Acquired hepatocerebral degeneration and hepatic encephalopathy: correlations and variety of clinical presentations in overt and subclinical liver disease

Acquired hepatocerebral degeneration (AHD) and hepatolenticular degeneration can have similar clinical presentations, but when a chronic liver disease and atypical motor findings coexist, the distinction between AHD and hepatic encephalopathy (HE) can be even more complicated. We describe three cases of AHD (two having HE) with different neuroimaging findings, distinct hepatic diseases and similar motor presentations, all presenting chronic arterial hypertension and weight loss before the disease manifestations. The diagnosis and physiopathology are commented upon and compared with previous reports. In conclusion, there are many correlations among HE, hepatolenticular degeneration and AHD, but the overlapping of AHD and HE could be more common depending on the clinical knowledge and diagnostic criteria adopted for each condition. Since AHD is not considered a priority that affects the liver transplant list, the prognosis in AHD patients remains poor, and flow interruption in portosystemic shunts must always be taken into account.     

Hepatic encephalopathy coexists with acquired chronic hepatocerebral degeneration

Hyperkinetic extrapyramidal syndrome is the typical clinical characteristic of acquired hepatocerebral degeneration (AHD), but is usually not observed with hepatic encephalopathy (HE). We present a case of AHD coexisting with HE. Both conditions were secondary to liver cirrhosis and hepatitis C virus infection. The brain MRI showed bilateral and symmetric high T1 signal-intensity in the globus pallidus, and diffuse high signal-intensity of the hemispheric white matter on T2-FLAIR images. As we usually neglect the existence of AHD, the diagnosis is often ignored, especially when it coexists with HE. This case highlights the need to distinguish irreversible AHD from HE.Progressive chronic liver disease often causes neurological manifestation, including hepatic encephalopathy (HE), acquired hepatocerebral degeneration (AHD), and hepatic myelopathy (HM). Among these dysfunctions, HE is the most common and reversible disorder, while AHD is a rare and irreversible syndrome. Hepatic encephalopathy is a serious complication of liver disease and is characterized by neuropsychiatric symptoms, which range from subtle neurocognitive alterations to severe life-threatening neurological impairment.1,2 Hepatic encephalopathy presents in as many as 28% of patients with liver cirrhosis, and can be alleviated by lowering the blood ammonia levels.1,2 However, AHD is rare and the best result among the possible treatments is orthotopic liver transplantation.3 The prevalence of this disease is between 0.8-2% of cirrhotic patients. Of note, the more relevant risk factors are the presence of portosystemic shunts and the multiple bouts of hepatic coma seen in some patients with HE.4,5 Acquired hepatocerebral degeneration is a progressive, irreversible neurological syndrome caused by persistent and decompensated liver disease, and characterized by abnormal movements, dysarthria, rigidity, intention tremor, ataxia, and impairment of intellectual functions.6 In AHD physiopathology, manganese accumulation in the basal nuclei appears to be a key factor. This metal concentration is responsible for the MRI T1 hyperintensity mainly involving the basal ganglia, which can be considered a biomarker of manganese overload.3,6 Hepatic encephalopathy and AHD are 2 different CNS disorders secondary to hepatic dysfunction. Hyperkinetic extrapyramidal syndrome is the typical clinical characteristic of AHD, but usually not observed in HE. Here, we describe a case coexisting with HE and AHD in the presence of symmetrical basal ganglia high signal intensity on T1-weighted images and widespread T2 high signal intensity of the hemispheric white matter. Our objective in presenting this particular case is to highlight the presence of AHD that is considered rare as the diagnosis tends to be ignored.     

Acquired hepatocerebral degeneration

Cirrhosis and its co-morbidities may cause a variety of neurological complications, the most common being bouts of toxic metabolic encephalopathy. A proportion of patients with chronic liver disease develop acquired hepatocerebral degeneration (AHD), a chronic progressive neurological syndrome characterized by parkinsonism, ataxia and other movement disorders. This article reviews the clinical spectrum, pathophysiology, neuroimaging features and differential diagnosis of AHD along with emerging treatment options.     

