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Li S, Zhua Y, Liu X. Parkinsonism in liver diseases or dysfunction. Med Clin (Barc) 2024; 163:461-468. [PMID: 38955605 DOI: 10.1016/j.medcli.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 04/20/2024] [Indexed: 07/04/2024]
Abstract
Parkinsonism in liver diseases or dysfunction, mainly including neurological manifestations in hereditary liver diseases and neurological complications of advanced liver diseases, occur in isolation or in combination with other movement disorders, and progress along disease course. Prominent akinetic-rigidity syndrome, various onset and progression, poor levodopa response and metabolism abnormalities reflected by serum biomarkers and neuroimaging, make this atypical parkinsonism recognizable and notable in clinical practice. Different susceptibility of brain areas, especially in basal ganglia, to manganese, iron, copper, ammonia overload, together with subsequent oxidative stress, neurotransmitter alterations, disturbed glia-neuron homeostasis and eventually neurotoxicity, contribute to parkinsonism under the circumstances of insufficient liver clearance ability. These mechanisms are interrelated and may interact collectively, adding to the complexity of clinical manifestations and treatment responses. This review summarizes shared clinical features of parkinsonism in liver diseases or dysfunction, depicts their underlying mechanisms and suggests practical flowchart for differential diagnosis.
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Affiliation(s)
- Sichen Li
- Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuxia Zhua
- Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Liu
- Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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2
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Olszewska DA, Rawal S, Fearon C, Alcaide‐Leon P, Stell R, Paramanandan V, Lynch T, Jawad T, Vittal P, Barton B, Miyajima H, Kono S, Kandadai RM, Borgohain R, Lang AE. Neuroimaging Pearls from the MDS Congress Video Challenge. Part 1: Genetic Disorders. Mov Disord Clin Pract 2022; 9:297-310. [PMID: 35402643 PMCID: PMC8974871 DOI: 10.1002/mdc3.13412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/29/2021] [Accepted: 12/30/2021] [Indexed: 02/05/2023] Open
Abstract
We selected several "imaging pearls" presented during the Movement Disorder Society (MDS) Video Challenge for this review. While the event, as implicated by its name, was video-centered, we would like to emphasize the important role of imaging in making the correct diagnosis. We divided this anthology into two parts: genetic and acquired disorders. Genetic cases described herein were organized by the inheritance pattern and the focus was put on the imaging findings and differential diagnoses. Despite the overlapping phenotypes, certain described disorders have pathognomonic MRI brain findings that would provide either the "spot" diagnosis or result in further investigations leading to the diagnosis. Despite this, the diagnosis is often challenging with a broad differential diagnosis, and hallmark findings may be present for only a limited time.
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Affiliation(s)
- Diana A. Olszewska
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital—UHN, Division of NeurologyUniversity of TorontoTorontoOntarioCanada
| | - Sapna Rawal
- Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western HospitalUniversity Health NetworkTorontoOntarioCanada
| | - Conor Fearon
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital—UHN, Division of NeurologyUniversity of TorontoTorontoOntarioCanada
| | - Paula Alcaide‐Leon
- Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western HospitalUniversity Health NetworkTorontoOntarioCanada
| | - Rick Stell
- Movement Disorders Unit, Perron Institute of Neurological Translational ScienceSir Charles Gairdner HospitalPerthWestern AustraliaAustralia
| | | | - Tim Lynch
- Centre for Brain HealthDublin Neurological Institute at the Mater Misericordiae University HospitalDublinIreland
- School of Medicine and Medical ScienceUniversity College DublinDublinIreland
| | - Tania Jawad
- Department of NeurologyThe Royal Free HospitalLondonUnited Kingdom
| | - Padmaja Vittal
- Northwestern Medicine Central Dupage HospitalNeurodegenerative Diseases CenterWinfieldIllinoisUSA
| | - Brandon Barton
- Rush University Medical CenterChicagoIllinoisUSA
- Parkinson's Disease Research, Education, and Clinical Care ConsortiumJesse Brown VA Medical CenterChicagoIllinoisUSA
| | - Hiroaki Miyajima
- First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
| | | | | | - Rupam Borgohain
- Department of NeurologyNizam's Institute of Medical SciencesHyderabadIndia
| | - Anthony E. Lang
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital—UHN, Division of NeurologyUniversity of TorontoTorontoOntarioCanada
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New Insight in Hyperinsulinism/Hyperammonemia Syndrome by Magnetic Resonance Imaging and Spectroscopy. Brain Sci 2022; 12:brainsci12030389. [PMID: 35326344 PMCID: PMC8946637 DOI: 10.3390/brainsci12030389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/21/2022] [Accepted: 03/07/2022] [Indexed: 11/16/2022] Open
Abstract
Hyperinsulinism/hyperammonemia syndrome (HI/HA) is an autosomal dominant disorder caused by monoallelic activating mutations in the glutamate dehydrogenase 1 (GLUD1) gene. While hyperinsulinism may be explained by a reduction in the allosteric inhibition of GLUD1, the pathogenesis of HA in HI/HA remains uncertain; interestingly, HA in the HI/HA syndrome is not associated with acute hyperammonemic intoxication events. We obtained a brain magnetic resonance (MR) in a woman with HI/HA syndrome with chronic asymptomatic HA. On MR spectroscopy, choline and myoinositol were decreased as in other HA disorders. In contrast, distinct from other HA disorders, combined glutamate and glutamine levels were normal (not increased). This observation suggests that brain biochemistry in HI/HA may differ from that of other HA disorders. In HI/HA, ammonia overproduction may come to the expense of glutamate levels, and this seems to prevent the condensation of ammonia with glutamate to produce glutamine that is typical of the other HA disorders. The absence of combined glutamate and glutamine elevation might be correlated to the absence of acute cerebral ammonia toxicity.
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Gurol KC, Aschner M, Smith DR, Mukhopadhyay S. Role of excretion in manganese homeostasis and neurotoxicity: a historical perspective. Am J Physiol Gastrointest Liver Physiol 2022; 322:G79-G92. [PMID: 34786983 PMCID: PMC8714252 DOI: 10.1152/ajpgi.00299.2021] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The essential metal manganese (Mn) induces incurable neurotoxicity at elevated levels that manifests as parkinsonism in adults and fine motor and executive function deficits in children. Studies on Mn neurotoxicity have largely focused on the role and mechanisms of disease induced by elevated Mn exposure from occupational or environmental sources. In contrast, the critical role of excretion in regulating Mn homeostasis and neurotoxicity has received less attention although 1) studies on Mn excretion date back to the 1920s; 2) elegant radiotracer Mn excretion assays in the 1940s to 1960s established the routes of Mn excretion; and 3) studies on patients with liver cirrhosis in the 1990s to 2000s identified an association between decreased Mn excretion and the risk of developing Mn-induced parkinsonism in the absence of elevated Mn exposure. Notably, the last few years have seen renewed interest in Mn excretion largely driven by the discovery that hereditary Mn neurotoxicity due to mutations in SLC30A10 or SLC39A14 is caused, at least in part, by deficits in Mn excretion. Quite remarkably, some of the recent results on SLC30A10 and SLC39A14 provide explanations for observations made ∼40-50 years ago. The goal of the current review is to integrate the historic studies on Mn excretion with more contemporary recent work and provide a comprehensive state-of-the-art overview of Mn excretion and its role in regulating Mn homeostasis and neurotoxicity. A related goal is to discuss the significance of some of the foundational studies on Mn excretion so that these highly consequential earlier studies remain influential in the field.
