white matter fibers connecting the gray matter.46,47 On MRS, alcohol-induced neurochemical changes can be detected as increased myoinositol coupled with decreased NAA and cholinecontaining metabolites. Increased myoinositol reflects astrocyte proliferation whereas decrease NAA reflects axonal damage.42,48 Clinically, patients may manifest neuropsychological impairments in the form of lack of insight, disinhibition, and abnormalities in planning, judgment, reasoning, organization, and problem solving, reflecting preferential involvement and atrophy of the frontal lobes.

458

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

Fig. 11. Marchiafava-Bignami disease. Sagittal (A and B) T2W MR images in a chronic alcoholic male patient reveal relative atrophy of posterior body of corpus callosum (black arrow) with focal area of hyperintensity involving splenium (thick white arrow). In addition, note is made of disproportionate cerebellar atrophy (arrowhead)—likely representing alcoholic cerebellar degeneration.

Alcoholic Cerebellar Degeneration In addition to the frequently reported effects of alcohol-related cerebral involution, cerebellar atrophy is also not uncommon in chronic alcoholics with history of 10 or more years of substantial alcohol abuse. Alcohol-induced degeneration of Purkinje cells in the cerebellar cortex is presumably responsible for the development of a chronic cerebellar syndrome.31,41,42,45 Midline cerebellar structures, especially the anterior and superior vermis, are predominantly

affected (Fig 13).42 Often this is accompanied by the prominence of the cerebellar fissures without associated pontine atrophy.31

IIb. Neurologic Complications Related to Wilson Disease Wilson disease also known as hepatolenticular degeneration is an autosomal recessive, inborn defect in ceruloplasmin metabolism characterized by abnormal accumulation of copper

Fig. 12. Cerebral atrophy. Axial noncontrast CT (A, B) showing disproportionate bifrontal cerebral atrophy (arrow) with attendant ventricular enlargement (asterisk) and prominent extra-axial CSF spaces including sylvian fissures (arrowheads) in a chronic alcoholic male patient with underlying liver cirrhosis. CSF, cerebrospinal fluid.

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

459

Fig. 13. Alcoholic cerebellar degeneration. Coronal (A and B) T2W images show diffuse cerebellar atrophy as evidenced by generalized prominence of cerebellar foliae, ventricular enlargement, and prominence of infratentorial subarachnoid CSF spaces (white arrow) in a patient with cirrhosis with history of chronic alcohol abuse. CSF, cerebrospinal fluid.

in various tissues, particularly in the liver and the brain.49,50 It was initially described by S.A.K. Wilson in 1912. Clinically, the patients (typically 5-35 years of age) present with weakening of hands, dysarthria, dystonia, pseudoparkinsonian, and

cerebellar symptoms with or without nonspecific psychiatric symptoms. On MRI, earliest abnormality is seen as T1 hyperintensity in basal ganglia particularly putamen followed by caudate nucleus,

Fig. 14. Wilson disease. Axial (A) and coronal (B) T2W MR images depicting symmetrical increased signal intensity of bilateral ventrolateral thalami (white arrow).

460

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461

globus pallidus, thalamus, and midbrain.49-51 On T2-weighted images, hyperintensity is seen in basal ganglia and ventrolateral thalamus (Fig 14). Acute cases may show diffusion restriction. The classical MR findings of Wilson disease include the “face of a giant panda” sign. This appearance is seen in midbrain on T2-weighted imaging and is caused by high signal in tegmentum and hypointensity in the superior colliculus with relative sparing of red nucleus and lateral portion of the pars reticulata. Other signs include. Sometimes, coexisting signal alteration may also be encountered within the dorsal pons, which has been popularly called “giant panda cub” or “face of miniature panda” sign.49-51

IIc. HCV-Related Central Nervous System Complications Chronic infection with hepatitis C virus (HCV) is a growing major health problem affecting an estimated 170 million people worldwide.52-55 HCV-related central nervous system complications encompass acute cerebrovascular events (ischemic stroke, transient ischemic attacks, lacunar syndromes, or rarely hemorrhages) secondary to occlusive vasculopathy and vasculitis and include acute or subacute cerebral encephalopathies seen on MRI as small focal lesions in subcortical and periventricular white matter.52-55 The proposed pathophysiology of these neurologic manifestations although uncertain includes exaggerated host immune response leading to production of autoantibodies, immune complexes, and cryoglobulins leading to lymphocytic or necrotizing vasculitis. Other proposed mechanisms include replication of HCV in the cerebral tissue and the effects of circulating inflammatory cytokines and chemokines, which are believed to be responsible for acute disseminated encephalomyelitis, myelitis, and meningoradiculitis or polyradiculitis. Although focal white matter lesions in CLD may decrease in volume over a period, the neurologic lesions in HCV-related small vessel disease tend to increase with time.52-55