Clinical and neuroradiological improvement in chronic acquired hepatocerebral degeneration after branched-chain amino acid therapy

We report two patients with chronic acquired hepatocerebral degeneration (CAHD) who showed neurological and radiological improvement after the administration of branched-chain amino acids (BAA). The first patient with chronic hepatitis C presented with progressive parkinsonism for 7 months, whereas the second patient with liver cirrhosis presented with progressive ataxia for 15 months. T1-weighted magnetic resonance imaging (MRI) showed symmetric high intensity signals in the lenticular nuclei in both patients. In the first patient, single photon emission computed tomography (SPECT) disclosed a marked decrease in cerebral blood flow in the parieto-occipital regions. In the second patient, T2-weighted MRI demonstrated symmetric high intensity signals in the deep cerebral and cerebellar white matter. After the administration of BAA, their neurological signs and radiological abnormalities markedly improved in both patients. CAHD might be a reversible and treatable disorder where aromatic amino acids are deeply involved in its pathogenesis.     

Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration

CONTEXT: The clinical, neuroradiological, and biological characteristics of the so-called acquired hepatocerebral degeneration have not yet been fully determined and its frequency remains largely uncertain. OBJECTIVES: To prospectively study the prevalence of extrapyramidal symptoms in patients with moderate to severe cirrhosis of various causes, to delineate the main neurological features of the condition, and to establish correlations with neuroradiological and biological findings. PATIENTS AND METHODS: During a 1-year period, all consecutive patients with cirrhosis who were potential candidates for liver transplantation were screened for extrapyramidal features. When extrapyramidal features were present, further workup included a detailed neurological examination, magnetic resonance imaging of the brain, a comprehensive battery of neuropsychological tests, extensive blood tests, and, in some cases, cerebrospinal fluid analysis. SETTING: A community-based hospital. RESULTS: From 51 patients screened, 11 (21.6%) exhibited moderate to severe parkinsonism sometimes associated with focal dystonia. Typical features included rapid progression over months, symmetric akinetic-rigid syndrome, postural but not resting tremor, and early postural and gait impairment. Neuropsychiatric manifestations were minimal. Some patients were responsive to levodopa therapy. In all patients, magnetic resonance imaging scans showed striking hyperintensities on T1-weighted images typically involving the substantia nigra and the globus pallidus bilaterally. Whole blood and cerebrospinal fluid manganese concentrations were severalfold above the reference range. CONCLUSIONS: Cirrhosis-related parkinsonism may represent a unique, consistent, and common subset of acquired hepatocerebral degeneration, whose features are permanent and entirely different from acute hepatic encephalopathy episodes. This form of parkinsonism can be clearly distinguished from other forms of parkinsonism of middle to advanced age, based on a suggestive association of clinical, neuroradiological, and biological abnormalities. Our findings support the concept of the toxic effects of manganese being the major determinant of basal ganglia dysfunction leading to the predominantly extrapyramidal central nervous system manifestations of cirrhosis observed in these patients.     

Chronic acquired hepatocerebral degeneration,pallidal T1 MRI hyperintensity and manganese in a series of cirrhotic patients

Chronic acquired hepatocerebral degeneration (CAHD) is a rare neurological disorder of cirrhotic patients, characterized by parkinsonism and cognitive impairment. A T1 hyperintensity on the globus pallidum due to an accumulation of manganese (Mn) is found in these patients. The aim of the study was to investigate CAHD, Mn and the MRI pallidal signal in a series of cirrhotic patients. The association between pallidal T1 hyperintensity, CAHD, and blood levels of Mn, the effect of orthotopic liver transplantation (OLT) on the MRI signal and neurological findings, and the role of the pallidal signal as a predictor of CAHD were evaluated. Twenty-six out of 90 patients with cirrhosis had pallidal T1 hyperintensity. Seven patients had CAHD. OLT was followed by the disappearance of CAHD and MRI signal in 2/2 patients. The MRI signal disappeared after OLT in 8/13 patients after a median follow-up time of 24 months. In the patients who did not undergo OLT, CAHD did not present after a median follow-up time of 18 months. The cause of cirrhosis, episodes of acute hepatic encephalopathy and signal intensity were not correlated with CAHD. The blood levels of Mn did not reflect either the MRI signal or CAHD. In conclusion, the pallidal T1 hyperintensity is a prerequisite for the clinical manifestations of CAHD but is not sufficient. The blood levels of Mn as routinely monitored are not a useful marker of Mn burden. The MRI pallidal signal is not a predictor of CAHD.     