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Affiliation(s)
- Kerem C. Gurol
- 1Division of Pharmacology & Toxicology, College of Pharmacy, and Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
| | - Michael Aschner
- 2Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York
| | - Donald R. Smith
- 3Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, California
| | - Somshuvra Mukhopadhyay
- 1Division of Pharmacology & Toxicology, College of Pharmacy, and Institute for Neuroscience, The University of Texas at Austin, Austin, Texas
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Rudler M, Weiss N, Perlbarg V, Mallet M, Tripon S, Valabregue R, Marjańska M, Cluzel P, Galanaud D, Thabut D. Combined diffusion tensor imaging and magnetic resonance spectroscopy to predict neurological outcome before transjugular intrahepatic portosystemic shunt. Aliment Pharmacol Ther 2018; 48:863-874. [PMID: 30178870 DOI: 10.1111/apt.14938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/14/2018] [Accepted: 07/18/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) may occur after transjugular intrahepatic portosystemic shunt (TIPSS) placement. Multimodal magnetic resonance imaging (MRI), combining anatomical sequences, diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy, is modified in cirrhotic patients. AIMS To describe multimodal MRI images before TIPSS, to assess if TIPSS induces changes in multimodal MRI, and to find predictors of HE after TIPSS in patients with cirrhosis. METHODS Consecutive cirrhotic patients with an indication for TIPSS were prospectively screened. Diagnosis of minimal HE was performed using psychometric HE test score. Multimodal MRI was performed before and 3 months after TIPSS placement. RESULTS Twenty-five consecutive patients were analysed (median age = 59, male gender 76%, median Child-Pugh score = 8 [5-8], MELD score = 12 [9-17], indication for TIPSS placement: ascites/secondary prophylaxis of variceal bleeding/other 20/3/2), no HE/minimal HE/overt HE: 21/4/0. 8/25 patients developed HE after TIPSS. Before TIPSS placement, metabolite concentrations were different in patients with or without minimal HE (lower myo-inositol, mI, higher glutamate/glutamine), but there were no differences in DTI data. TIPSS placement induced changes in metabolite concentrations even in asymptomatic patients, but not in DTI metrics. Baseline fractional anisotropy was significantly lower in patients who developed HE after TIPSS in five regions of interest. CONCLUSIONS TIPSS placement induced significant changes in cerebral metabolites, even in asymptomatic patients. Patients who developed HE after TIPSS displayed lower fractional anisotropy before TIPSS. Brain MRI with DTI acquisition may help selecting patients at risk of HE.
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Affiliation(s)
- Marika Rudler
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Hepatology Department, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nicolas Weiss
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Vincent Perlbarg
- Bioinformatics and Biostatistics Platform, IHU-A-ICM, Brain and Spine Institute, Paris, France
| | - Maxime Mallet
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Simona Tripon
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Romain Valabregue
- CENIR, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne University, Pierre et Marie Curie University, UMR S 1127F, Paris, France
| | - Małgorzata Marjańska
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota
| | - Philippe Cluzel
- AP-HP, UPMC, Department of Radiology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University, Paris, France
| | - Damien Galanaud
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,AP-HP, UPMC, Department of Radiology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University, Paris, France.,Institut-Hospitalo-Universitaire-A-Institut du Cerveau et de la Moelle (IHU-A-ICM), Paris, France
| | - Dominique Thabut
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Hepatology Department, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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Xu S, Zhu W, Wan Y, Wang J, Chen X, Pi L, Lobo MK, Ren B, Ying Z, Morris M, Cao Q. Decreased Taurine and Creatine in the Thalamus May Relate to Behavioral Impairments in Ethanol-Fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy. Mol Imaging 2018; 17:1536012117749051. [PMID: 29318932 PMCID: PMC5768247 DOI: 10.1177/1536012117749051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/22/2017] [Accepted: 10/10/2017] [Indexed: 12/23/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease-induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.
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Affiliation(s)
- Su Xu
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Wenjun Zhu
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Yamin Wan
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - JiaBei Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Xi Chen
- McLean Hospital, Harvard Medical School, Belmont, MA, USA
| | - Liya Pi
- The Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Mary Kay Lobo
- Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bin Ren
- Blood Research Institute, Blood Center of Wisconsin, Department of Medicine, Medical College of Wisconsin Milwaukee, WI, USA
| | - Zhekang Ying
- The Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Michael Morris
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Qi Cao
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Suárez I, Bodega G, Rubio M, Fernández B. Reduced TH expression and α-synuclein accumulation contribute towards nigrostriatal dysfunction in experimental hepatic encephalopathy. Restor Neurol Neurosci 2017; 35:469-481. [PMID: 28984618 DOI: 10.3233/rnn-170728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE The present work examines α-synuclein expression in the nigrostriatal system of a rat chronic hepatic encephalopathy model induced by portacaval anastomosis (PCA). There is evidence that dopaminergic dysfunction in disease conditions is strongly associated with such expression. Possible relationships among dopaminergic neurons, astroglial cells and α-synuclein expression were sought. METHODS Brain tissue samples from rats at 1 and 6 months post-PCA, and controls, were analysed immunohistochemically using antibodies against tyrosine hydroxylase (TH), α-synuclein, glial fibrillary acidic protein (GFAP) and ubiquitin (Ub). RESULTS In the control rats, TH immunoreactivity was detected in the neuronal cell bodies and processes in the substantia nigra pars compacta (SNc). A dense TH-positive network of neurons was also seen in the striatum. In the PCA-exposed rats, however, a reduction in TH-positive neurons was seen at both 1 and 6 months in the SNc, as well as a reduction in TH-positive fibres in the striatum. This was coincident with the appearance of α-synuclein-immunoreactive neurons in the SNc; some of the TH-positive neurons also showed α-synuclein immunoreactivity. In addition, α-synuclein accumulation was seen in the SNc and striatum at both 1 and 6 months post-PCA, whereas α-synuclein was only mildly expressed in the nigrostriatal pathway of the controls. Astrogliosis was also seen following PCA, as revealed by increased GFAP expression from 1 month to 6 months post-PCA in both the SN and striatum. The astroglial activation level in the SN paralleled the reduced neuronal expression of TH throughout PCA exposure. CONCLUSION α-synuclein accumulation following PCA may induce dopaminergic dysfunction via the downregulation of TH, as well as astroglial activation.
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Affiliation(s)
- Isabel Suárez
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Guillermo Bodega
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Miguel Rubio
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Madrid, Spain
| | - Benjamín Fernández
- Departamento de Biología Celular, Universidad Complutense, Madrid, Spain
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Feltracco P, Cagnin A, Carollo C, Barbieri S, Ori C. Neurological disorders in liver transplant candidates: Pathophysiology and clinical assessment. Transplant Rev (Orlando) 2017; 31:193-206. [DOI: 10.1016/j.trre.2017.02.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/29/2016] [Accepted: 02/20/2017] [Indexed: 12/14/2022]
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Gómez-Ansón B, Román E, Fernández de Bobadilla R, Pires-Encuentra P, Díaz-Manera J, Núñez F, Martinez-Horta S, Vives-Gilabert Y, Pagonabarraga J, Kulisevsky J, Cordoba J, Guarner C, Soriano G. Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls. PLoS One 2015; 10:e0118930. [PMID: 25793766 PMCID: PMC4368732 DOI: 10.1371/journal.pone.0118930] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 01/07/2015] [Indexed: 12/15/2022] Open
Abstract
Background & Aim Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. Patients and methods Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson’s Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson’s Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. Results The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson’s Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). Conclusions With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment.