Conclusion CLD and liver failure can be associated with a diverse range of neurologic manifestations. Of these, HE is the most frequently encountered and most widely recognized whereas hepatic parkinsonism, AHD, and HM are rare associations. Osmotic demyelination disorders albeit not exclusive to hepatic dysfunction can be encountered in conjunction with liver decompensation. Furthermore, Wilson disease and chronic alcohol consumption can lead to neurologic involvement and a spectrum of neuroradiological changes. It is important to be aware of these diagnostic possibilities and their radiological manifestations while reporting neurologic examinations in this subset of patient population. Although frequently a multidisciplinary approach is required to arrive at the accurate diagnosis, the radiologist plays a central role in leading the neurologist and hepatologist to apposite therapeutic planning. References 1. Neff GW, Duncan CW, Schiff ER. The current economic burden of cirrhosis. Gastroenterol Hepatol 2011;7(10):661–71. 2. Ly KN, Speers S, Klevens RM, et al. Measuring chronic liver disease mortality using an expanded cause of death definition and medical records in Connecticut, 2004. Hepatol Res 2014 Oct 16. 10.1111/hepr.12437. 3. Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: Part I. Diagnosis and evaluation. Am Fam Physician 2006;74(5):756–62. 4. Arora A, Mukund A, Rajesh S, et al. The nervous liver: Neurological complications associated with cirrhosis & liver transplantation. Electronic poster presented on electronic poster online system (EPOS) as part of ECR 2013. http://dx.doi.org/10.1594/ecr2014/C-1397. 5. Ferro JM, Oliveira S. Neurologic manifestations of gastrointestinal and liver diseases. Curr Neurol Neurosci Rep 2014;14(10):487.

6. White H. Neurologic manifestations of acute and chronic liver disease. Continuum (Minneap Minn). 2014 Jun;20(3 Neurology of Systemic Disease):670-80. http://dx.doi.org/10.1212/01.CON.0000450973.84075.a7. 7. Ardizzone G, Arrigo A, Schellino MM, et al. Neurological complications of liver cirrhosis and orthotopic liver transplant. Transplant Proc 2006;38(3):789–92. 8. Lewis M, Howdle PD. The neurology of liver failure. QJM 2003;96(9):623–33. 9. Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry 1997;63(3):279–93. 10. Rothstein JD, Herlong HF. Neurologic manifestations of hepatic disease. Neurol Clin 1989;7(3):563–78. 11. Leevy C. Economic impact of treatment options for hepatic encephalopathy. Semin Liver Dis 2007;27:26–31. 12. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congress of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21. 13. Zwingmann C, Butterworth R. An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: Further studies using NMR spectroscopy. Neurochem Int 2005;47(1-2):19–30. 14. Alonso J, Córdoba J, Rovira A. Brain magnetic resonance in hepatic encephalopathy. Semin Ultrasound CT MR 2014;35(2):136–52. 15. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. Am J Neuroradiol 2008;29(9):1612–21. 16. Grover VP, Dresner MA, Forton DM, et al. Current and future applications of magnetic resonance imaging and spectroscopy of the brain in hepatic encephalopathy. World J Gastroenterol 2006;12(19):2969–78. 17. Zhang LJ, Zhong J, Lu GM. Multimodality MRimaging findings of low-grade brain edema in hepatic encephalopathy. Am J Neuroradiol 2013;34(4):707–15. 18. Poveda MJ, Bernabeu A, Concepción L, et al. Brain edema dynamics in patients with overt hepatic encephalopathy. A magnetic resonance imaging study. Neuroimage 2010;52(2):481–7. 19. Weissenborn K, Ahl B, Fischer-Wasels D, et al. Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 2007;56(12):1736–42. 20. Geissler A, Lock G, Fründ R, et al. Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging. Hepatology 1997;25(1):48–54. 21. Tarasów E, Panasiuk A, Siergiejczyk L, et al. MR and 1H MR spectroscopy of the brain in patients with liver cirrhosis and early stages of hepatic encephalopathy. Hepatogastroenterology 2003;50(54):2149–53. 22. Fernández-Rodriguez R, Contreras A, De Villoria JG, et al. Acquired hepatocerebral degeneration: Clinical characteristics and MRI findings. Eur J Neurol 2010;17(12):1463–70. 23. Meissner W, Tison F. Acquired hepatocerebral degeneration. Handb Clin Neurol 2011;100:193–7. 24. Miletić V, Ozretić D, Relja M. Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration. Metab Brain Dis 2014;29(1):207–9. 25. Maffeo E, Montuschi A, Stura G, et al. Chronic acquired hepatocerebral degeneration, pallidal T1 MRI hyperintensity and manganese in a series of cirrhotic patients. Neurol Sci 2014;35(4):523–30. 26. Tryc AB, Goldbecker A, Berding G, et al. Cirrhosis-related Parkinsonism: Prevalence, mechanisms and response to treatments. J Hepatol 2013;58(4): 698–705. 27. Burkhard PR, Delavelle J, Du Pasquier R, et al. Chronic parkinsonism associated with cirrhosis: A distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003;60(4):521–8. 28. Butterworth RF. Parkinsonism in cirrhosis: Pathogenesis and current therapeutic options. Metab Brain Dis 2013;28(2):261–7. 29. Premkumar M, Bagchi A, Kapoor N, et al. Hepatic myelopathy in a patient with decompensated alcoholic cirrhosis and portal colopathy. Case Reports Hepatol 2012;2012:735906. 30. Koo JE, Lim YS, Myung SJ, et al. Hepatic myelopathy as a presenting neurological complication in patients with cirrhosis and spontaneous splenorenal shunt. Korean J Hepatol 2008;14:89–96. 31. Geibprasert S, Gallucci M, Krings T. Alcohol-induced changes in the brain as assessed by MRI and CT. Eur Radiol 2010;20(6):1492–501. 32. Huang HH, Lin HH, Shih YL, et al. Spontaneous intracranial hemorrhage in cirrhotic patients. Clin Neurol Neurosurg 2008;110:253–8. 33. Chung CL, Lieu AS, Chen IY, et al. Brain abscess in adult cirrhotic patients: Two case reports. Kaohsiung J Med Sci 2007;23:34–9. 34. Brann OS. Infectious complications of cirrhosis. Curr Gastroenterol Rep 2001; 3(4):285–92. 35. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol 2007;21(1):77–93. 36. Christou L, Pappas G, Falagas ME. Bacterial infection-related morbidity and mortality in cirrhosis. Am J Gastroenterol 2007;102(7):1510–7. 37. Datar S, Wijdicks EF. Neurologic manifestations of acute liver failure. Handb Clin Neurol 2014;120:645–59. 38. Shawcross DL, Wendon JA. The neurological manifestations of acute liver failure. Neurochem Int 2012;60(7):662–71. 39. Rabinstein AA. Treatment of brain edema in acute liver failure. Curr Treat Options Neurol 2010;12:129–41. 40. Scott TR, Kronsten VT, Hughes RD, et al. Pathophysiology of cerebral oedema in acute liver failure. World J Gastroenterol 2013;19(48):9240–55.