Extraocular muscle dystonia due to acquired (non‐Wilsonian) hepatocerebral degeneration

We present a video report of a patient with advanced non‐Wilsonian cirrhotic liver disease who developed extraocular muscle dystonia (oculogyric crisis) and severe orofaciolingual dyskinesias. Acquired hepatocerebral degeneration causes choreic movements, especially of cranial muscles, but dystonic ocular spasm is an infrequent manifestation of this disorder. This case illustrates that AHD should be considered in the differential diagnosis of extraocular muscle dystonia. © 2008 Movement Disorder Society     

Acquired hepatocerebral degeneration in a liver transplant recipient

A 47-year-old-man lapsed into coma 12 h after liver transplantation, and remained comatose until death 38 days later. Prior to transplantation he had repeated episodes of hepatic encephalopathy, but no fixed neurological signs. Autopsy revealed typical features of acquired hepatocerebral degeneration with diffuse but patchy pseudolaminar cortical necrosis, variable amount of neuronal loss in the cerebral cortex, basal ganglia and other areas, and proliferation of Alzheimer type II glia. In addition, there was central pontine and extensive extrapontine myelinolysis involving the lateral and medical geniculate bodies, the thalamus, internal capsule, fornix, mamillothalamic tract, white matter bundles in the caudate and pallidum, the oculomotor nuclei and the foliar white matter of the cerebellum. The distinction between myelinolytic lesions and lesions due to hepatocerebral degeneration was not always clear. Although neurological complications and brain lesions are rather common after liver transplantation, there have been no reports of acquired hepatocerebral degeneration in liver transplant recipients. Our data lend support to the idea that a single prolonged comatose episode, due to hepatic dysfunction, may induce permanent parenchymal brain damage.     

获得性肝脑变性的临床与影像学特点

目的分析获得性肝脑变性的临床和影像学特征，探讨其规律性。方法分析9例获得性肝脑变性病例的临床表现、实验室检查和影像学改变的数据。结果5例既往有明确的肝硬化病史，4例没有明确的肝病病史，发病后检查分别发现肝血管病、肝胰脾等弥漫钙化或者肝硬化。主要临床表现为：精神异常、认知能力下降、帕金森病样综合征、构音障碍、共济失调、睡眠障碍。肝酶学轻中度异常，而血氨均升高。脑电图提示脑电活动呈弥漫性减慢，4例出现三相波节律。影像学改变为苍白球、大脑脚、小脑和大脑皮层下对称性短T1加权像信号，以及基底节、中脑、脑桥、延髓橄榄核对称性长T2加权像信号。结论获得性肝脑变性是肝细胞和肝血管病变引起的神经功能损害综合征，肝酶改变、血氮升高和脑电图符合代谢性疾病改变，结合特征性影像学改变，对疾病的诊断具有重要意义。     

Clinical report of three patients with hereditary hemochromatosis and movement disorders.

Neurologic manifestations are rarely described in hereditary hemochromatosis (HH). We describe three patients with HH and movement disorders. Patient 1, a 69-year-old man, had a 13-year history of disabling cerebellar syndrome, action tremor and myoclonus, and secondary dementia. Patient 2 was a 40-year-old man with a 9-year history of cerebellar syndrome, head and arm tremor, and cervical dystonia. Patient 3, a 75-year-old woman, had a 5-year history of rapidly disabling parkinsonian syndrome unresponsive to levodopa. The diagnosis of HH was established in the three patients by iron tests, evidence of a C282Y mutation, and, in two patients, by liver biopsy. High-field T2-weighted magnetic resonance imaging showed hyperintense signals in hemispheric white matter in patient 1, cerebellar atrophy in patient 2, and cerebellar and cerebral atrophy in patient 3 and no significant hypointense signals in the three patients. Phlebotomies and symptomatic treatments did not change the course of the disease. Our cases are compared with the five previously reported observations of HH with movement disorders. This rare association is one cause of the chronic acquired non-Wilsonian hepatocerebral degeneration syndromes and represents a separate entity from aceruloplasminemia. The pathophysiologic mechanism of movement disorders in HH is unresolved. No hepatic insufficiency and portosystemic encephalopathy is evidenced in our cases, whereas the putative role of abnormal iron load remains to be ascertained. HH should be investigated more systematically in patients with movement disorders.     