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Affiliation(s)
- Beatriz Gómez-Ansón
- Neuroradiology Unit, Department of Radiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Eva Román
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Escola Universitària d’Infermeria EUI-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Ramón Fernández de Bobadilla
- Movement Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Jordi Díaz-Manera
- Neuromuscular Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
| | - Fidel Núñez
- Neuroradiology Unit, Department of Radiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Saül Martinez-Horta
- Movement Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Yolanda Vives-Gilabert
- Port d’Informació Científica (PIC), Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Institut de Física d’Altes Energies (IFAE), Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
| | - Javier Pagonabarraga
- Movement Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jaume Kulisevsky
- Movement Disorders Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Juan Cordoba
- Department of Internal Medicine, Hospital Vall d’Hebron, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Carlos Guarner
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Germán Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Institut de Recerca IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
- * E-mail:
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Mortera-Balsa V, Penderis J, Wessmann A, Gonçalves R, Lowrie M, Gutierrez-Quintana R. Magnetic resonance imaging of the lentiform nuclei in dogs with portosystemic shunts. J Small Anim Pract 2015; 56:307-11. [PMID: 25677834 DOI: 10.1111/jsap.12337] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 12/30/2014] [Accepted: 01/01/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To develop and evaluate a method to quantify the T1-weighted magnetic resonance imaging signal intensity of the lentiform nuclei in dogs, and to determine if there is any significant difference in this signal intensity between dogs with portosystemic shunts and a control group. MATERIALS AND METHODS A retrospective blinded study was performed to investigate the reliability and use of a quantitative method for assessing the T1-weighted magnetic resonance imaging signal intensity of the lentiform nuclei in dogs with and without portosystemic shunts. The lentiform nuclei index (mean lentiform nucleus signal intensity/mean white matter signal intensity) was calculated for nine dogs with portosystemic shunts and a control group of 14 dogs. RESULTS The intra- and inter-observer intraclass correlation coefficients were considered excellent (>0 · 75), suggesting that the lentiform nuclei index is a reliable method. The dogs with portosystemic shunts had a higher lentiform nuclei index than the control group (P = 0 · 0127). CLINICAL SIGNIFICANCE This method of quantifying the T1-weighted magnetic resonance imaging signal intensity of the lentiform nuclei was reliable and showed that dogs with portosystemic shunts tend to have increased signal intensity. Further prospective studies are necessary to investigate the clinical significance and applications of these findings.
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Affiliation(s)
- V Mortera-Balsa
- School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH
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Alonso J, Córdoba J, Rovira A. Brain magnetic resonance in hepatic encephalopathy. Semin Ultrasound CT MR 2014; 35:136-52. [PMID: 24745889 DOI: 10.1053/j.sult.2013.09.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The term hepatic encephalopathy (HE) covers a wide spectrum of neuropsychiatric abnormalities caused by portal-systemic shunting. The diagnosis requires demonstration of liver dysfunction or portal-systemic shunts and exclusion of other neurologic disorders. Most patients with this condition have liver dysfunction caused by cirrhosis, but it also occurs in patients with acute liver failure and less commonly, in patients with portal-systemic shunts that are not associated with hepatocellular disease. Various magnetic resonance (MR) techniques have improved our knowledge about the pathophysiology of HE. Proton MR spectroscopy and T1-weighted imaging can detect and quantify accumulations of brain products that are normally metabolized or eliminated such as glutamine and manganese. Other MR techniques such as T2-weighted and diffusion-weighted imaging can identify white matter abnormalities resulting from disturbances in cell volume homeostasis secondary to brain hyperammonemia. Partial or complete recovery of these abnormalities has been observed with normalization of liver function or after successful liver transplantation. MR studies have undoubtedly improved our understanding of the mechanisms involved in the pathogenesis of HE, and some findings can be considered biomarkers for monitoring the effects of therapeutic measures focused on correcting this condition.
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Affiliation(s)
- Juli Alonso
- Departament de Radiologia, Unitat de Ressonància Magnètica (IDI), Hospital Vall d'Hebron, Vall d'Hebron Institut of Research (VHIR), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Juan Córdoba
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; Servei de Medicina Interna-Hepatologia, Hospital Vall d'Hebron, Vall d'Hebron Institut of Research (VHIR), Barcelona, Spain
| | - Alex Rovira
- Departament de Radiologia, Unitat de Ressonància Magnètica (IDI), Hospital Vall d'Hebron, Vall d'Hebron Institut of Research (VHIR), Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
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12
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Hepatic Encephalopathy: From the Pathogenesis to the New Treatments. ISRN HEPATOLOGY 2014; 2014:236268. [PMID: 27335836 PMCID: PMC4890879 DOI: 10.1155/2014/236268] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 01/28/2014] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy is a frequent and serious complication of liver cirrhosis; the pathophysiology of this complication is not fully understood although great efforts have been made during the last years. There are few prospective studies on the epidemiology of this complication; however, it is known that it confers with high short-term mortality. Hepatic encephalopathy has been classified into different groups depending on the degree of hepatic dysfunction, the presence of portal-systemic shunts, and the number of episodes. Due to the large clinical spectra of overt EH and the complexity of cirrhotic patients, it is very difficult to perform quality clinical trials for assessing the efficacy of the treatments proposed. The physiopathology, clinical manifestation, and the treatment of HE is a challenge because of the multiple factors that converge and coexist in an episode of overt HE.
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13
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Long Z, Jiang YM, Li XR, Fadel W, Xu J, Yeh CL, Long LL, Luo HL, Harezlak J, Murdoch JB, Zheng W, Dydak U. Vulnerability of welders to manganese exposure--a neuroimaging study. Neurotoxicology 2014; 45:285-92. [PMID: 24680838 DOI: 10.1016/j.neuro.2014.03.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 03/01/2014] [Accepted: 03/19/2014] [Indexed: 01/19/2023]
Abstract
Increased manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn exposure occurs in different occupational settings, where the airborne Mn level and the size of respirable particulates may vary considerably. Recently the importance of the role of the cerebral cortex in Mn toxicity has been highlighted, especially in Mn-induced neuropsychological effects. In this study we used magnetic resonance imaging (MRI) to evaluate brain Mn accumulation using T1 signal intensity indices and to examine changes in brain iron content using T2* contrast, as well as magnetic resonance spectroscopy (MRS) to measure exposure-induced metabolite changes non-invasively in cortical and deep brain regions in Mn-exposed welders, Mn-exposed smelter workers and control factory workers with no measurable exposure to Mn. MRS data as well as T1 signal intensity indices and T2* values were acquired from the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. Smelters were exposed to higher air Mn levels and had a longer duration of exposure, which was reflected in higher Mn levels in erythrocytes and urine than in welders. Nonetheless, welders had more significant metabolic differences compared to controls than did the smelter workers, especially in the frontal cortex. T1 hyperintensities in the globus pallidus were observed in both Mn-exposed groups, but only welders showed significantly higher thalamic and hippocampal T1 hyperintensities, as well as significantly reduced T2* values in the frontal cortex. Our results indicate that (1) the cerebral cortex, in particular the frontal cortex, is clearly involved in Mn neurotoxic effects and (2) in spite of the lower air Mn levels and shorter duration of exposure, welders exhibit more extensive neuroimaging changes compared to controls than smelters, including measurable deposition of Mn in more brain areas. These results indicate that the type of exposure (particulate sizes, dust versus fume) and route of exposure play an important role in the extent of Mn-induced toxic effects on the brain.