B. Sureka et al. / Current Problems in Diagnostic Radiology 44 (2015) 449–461 41. Zuccoli G, Siddiqui N, Cravo I, et al. Neuroimaging findings in alcohol-related encephalopathies. Am J Roentgenol 2010;195:1378–84. 42. Kim TE, Lee EJ, Young JB, et al. Wernicke encephalopathy and ethanol-related syndromes. Semin Ultrasound CT MR 2014;35(2):85–96. 43. Harper C. The neuropathology of alcohol-related brain damage. Alcohol Alcohol 2009;44(2):136–40. 44. Sutherland GT, Sheedy D, Kril JJ. Neuropathology of alcoholism. Handb Clin Neurol 2014;125:603–15. 45. Mann K, Agartz I, Harper C, et al. Neuroimaging in alcoholism: Ethanol and brain damage. Alcohol Clin Exp Res 2001;25(5 suppl ISBRA):104S–9S. 46. Chanraud S, Martelli C, Delain F, et al. Brain morphometry and cognitive performance in detoxified alcohol-dependents with preserved psychosocial functioning. Neuropsychopharmacology 2007;32(2):429–38. 47. Rosenbloom M, Sullivan EV, Pfefferbaum A. Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics. Alcohol Res Health 2003;27(2):146–52. 48. Martin B, Heinz-Gerd W, Gerd W, et al. Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic

49. 50.

51. 52. 53. 54.

55.

461

alcoholism: Correlation with clinical and neuropsychological data. Am J Neuroradiol 2001;22:1926–32. Panda AK. Classic neuroimaging, the bird's eye view in Wilson's disease. BMJ Case Rep 2013;9:2013 [pii: bcr2013200701]. Kim TJ, Kim IO, Kim WS, et al. MR imaging of the brain in Wilson disease of childhood: Findings before and after treatment with clinical correlation. Am J Neuroradiol. 2006;27(6):1373–8. Hermann W. Morphological and functional imaging in neurological and nonneurological Wilson's patients. Ann N Y Acad Sci 2014;1315:24–9. Himoto T, Masaki T. Extrahepatic manifestations and autoantibodies in patients with hepatitis C virus infection. Clin Dev Immunol 2012;2012:871401. Stübgen JP. Neuromuscular diseases associated with chronic hepatitis C virus infection. J Clin Neuromuscul Dis 2011;13(1):14–25. Benstead TJ, Chalk CH, Parks NE. Treatment for cryoglobulinemic and noncryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection. Cochrane Database Syst Rev 2014;20(12):CD010404. Mariotto S, Ferrari S, Monaco S. HCV-related central and peripheral nervous system demyelinating disorders. Inflamm Allergy Drug Targets 2014;13(5):299–304.

Neurologic Manifestations of Chronic Liver Disease and Liver Cirrhosis.

The normal functioning of brain is intimately as well as intricately interrelated with normal functioning of the liver. Liver plays a critical role of...
4MB Sizes 1 Downloads 9 Views