Prominent cerebellar symptoms with unusual magnetic resonance imaging findings in acquired hepatocerebral degeneration

BACKGROUND: Cerebellar lesions revealed by abnormal signals on magnetic resonance images are extremely rare in acquired hepatocerebral degeneration (AHCD). OBJECTIVE: To report a case of AHCD with prominent cerebellar findings both clinically and radiologically. DESIGN AND SETTING: Case report and tertiary-care hospital. PATIENT: A 46-year-old man complained of progressive speech difficulties of 5 months' duration. Two years earlier, he had been diagnosed as having cirrhosis of the liver caused by alcoholism and hepatitis B virus infection. RESULTS: The patient had progressive ataxic dysarthria and limb and gait ataxia as manifestations of AHCD. Magnetic resonance imaging of the brain revealed distinctive symmetrical T2 high-signal intensities in the bilateral cerebellar hemispheres and brachium pontis, which were consistent with his neurologic deficits. Simultaneously, high T1 signals in the bilateral pallidum and ventral midbrain were noted, which are typical manifestations of AHCD. Follow-up magnetic resonance imaging 3 months later showed the same cerebellar signs and abnormal signals. CONCLUSIONS: The cerebellar cortex and middle cerebellar peduncle are considered highly vulnerable structures to metabolic insults in liver disease. Findings from our patient suggest that dominant cerebellar deficits with compatible T2 high-signal lesions are another type of clinical manifestation in AHCD.     

Chronic acquired hepatocerebral degeneration: effects of liver transplantation on neurological manifestations

Three cirrhotic patients with chronic acquired hepatocerebral degeneration (CAHD) received neurologic, neuropsychologic and neuroimaging assessment before and after liver transplantation (LT). Before transplantation, neurologic dysfunction consisted in severe bradykinesia, dystonia, dyskinesia, ataxia and dysarthria. Cognitive impairment affected mainly attentional and executive domains. Brain MRI showed bilateral hyperintensities of the basal ganglia on T1-weighted images. After transplantation, motor manifestations promptly resolved. Cognitive testing showed a major improvement in two patients, whereas cognitive performances were slightly worsened in the third, reasonably due to the effects of a head injury before LT and a tacrolimus-related encephalopathy arising early after LT. MRI images 12 months later showed a slight reduction of the previously disclosed abnormalities in all three patients. None of them experienced recurrence of CAHD. Our observation reinforces the assumption that surgery is the best treatment option for CAHD and that severe neurological impairment in CAHD should not be considered a contraindication for LT.     

The cerebellar form of acquired hepatocerebral degeneration: The hepatic ataxia

This article reports a patient with acquired hepatocerebral degeneration that presented with progressive cerebellar ataxia, cerebellar atrophy, and middle cerebellar peduncle lesions. He had a marked improvement after liver transplantation. We reinforce that hepatic failure should be investigated in patients with pure cerebellar syndrome, resembling neurodegenerative diseases.     

Features of cell death in brain and liver,the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease)