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Affiliation(s)
- Zaiyang Long
- School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yue-Ming Jiang
- Department of Health Toxicology, Guangxi Medical University, Nanning, China.
| | - Xiang-Rong Li
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - William Fadel
- Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA
| | - Jun Xu
- School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chien-Lin Yeh
- School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Li-Ling Long
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hai-Lan Luo
- Department of Health Toxicology, Guangxi Medical University, Nanning, China
| | - Jaroslaw Harezlak
- Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA; Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - James B Murdoch
- Toshiba Medical Research Institute USA, Mayfield Village, OH, USA
| | - Wei Zheng
- School of Health Sciences, Purdue University, West Lafayette, IN, USA
| | - Ulrike Dydak
- School of Health Sciences, Purdue University, West Lafayette, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
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14
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Abstract
BACKGROUND Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS Trials were identified through the Cochrane Hepato-Biliary Group Controlled Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12 of 12, 2013), MEDLINE (1946 to January 2014), EMBASE (1974 to January 2014), and Science Citation Index-Expanded (1900 to January 2014). Manual searches in reference lists, conference proceedings, and online trial registers were also performed. SELECTION CRITERIA Randomised trials were included, irrespective of publication status or language. The primary analyses included data from randomised trials using a parallel-group design or the first period of cross-over trials. Paired data from cross-over trials were included in sensitivity analyses. DATA COLLECTION AND ANALYSIS Three review authors extracted data independently. Random-effects meta-analyses were performed as the result of an expected clinical heterogeneity. Fixed-effect meta-analyses, meta-regression analyses, subgroup analyses, and sensitivity analyses were performed to evaluate sources of heterogeneity and bias (systematic errors). Trial sequential analysis was used to control the risk of play of chance (random errors). MAIN RESULTS Five trials that randomly assigned 144 participants with overt hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy in the primary analyses (15/80 (19%) versus 14/80 (18%); odds ratio (OR) 2.99, 95% confidence interval (CI) 0.09 to 100.55; two trials) or when paired data from cross-over trials were included (OR 1.04, 95% CI 0.75 to 1.43). Clear evidence of intertrial heterogeneity was identified both in the primary analysis (I(2) = 65%) and when paired data from cross-over trials were included (I(2) = 40%).Dopamine agents had no beneficial or harmful effect on mortality (42/144 (29%) versus 38/144 (26%); OR 1.11, 95% CI 0.35 to 3.54; five trials). Trial sequential analyses demonstrated that we lacked information to refute or recommend the interventions for all outcomes. Dopamine agonists did not seem to increase the risk of adverse events. AUTHORS' CONCLUSIONS This review found no evidence to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to permit firm decisions on dopamine agents for patients with hepatic encephalopathy.
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Affiliation(s)
| | - Bodil Als‐Nielsen
- The Child and Youth ClinicDepartment of Paediatric Haematology/Oncology (5054)RigshospitaletUniversity Hospital of CopenhagenCopenhagenDenmark2200
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastro Unit, Medical DivisionKettegaards AlleHvidovreDenmark
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15
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Abstract
Systemic inflammation is common in liver failure and its acquisition is a predictor of hepatic encephalopathy severity. New studies provide convincing evidence for a role of neuroinflammation (inflammation of the brain per se) in liver failure; this evidence includes activation of microglia, together with increased synthesis in situ of the proinflammatory cytokines TNF, IL-1β and IL-6. Liver-brain signalling mechanisms in liver failure include: direct effects of systemic proinflammatory molecules, recruitment of monocytes after microglial activation, brain accumulation of ammonia, lactate and manganese, and altered permeability of the blood-brain barrier. Ammonia and cytokines might act synergistically. Existing strategies to reduce ammonia levels (including lactulose, rifaximin and probiotics) have the potential to dampen systemic inflammation, as does albumin dialysis, mild hypothermia and N-acetylcysteine, the latter two agents acting at both peripheral and central sites. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain oedema and encephalopathy in liver failure, as does the anti-TNF agent etanercept.
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16
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Butz M, May ES, Häussinger D, Schnitzler A. The slowed brain: Cortical oscillatory activity in hepatic encephalopathy. Arch Biochem Biophys 2013; 536:197-203. [DOI: 10.1016/j.abb.2013.04.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/04/2013] [Accepted: 04/08/2013] [Indexed: 12/12/2022]
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17
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El Hiba O, Gamrani H, Chatoui H, Ahboucha S. Loss of tyrosine hydroxylase expression within the nigro-striato-cortical pathways in the cirrhotic rat: the possible restorative effect of the neurosteroid dehydroepiandrosterone sulfate. Acta Histochem 2013; 115:637-645. [PMID: 23453752 DOI: 10.1016/j.acthis.2013.01.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 01/21/2013] [Accepted: 01/23/2013] [Indexed: 12/25/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disorder occurring as a consequence of both acute and chronic liver failure. Advanced HE is generally accompanied with extrapyramidal symptoms including rigidity and tremor, which may reflect alterations of the dopaminergic system. Recently we reported a beneficial effect of the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) in cirrhotic rats, however the mechanisms of such an effect by DHEAS were not addressed. In the present study, we describe the changes of the dopaminergic system occurring in the cirrhotic rats and concomitantly we investigated the effect of DHEAS on this system in Sprague-Dawley rats using the expression of tyrosine hydroxylase (TH) as a neuronal marker. Rats were submitted to bile duct ligation (BDL) surgery and TH immunohistochemistry was assessed in the Substantia nigra pars compacta (SNc), striatum, ventral tegmental area (VTA) and the cortex. TH immunoreactivity showed a significant diminution in both SNc and VTA concomitantly with the cortical and the striatal outputs in the BDL rats vs. controls. Three daily injections of 5mg/kg of DHEAS to BDL rats significantly normalized TH expression decrease in both SNc and VTA as well as dopaminergic projections to the striatum and the cortex of BDL rats. The present data support an involvement of the dopaminergic system in mild HE and a possible beneficial effect of the neurosteroid DHEAS as a potential pharmacological treatment of mild HE.
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Affiliation(s)
- Omar El Hiba
- Neurosciences, Pharmacology and Environment Unit, Faculty of Sciences Semlalia, Cadi University Ayyad, Marrakesh, Morocco
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18
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Butterworth RF. Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. Metab Brain Dis 2013; 28:261-7. [PMID: 23086199 DOI: 10.1007/s11011-012-9341-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 10/07/2012] [Indexed: 12/28/2022]
Abstract
Acquired hepatolenticular degeneration, also known as "Parkinsonism in cirrhosis" is characterized by extrapyramidal symptoms including hypokinesia, dystonia and rigidity that are rapidly progressive and may be independent of the severity of cognitive dysfunction. Magnetic resonance imaging reveals T1-weighted hyperintense signals in both globus pallidus and substantia nigra. Estimates of the prevalence of Parkinsonism in cirrhosis have been reported as high as 21 %. The cause of Parkinsonism in cirrhosis has been attributed to manganese deposition in basal ganglia structures, leading to the dysfunction of the dopaminergic neurotransmitter system. In particular, there is evidence from both spectroscopic and biochemical investigations for damage to (or dysfunction of) presynaptic dopamine transporters together with a loss of post-synaptic dopamine receptors in basal ganglia of affected patients. Therapeutic options are limited; ammonia-lowering strategies are without substantial benefit, and an effective manganese chelator is not available. In many patients, L-Dopa replacement therapy and the dopamine receptor agonist bromocriptine are beneficial, and liver transplantation is generally effective. However, reports of post-transplant residual extrapyramidal symptoms suggest an element of irreversibility in some cases.
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Affiliation(s)
- Roger F Butterworth
- Unité de recherche en neurosciences, Hôpital Saint-Luc (CHUM), Université de Montréal, Montréal, Canada.
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19
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Manganese and ammonia interactions in the brain of cirrhotic rats: effects on brain ammonia metabolism. Neurochem Res 2012; 37:1074-84. [PMID: 22290316 DOI: 10.1007/s11064-012-0710-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 01/13/2012] [Accepted: 01/18/2012] [Indexed: 01/18/2023]
Abstract
Hepatic encephalopathy is a major complication of cirrhosis. Ammonia and manganese have been associated with hepatic encephalopathy underlying mechanisms. Motor impairment and brain edema are common signs of hepatic encephalopathy. In the present study a model of liver damage in rats was combined with ammonia and manganese exposure to evaluate the role of these substances separately and their interactions on brain glutamine, water content and motor coordination. Additionally, we explored brain levels of each substance -Mn and ammonia- in the presence or absence of the other. Liver damage was induced by bile duct ligation. Rats were exposed to MnCl2 in drinking water (1 mg Mn/ml) and to ammonia in chow pellets containing 20% ammonium acetate (w/w). As expected, manganese and ammonia levels increased in the brain of cirrhotic rats exposed to these substances; in these animals, glutamine brain levels also increased and positively correlated with tissue water content in cortex. A three way-ANOVA showed that manganese favored ammonia and glutamine accumulation in brain, and possibly their subsequent deleterious effects, as evidenced by the fact that manganese and ammonia accumulation in the brain of cirrhotic rats severely affected motor function. These results suggest that even when controlling ammonia levels in cirrhotic patients, reduction of manganese intake is also a potential strategy to be considered in clinical practice.
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20
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Frederick RT. Extent of reversibility of hepatic encephalopathy following liver transplantation. Clin Liver Dis 2012; 16:147-58. [PMID: 22321470 DOI: 10.1016/j.cld.2011.12.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although hepatic encephalopathy (HE) is prevalent in the cirrhotic population, it has also been considered a potentially reversible condition. Liver transplantation represents the ultimate reversal of the decompensated cirrhotic state and should provide the best option for the reversibility of HE. However, the neurologic compromise associated with HE in the cirrhotic patient may not be completely reversible. Theories regarding fixed structural and reversible metabolic deficits as well as persistence of the hyperdynamic state with continued portosystemic shunting have been proposed to explain this lack of complete reversibility. Whether this remnant neurologic deficit is clinically significant remains unclear.
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Affiliation(s)
- R Todd Frederick
- Division of Hepatology, Department of Transplantation, California Pacific Medical Center, 2340 Clay Street, 3rd Floor, San Francisco, CA 94115, USA.
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21
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Ditisheim S, Giostra E, Burkhard PR, Goossens N, Mentha G, Hadengue A, Spahr L. A capillary blood ammonia bedside test following glutamine load to improve the diagnosis of hepatic encephalopathy in cirrhosis. BMC Gastroenterol 2011; 11:134. [PMID: 22151412 PMCID: PMC3253684 DOI: 10.1186/1471-230x-11-134] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 12/08/2011] [Indexed: 12/29/2022] Open
Abstract
Background Hepatic encephalopathy (HE) is a frequent and severe complication of cirrhosis. A single determination of ammonia in venous blood correlates poorly with neurological symptoms. Thus, a better biological marker is needed. Aim To make a diagnosis of HE, we explored the value of ammonia in capillary blood, an equivalent to arterial blood, measured at bedside following an oral glutamine challenge. Methods We included 57 patients (age 56 yrs; M/F: 37/20) with cirrhosis (alcoholic = 42; MELD score 13.8 [7-29], esophageal varices = 38) and previous episodes of HE (n = 19), but without neurological deficits at time of examination, and 13 healthy controls (age 54 yrs). After psychometric tests and capillary (ear lobe) blood ammonia measurements, 20 gr of glutamine was administered orally. Tests were repeated at 60 minutes (+ blood ammonia at 30'). Minimal HE was diagnosed if values were > 1.5 SD in at least 2 psychometric tests. Follow-up lasted 12 months. Results The test was well tolerated (nausea = 1; dizziness = 1). Patients showed higher values of capillary blood ammonia over time as compared to controls (0'-30'-60 minutes: 75, 117, 169 versus 52, 59, 78 umol/L, p < 0.05). At baseline, 25 patients (44%) had minimal HE, while 38 patients (67%) met the criteria for HE at 60 minutes (chi2: p < 0.01). For the diagnosis of minimal HE, using the ROC curve analysis, baseline capillary blood ammonia showed an AUC of 0.541 (CI: 0.38-0.7, p = 0.6), while at 60 minutes the AUC was 0.727 (CI: 0.58-0.87, p < 0.006). During follow-up, 18 patients (31%) developed clinical episodes of HE. At multivariate analysis, the MELD score (1.12 [1.018-1.236]), previous episodes of HE (3.2[1.069-9.58]), but not capillary blood ammonia, were independent predictors of event. Conclusions In patients with cirrhosis and normal neurological examination, bedside determination of ammonia in capillary blood following oral glutamine load is well tolerated and achieves a better diagnostic performance for minimal HE than basal capillary ammonia levels. However, capillary blood ammonia is a poor predictor of development of clinically overt HE.
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Affiliation(s)
- Saskia Ditisheim
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, 4, Rue Gabrielle Perret-Gentil, 1211 Geneva, Switzerland
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22
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Lin WC, Chou KH, Chen CL, Chen CH, Chen HL, Feekes JA, Hsu NW, Li SH, Cheng YF, Lin CP. Significant volume reduction and shape abnormalities of the basal ganglia in cases of chronic liver cirrhosis. AJNR Am J Neuroradiol 2011; 33:239-45. [PMID: 22095962 DOI: 10.3174/ajnr.a2769] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE Chronic liver disease frequently includes cognitive and movement disorders, suggesting an alteration of the striatum. With the exception of hyperintensities evident on T1-weighted images indicative of Mn deposition, radiographic findings of the BG are nonspecific. Volumetric and morphometric analysis of DGM is limited. Whether DGM undergoes degeneration and whether this change is associated with pallidal hyperintensity and cognitive performance are currently unknown in patients with cirrhosis. MATERIALS AND METHODS The DGM volumes of 28 patients with chronic cirrhosis and 28 control patients were compared. Using 3D high-resolution MR images, the volume and shape of each structure were automatically analyzed by the FSL. Correlations between the DGM volume and other clinical variables, including the pallidal signal intensity, were assessed by multiple regression analysis. RESULTS Patients with Child B and Child C liver disease had significantly smaller bilateral putaminal volumes than control patients, and patients with Child C also demonstrated smaller left caudate nucleus and left amygdala volumes than control patients. Pallidal hyperintensity correlated with smaller striatum volume, which was linearly related to worse cognitive performance. The nonuniform distributed shape abnormalities in the striatum further support the ascending spiral interconnecting theory of the striatum. CONCLUSIONS These findings strongly suggest lower DGM volume develops according to the severity of the liver cirrhosis. The Mn deposition might contribute the striatum deficit. These findings support the value of additional psychomotor research associated with liver cirrhosis.
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Affiliation(s)
- W-C Lin
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Rivera-Mancía S, Ríos C, Montes S. Manganese accumulation in the CNS and associated pathologies. Biometals 2011; 24:811-25. [PMID: 21533671 DOI: 10.1007/s10534-011-9454-1] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 04/13/2011] [Indexed: 12/13/2022]
Abstract
Manganese (Mn) is an essential metal for life. It is a key constituent of clue enzymes in the central nervous system, contributing to antioxidant defenses, energetic metabolism, ammonia detoxification, among other important functions. Until now, Mn transport mechanisms are partially understood; however, it is known that it shares some mechanisms of transport with iron. CNS is susceptible to Mn toxicity because it possesses mechanisms that allow Mn entry and favor its accumulation. Cases of occupational Mn exposure have been extensively reported in the literature; however, there are other ways of exposure, such as long-term parental nutrition and liver failure. Manganism and hepatic encephalopathy are the most common pathologies associated with the effects of Mn exposure. Both pathologies are associated with motor and psychiatric disturbances, related in turn to mechanisms of damage such as oxidative stress and neurotransmitters alterations, the dopaminergic system being one of the most affected. Although manganism and Parkinson's disease share some characteristics, they differ in many aspects that are discussed here. The mechanisms for Mn transport and its participation in manganism and hepatic encephalopathy are also considered in this review. It is necessary to find an effective therapeutic strategy to decrease Mn levels in exposed individuals and to treat Mn long term effects. In the case of patients with chronic liver failure it would be worthwhile to test a low-Mn diet in order to ameliorate symptoms of hepatic encephalopathy possibly related to Mn accumulation.