Alpers-Huttenlocher disease (AHD) is a rare encephalopathy of infancy and childhood characterized by myoclonic seizures and progressive neurological deterioration, usually associated with signs and symptoms of liver dysfunction. There is no biological marker of the disease, and ultimate diagnosis still relies on pathological examination. Features of clinical progression and pathological findings suggest AHD to be secondary to a genetically determined disorder of mitochondrial function. We report on four AHD patients and focus on their pathological features in brain, liver and muscle. Liver and muscle biopsy specimens were examined using histochemical markers of the oxidative pathways, probes to immunodetect molecules of the apoptotic cascades and electron microscopy. In liver (but not in muscle) biopsy samples, activated caspases were detected by immunohistochemistry: foci of caspase-9-positive cells were seen in a child affected with chronic, progressive fibrosis. In an 18-year-old boy, who suffered from valproic acid-associated acute hepatitis, caspase-3 cells were clustered among the necrotic foci and the foamy cells. In both patients electron microscopy revealed apoptotic nuclei. Normal muscle biopsy specimens were observed in two children, 2 and 8 years-old respectively; in the 18-year-old patient cytochrome oxidase-negative fibers as well as ultrastructural findings of mitochondrial abnormalities were observed. In no patient was there biochemical evidence of impaired oxidative metabolism. Neuropathological examination of the brains of two patients (13 months and 19 years old, respectively) showed focal distribution of the lesions affecting the telencephalic cortex and, to a lesser extent, subcortical gray nuclei. Along with the necrotizing lesions, characterized by neuronal loss, neuropil microcysts and newly formed vessels, we also observed acutely shrunken neurons and features of apoptotic cell death in the cerebral cortex only. Severe neuronal loss without necrotizing features was observed in the cerebellar cortex. The presence of both anoxic and apoptotic nuclei in brain and liver, the target tissues of the disease, is consistent with the hypothesis that abnormal activation of mitochondrion-related cell death pathways might be involved in the pathogenesis of AHD.     

Acquired hepatocerebral degeneration: report of an atypical case

A case of acquired hepatocerebral degeneration secondary to biliary cirrhosis is described. It differs from the conventional type because of the clinical predominance of cerebellar symptomatology and because the principal neuropathological abnormalities were restricted to the pallidum and to the cerebellum.     

Case of pediatric acquired chronic hepatocerebral degeneration

Acquired chronic hepatocerebral degeneration is a central nervous system disorder secondary to several conditions related to hepatic dysfunction. Clinical features of acquired chronic hepatocerebral degeneration include a hyperkinetic extrapyramidal syndrome, neuropsychiatric symptoms, or both. We present for the first time a pediatric case of acquired chronic hepatocerebral degeneration secondary to endstage biliary disease. The pediatric phenotype of acquired chronic hepatocerebral degeneration is presented, and the differential diagnosis in regard to Wilson's disease and management alternatives are discussed.     

The clinical versus radiological diagnosis of alcoholic cerebellar degeneration

We report the clinical characteristics of 65 patients with alcoholic cerebellar degeneration as verified by computerized tomography of the brain. Thirty-two patients (49%) had clear clinical signs of the disease such as broad-based staggering gait, impaired heel-to-toe walking, terminal oscillations in heel-knee test and slow (3/s) leg tremor. These signs were virtually absent in 33 patients (51%) who, nevertheless, had radiological signs of cerebellar degeneration. Traumatic brain injuries were more frequent in those patients who had both clinical and radiological signs of alcoholic cerebellar degeneration. Furthermore, this group showed longer periods of heavy drinking, more severe cerebral atrophy and more profound neuropsychological impairment than a control group of 92 alcoholics with neither clinical nor radiological signs of cerebellar disease. We conclude that careful clinical neurological examination is needed to diagnose alcoholic cerebellar degeneration which is apparently a more common disease than first realized. Subclinical cases can be diagnosed with the help of computerized tomography of the brain.     

Corticospinal involvement in patients with a portosystemic shunt due to liver cirrhosis

Hepatic myelopathy (HM) is a rare complication of chronic liver diseases usually associated with a portosystemic shunt, causing a progressive spastic paraparesis, and is likely to be overlooked. Thirteen patients with liver cirrhosis associated with surgical or spontaneous portosystemic shunts were studied to determine the frequency and gravity of HM. Six patients exhibited clear-cut signs of spinal cord involvement and four of them exhibited varying degrees of disability. Neurological examination did not reveal any abnormalities in the other patients. Motor evoked potentials (MEPs) were measured in all patients; in five of them the examinations were done before and after orthotopic liver transplantation (OLT). The patients with clinical signs of spinal cord involvement exhibited severe neurophysiological abnormalities, whereas milder but unequivocal MEP abnormalities were found in four of the seven patients with normal clinical examination. The clinical and neurophysiological features of patients with slight MEP abnormalities improved after OLT, whereas the patients with a more advanced stage of disease (severe MEPs abnormalities) did not. Our findings indicate that MEP studies may disclose an impairment of the corticospinal pathways even before HM is clinically manifest and provide evidence that early diagnosis of HM and subsequent immediate liver transplantation have to be recommended.