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Affiliation(s)
- Susana Rivera-Mancía
- Neurochemistry Department, National Institute of Neurology and Neurosurgery 'Manuel Velasco Suárez', Insurgentes Sur 3877, La Fama, Tlalpan, Mexico City 14269, Mexico
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Kang JH, Tsai MC, Lin CC, Lin HL, Lin HC. Increased risk of Parkinsonism among patients with cirrhosis: a 7-year follow-up study. Liver Int 2011; 31:685-91. [PMID: 21457440 DOI: 10.1111/j.1478-3231.2010.02432.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS Previous studies have suggested that hepatic (toxic-metabolic) encephalopathy, the major complication of cirrhosis, is a neuropsychiatric disorder typically seen in patients with liver dysfunction after exclusion of other known brain disease. This study aims to investigate the risk for parkinsonism during a 7-year follow-up period after a diagnosis of cirrhosis. METHODS In total, 1361 patients with cirrhosis and 6805 comparison patients without cirrhosis were included in this study. Each patient was then individually tracked for 7 years from the time of their initial diagnosis of cirrhosis to identify those who developed parkinsonism during the follow-up period. Stratified Cox proportional hazard regressions were conducted to calculate the hazard of parkinsonism for the two groups during the follow-up period, after adjusting for patient's age, monthly income, level of urbanization and geographic location. RESULTS Of the total 8166 sampled patients, 141 (1.7%) developed parkinsonism during the follow-up period, 48 from the study group (3.5% of the patients with cirrhosis) and 93 from the comparison group (1.4% of patients in the comparison group). Stratified Cox proportional hazard regressions show that the hazard for parkinsonism for patients with cirrhosis was 2.65 times as high (95% confidence interval=1.85-3.80, P<0.001) as the patients in the comparison group over the 7-year follow-up period, after adjusting for patient's age, monthly income, level of urbanization and the geographic location of the community in which the patient resided. CONCLUSIONS We concluded that cirrhosis significantly increased the risk of parkinsonism.
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Affiliation(s)
- Jiunn-Horng Kang
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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Zhang LJ, Lu GM, Yin JZ, Qi J. Metabolic changes of anterior cingulate cortex in patients with hepatic cirrhosis: A magnetic resonance spectroscopy study. Hepatol Res 2010; 40:777-85. [PMID: 20649817 DOI: 10.1111/j.1872-034x.2010.00681.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIM The anterior cingulate cortex (ACC) plays an important role in cognitive functions. The purpose of this study is to compare metabolite concentrations in the ACC of cirrhotic patients with normal controls, and to correlate metabolite changes with Child-Pugh class and with severity of hepatic encephalopathy (HE). METHODS Fifty-two cirrhotic patients and 30 healthy volunteers were included in this study. All subjects performed the number connection test type A (NCT-A) and digital symbol test (DST) before multiple resonance (MR) examinations. Single-voxel proton MR spectroscopy (MRS) data in the ACC were acquired on a 1.5-T scanner. The ratios of all metabolites to creatine and phosphocreatine (Cr) were obtained. Statistical analysis was performed to evaluate the difference between control and cirrhotic patients, with respect to metabolite ratios. The correlation between metabolite ratios and Child-Pugh scale, severity of HE, venous ammonia and neuropsychiatric test results was analyzed. RESULTS The ratios of choline (Cho)/Cr and myo-inositol (mIns)/Cr were significantly lower, and the ratio of glutamine- glutamate (Glx)/Cr was significantly higher in cirrhotic patients than those in controls (P < 0.001). mIns/Cr correlated negatively with Child-Pugh scale (r = -0.496, P < 0.001) and HE degree (r = -0.313, P < 0.05). Venous ammonia had a significant correlation with Cho/Cr (r = -0.329, P < 0.05) and mIns/Cr (r = -0.347, P < 0.05). No statistical correlation between metabolite ratios and neuropsychological tests was found for cirrhotic patients, but mIns/Cr did have a statistical correlation with NCT-A (r = -0.270, P < 0.05) and DST (r = 0.463, P < 0.001) when all subjects were included in the analysis. CONCLUSION Significant metabolite changes were seen in the ACC in cirrhotic patients. Of the metabolites examined, the mIns/Cr level in the ACC was most closely associated with the severity of HE and hepatic functional reserve reflected by Child-Pugh scale.
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Affiliation(s)
- Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu Province, China
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Butz M, Timmermann L, Braun M, Groiss SJ, Wojtecki L, Ostrowski S, Krause H, Pollok B, Gross J, Südmeyer M, Kircheis G, Häussinger D, Schnitzler A. Motor impairment in liver cirrhosis without and with minimal hepatic encephalopathy. Acta Neurol Scand 2010; 122:27-35. [PMID: 20003084 DOI: 10.1111/j.1600-0404.2009.01246.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM Manifest hepatic encephalopathy (HE) goes along with motor symptoms such as ataxia, mini-asterixis, and asterixis. The relevance of motor impairments in cirrhotics without and with minimal HE (mHE) is still a matter of debate. PATIENTS AND METHODS We tested three different groups of patients with liver cirrhosis: no signs of HE (HE 0), mHE, and manifest HE grade 1 according to the West Haven criteria (HE 1). All patients (n = 24) and 11 healthy control subjects were neuropsychometrically tested including critical flicker frequency (CFF), a reliable measure for HE. Motor abilities were assessed using Fahn Tremor Scale and International Ataxia Rating Scale. Fastest alternating index finger movements were analyzed for frequency and amplitude. RESULTS Statistical analyses showed an effect of HE grade on tremor and ataxia (P < 0.01). Additionally, both ratings yielded strong negative correlation with CFF (P < 0.01, R = -0.5). Analysis of finger movements revealed an effect of HE grade on movement frequency (P < 0.03). Moreover, decreasing movement frequency and increasing movement amplitude parallel decreasing CFF (P < 0.01, R = 0.6). CONCLUSION Our results indicate that ataxia, tremor, and slowing of finger movements are early markers for cerebral dysfunction in HE patients even prior to neuropsychometric alterations becoming detectable.
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Extrapyramidal signs predict the development of overt hepatic encephalopathy in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2010; 22:519-25. [PMID: 20010298 DOI: 10.1097/meg.0b013e328333df0f] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS The long-term evolution of cirrhotic patients with extrapyramidal signs has not yet been studied. We have investigated the influence of extrapyramidal signs on the prognosis, evolution, and quality of life of patients with liver cirrhosis. METHODS Forty-six patients with cirrhosis were followed up and 18 of them were reevaluated, a mean of 45 months later. Cognitive impairment was measured with psychometric tests (Trail-Making Test part A, Grooved-Pegboard, Block-Design, Oral Symbol Digit and Stroop Test). Extrapyramidal signs were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Health-related quality of life was measured using the SF-36 scale and the Chronic Liver Disease Questionnaire. RESULTS Eleven of the 46 patients who were followed up developed overt hepatic encephalopathy (HE) during the follow-up. The presence of extrapyramidal signs was the unique factor that predicted overt HE and patients with basal higher score in the part 3 of the UPDRS developed overt HE more frequently [hazard ratio=1.29; 95% confidence interval (1.04-1.60) P=0.023]. In the 18 reevaluated patients, there was an increase in the score of the UPDRS part 3 after follow-up. There was a worsening in the score values of the block design and the Number Connection Test. In health-related quality of life scales, patients scored better in the area of mental health of the SF-36 scale. Patients with extrapyramidal signs persisted with worse scores in several items of the SF-36 scale and the Chronic Liver Disease Questionnaire. CONCLUSION The presence of extrapyramidal signs in patients with liver cirrhosis predicts the development of overt HE. These signs increased along the follow-up, and remain a bad influence on quality of life.
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29
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Chang Y, Woo ST, Lee JJ, Song HJ, Lee HJ, Yoo DS, Kim SH, Lee H, Kwon YJ, Ahn HJ, Ahn JH, Park SJ, Weon YC, Chung IS, Jeong KS, Kim Y. Neurochemical changes in welders revealed by proton magnetic resonance spectroscopy. Neurotoxicology 2009; 30:950-7. [PMID: 19631686 DOI: 10.1016/j.neuro.2009.07.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Revised: 07/13/2009] [Accepted: 07/14/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Occupational and environmental exposure to manganese (Mn) is associated with various neurobehavioral and movement dysfunctions. However, few studies have systemically examined the neurochemical effects of Mn exposure. OBJECTIVES We examined typical changes in cerebral metabolite ratios in welders chronically exposed to Mn, compared with control individuals, using proton magnetic resonance spectroscopy (MRS), investigated whether an abnormality in brain metabolism is associated with neurobehavioral changes, and assessed possible implications of chronic Mn exposure. METHODS Thirty-five welders chronically exposed to Mn and 20 age-matched healthy subjects underwent single-voxel MRS at short echo time to assess the N-acetylaspartate (NAA), myoinositol (mI), total choline (tCho), and glutamine plus glutamate (Glx) levels, each of which was expressed as a ratio to total creatine (tCr). Neurobehavioral tests were also performed to define cognitive status. RESULTS NAA/tCr, Glx/tCr, and tCho/tCr ratios in the frontal gray matter (anterior cingulate cortex; ACC) and parietal white matter did not differ significantly between welders and control subjects. These metabolite ratios did not correlate significantly with blood Mn concentration or neurobehavioral parameters. However, mI levels in the ACC, but not in the parietal white matter, were significantly reduced in welders compared with control individuals (P<0.01). Furthermore, in the frontal lobe of the brain, the mI/tCr ratio was significantly correlated with verbal memory scores as well as blood Mn concentration (P<0.05). CONCLUSIONS The cognitive decline observed in welders exposed to Mn was associated with a decreased mI/tCr ratio in the ACC. The depletion of mI in welders may reflect possible glial cell swelling and/or detoxification processes associated with long-term exposure to Mn.
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Affiliation(s)
- Yongmin Chang
- Department of Molecular Medicine, Kyungpook National University College of Medicine, Kyungpook National University Hospital, Daegu, South Korea
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30
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Ferrara J, Jankovic J. Acquired hepatocerebral degeneration. J Neurol 2009; 256:320-32. [PMID: 19224314 DOI: 10.1007/s00415-009-0144-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2008] [Accepted: 10/20/2008] [Indexed: 12/20/2022]
Abstract
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.
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Affiliation(s)
- Joseph Ferrara
- Dept. of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, Texas 77030, USA
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31
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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; 53:2793-8. [PMID: 18688722 DOI: 10.1007/s10620-008-0383-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2006] [Accepted: 06/05/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hyperintense signals in the basal ganglia, namely the globus pallidus, have been reported on magnetic resonance imaging (MRI) in 70-100% of patients with cirrhosis of the liver. Deposition of paramagnetic substances, particularly manganese (Mn), has been reported to be responsible for these hyperintense signals. They are found in cirrhotics with or without overt/subclinical hepatic encephalopathy. Deposition of Mn has been attributed to hepatocellular failure and/or portosystemic shunting. Reports of MRI brain findings in patients with extra hepatic portal venous obstruction (EHPVO) and non-cirrhotic portal fibrosis (NCPF) are scanty in the literature. AIMS The purpose was to determine the basal ganglia changes on MRI in patients with EHPVO and NCPF and to compare it with patients with cirrhosis of the liver. PATIENTS AND METHODS A total of 27 patients (EHPVO = 10, mean age 28.4 +/- 19.0 years, NCPF = 7, mean age 37.1 +/- 10.4 years, cirrhosis = 10, mean age 47.0 +/- 19.6 years) was studied prospectively from January to December 2001. MRI of the brain was done with a standard spin echo axial T1- and fast spin echo T2-weighted scan obtained on a 1.5-T MRI unit. Two radiologists in a blinded fashion graded the signal intensity of basal ganglia on T1-weighted (T1 W) sequences by comparing it with the adjacent unaffected grey matter. RESULTS None of the patients with EHPVO or NCPF had any past history of hepatic decompensation and/or overt encephalopathy. Seven (70%) of the cirrhotics had a past history of overt encephalopathy. None of the patients with EHPVO showed any hyperintensity of basal ganglia on T1-weighted MRI images. Hyperintense globus pallidus was seen in four (57%) and eight (80%) patients with NCPF and cirrhosis, respectively. CONCLUSION Hyperintense globus pallidus on MRI is common in patients liver cirrhosis and also occurs in patients with NCPF. Patients with EHPVO do not have hyperintense globus pallidus on T1-weighted MRI images.
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Affiliation(s)
- Kshaunish Das
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Shah NJ, Neeb H, Kircheis G, Engels P, Häussinger D, Zilles K. Quantitative cerebral water content mapping in hepatic encephalopathy. Neuroimage 2008; 41:706-17. [PMID: 18456518 DOI: 10.1016/j.neuroimage.2008.02.057] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2007] [Revised: 02/19/2008] [Accepted: 02/21/2008] [Indexed: 11/17/2022] Open
Abstract
There is increasing evidence that the pathophysiology of hepatic encephalopathy is tightly associated with low-grade cerebral oedema; however, no method has yet specifically and unambiguously confirmed this hypothesis in vivo. The current study describes the quantitative measurement of localised water content using MRI in a cohort of 38 patients suffering from hepatic encephalopathy. A significant global increase in cerebral water content was observed in white matter whereas water content in grey matter was globally unaffected. However, significant spatial variations in the water content distribution, especially in grey matter, were observed and were correlated with disease grade and critical flicker frequency. In addition, regions-of-interest were defined and a significant change in water content with disease grade was found in the frontal and occipital white matter, the globus pallidus, the anterior limb of the internal capsule and the putamen. No association of water content and HE grade was established for the occipital visual and frontal cortices, the thalamus, the posterior limb of the internal capsule, the caudate nucleus and the coronal white matter. In conclusion, the measurements presented here are the first direct and quantitative demonstration of the presence of low-grade cerebral oedema in patients with hepatic encephalopathy. Further, absolute changes in tissue water content were quantified for various brain regions.
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Affiliation(s)
- N J Shah
- Institute of Neuroscience and Biophysics 3 - Medicine, Research Centre Jülich GmbH, 52425 Jülich, Germany.
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33
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Weissenborn K, Ahl B, Fischer-Wasels D, van den Hoff J, Hecker H, Burchert W, Köstler H. Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 2007; 56:1736-42. [PMID: 17660226 PMCID: PMC2095692 DOI: 10.1136/gut.2006.110569] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatic encephalopathy is considered to be mainly caused by increased ammonia metabolism of the brain. If this hypothesis is true, cerebral glucose utilisation, which is considered to represent brain function, should be closely related to cerebral ammonia metabolism. The aim of the present study was to analyse whether cerebral ammonia and glucose metabolism in cirrhotic patients with early grades of hepatic encephalopathy are as closely related as could be expected from current hypotheses on hepatic encephalopathy. METHODS (13)N-ammonia and (18)F-fluorodesoxyglucose positron emission tomography, magnetic resonance imaging and magnetic resonance spectroscopy (MRS) were performed in 21 cirrhotic patients with grade 0-1 hepatic encephalopathy. Quantitative values of cerebral ammonia uptake and retention rate and glucose utilisation were derived for several regions of interest and were correlated with the MRS data of the basal ganglia, white matter and frontal cortex. RESULTS A significant correlation between plasma ammonia levels and cerebral ammonia metabolism, respectively, and MRS alterations could be shown only for white matter. In contrast, MRS alterations in all three regions studied were significantly correlated with the glucose utilisation of several brain regions. Cerebral ammonia and glucose metabolism were not correlated. CONCLUSION Increase of cerebral ammonia metabolism is an important but not exclusive causal factor for the development of hepatic encephalopathy.
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Affiliation(s)
- Karin Weissenborn
- Department of Neurology, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
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Neuropsychological Aspects of Liver Disease and its Treatment. Neurochem Res 2007; 33:683-90. [DOI: 10.1007/s11064-007-9522-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2007] [Indexed: 01/18/2023]
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Cauli O, Mlili N, Llansola M, Felipo V. Motor activity is modulated via different neuronal circuits in rats with chronic liver failure than in normal rats. Eur J Neurosci 2007; 25:2112-22. [PMID: 17439495 DOI: 10.1111/j.1460-9568.2007.05435.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The mechanisms by which liver failure alters motor function remain unclear. It has been suggested that liver disease alters the neuronal circuit between basal ganglia and cortex that modulates motor function. Activation of group I metabotropic glutamate receptors in the nucleus accumbens (NAcc) by injecting (S)-3,5-dihydroxyphenylglycine (DHPG) activates this circuit and induces locomotion We analysed by in vivo brain microdialysis the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS). We inserted cannulae in the NAcc and microdialysis probes in the NAcc, ventral pallidum (VP), substantia nigra pars reticulata (SNr), medio-dorsal thalamus (MDT), ventro-medial thalamus (VMT) or prefrontal cortex (PFCx). We injected DHPG in the NAcc and analysed extracellular neurotransmitters concentration in these areas. The results indicate that in control rats DHPG induces locomotion by activating the 'normal' neuronal circuit: NAcc --> VP --> MDT --> PFCx. In PCS rats this circuit is not activated. In PCS rats, DHPG injection activates an 'alternative' circuit: NAcc --> SNr --> VMT --> PFCx. This circuit is not activated in control rats. DHPG injection increases dopamine in the NAcc of control but not of PCS rats, and glutamate in PCS but not in control rats. DHPG-induced increase in dopamine would activate the 'normal' neuronal circuit, while an increase in glutamate would activate the 'alternative' circuit. The identification of the mechanisms responsible for altered motor function and coordination in liver disease would allow designing treatments to improve motor function in patients with hepatic encephalopathy.
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Affiliation(s)
- Omar Cauli
- Laboratory of Neurobiology, Centro de Investigacion Príncipe Felipe, Valencia, Spain
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36
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Kim J, Kim JM, Kim YK, Shin JW, Choi SH, Kim SE, Kim Y. Dopamine transporter SPECT of a liver cirrhotic with atypical parkinsonism. INDUSTRIAL HEALTH 2007; 45:497-500. [PMID: 17634700 DOI: 10.2486/indhealth.45.497] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
High level of exposure to manganese (Mn) can cause a clinically and pathophysiologically distinct syndrome from idiopathic Parkinson's disease (PD). We describe the clinical features and results of [123I]-fluoropropyl (FP)-CIT SPECT of a liver cirrhotic with atypical parkinsonism. The patient developed atypical parkinsonian features associated with elevated blood Mn from hepatic dysfunction. [123I]-FP-CIT brain SPECT images of dopamine transporter (DAT) demonstrated overall normal range of DAT uptake in the striatum although there were scattered small hypodense regions. The globus pallidum had increased signal on T1-weighted magnetic resonance imaging (MRI). All these findings are compatible with those of manganism, and are remarkably different from that in PD.
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Affiliation(s)
- Jongchul Kim
- Department of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, South Korea
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37
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Pidoplichko VI, Dani JA. Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proc Natl Acad Sci U S A 2006; 103:11376-80. [PMID: 16847263 PMCID: PMC1544094 DOI: 10.1073/pnas.0600768103] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Acid-sensitive ion channels (ASICs) are proton-gated and belong to the family of degenerin channels. In the mammalian nervous system, ASICs are most well known in sensory neurons, where they are involved in nociception, occurring when injury or inflammation causes acidification. ASICs also are widely expressed in the CNS, and some synaptic roles have been revealed. Because neuronal activity can produce pH changes, ASICs may respond to local acidic transients and alter the excitability of neuronal circuits more widely than is presently appreciated. Furthermore, ASICs have been found to underlie calcium transients that contribute to neuronal death. Degeneration of midbrain dopamine neurons is characteristic of advanced idiopathic Parkinson's disease. Therefore, we tested for functional ASICs in midbrain dopamine neurons of the ventral tegmental area and substantia nigra compacta. Patch-clamp electrophysiology applied to murine midbrain slices revealed abundant acid-sensitive channels. The ASICs were gated and desensitized by extracellular application of millimolar concentrations of NH(4)Cl. Although the NH(4)Cl solution contains micromolar concentrations of NH(3) at pH 7.4, our evidence indicates that NH(4)(+) gates the ASICs. The proton-gated and the ammonium-gated currents were inhibited by tarantula venom (psalmotoxin), which is specific for the ASIC1a subtype. The results show that acid-sensitive channels are expressed in midbrain dopamine neurons and suggest that ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus. The ammonium sensitivity suggests a role for ASIC1s in hepatic encephalopathy, cirrhosis, and other neuronal disorders that are associated with hyperammonemia.
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Affiliation(s)
- Volodymyr I. Pidoplichko
- Department of Neuroscience, Menninger Department of Psychiatry and Behavioral Science, and Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030
| | - John A. Dani
- Department of Neuroscience, Menninger Department of Psychiatry and Behavioral Science, and Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030
- *To whom correspondence should be addressed. E-mail:
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Clementi V, Tonon C, Lodi R, Malucelli E, Barbiroli B, Iotti S. Assessment of glutamate and glutamine contribution to in vivo N-acetylaspartate quantification in human brain by (1)H-magnetic resonance spectroscopy. Magn Reson Med 2006; 54:1333-9. [PMID: 16265633 DOI: 10.1002/mrm.20703] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
N-Acetylaspartate (NAA) is one of the most important metabolites detectable by brain (1)H-MRS being considered an index of neuronal integrity. At the low magnetic field used in most clinical settings beta,gamma-glutamate/glutamine (Glx) resonances are very close and partially overlap the methyl-NAA resonance interfering with NAA quantification especially at low TE and in the presence of increased Glx signals. NAA overestimation due to Glx on a set of model solutions containing NAA, glutamate, and glutamine in variable amounts was evaluated and the result tested in vivo in six healthy controls and five age- and sex-matched patients with hepatic encephalopathy (HE), the latter having an increased Glx content. A method to assess in vivo the NAA overestimation caused by Glx is proposed. A perfect match was obtained between the assessment of Glx contamination on the NAA of healthy controls and that obtained on the model solutions. However, a substantial difference in NAA overestimation was found between controls and HE patients that cannot be explained by our model. An interpretative hypothesis is provided.
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Affiliation(s)
- Valeria Clementi
- Biochimica Clinica, Dipartimento di Medicina Clinica e Biotecnologia Applicata "D Campanacci," Università di Bologna, Bologna, Italy
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Jover R, Madaria E, Felipo V, Rodrigo R, Candela A, Compañ A. Animal models in the study of episodic hepatic encephalopathy in cirrhosis. Metab Brain Dis 2005; 20:399-408. [PMID: 16382350 DOI: 10.1007/s11011-005-7925-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The availability of an animal model is crucial in studying the pathophysiological mechanisms of disease and to test possible therapies. Now, there are several models for the study of liver diseases, but there still remains a lack of a satisfactory animal model of chronic liver disease with hepatic encephalopathy (HE) and abnormalities in nitrogen metabolism, as seen in humans. In rats, two models of chronic HE are widely used: rats after portacaval anastomosis (PCA) and rats with chronic hyperammonemia. The first one mimics the situation induced in cirrhosis by collateral circulation, and has the problem of the absence of hepatocellular injury. The model of hyperammonemia is useful to study the effect of ammonia as a brain toxic substance, but also lacks liver failure. Bile-duct ligation has been used to induce cirrhosis and could also be a model of HE, probably with the addition of a precipitant factor. An ideal model of HE in chronic liver disease must have liver cirrhosis and a precipitant factor of HE; it must also show neuropathological characteristic findings of HE, neurochemical alterations in the main pathways impaired in these complications of cirrhosis, and low-grade brain edema.
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Affiliation(s)
- Rodrigo Jover
- Gastroenterology Department, Hospital General Universitario de Alicante, Alicante, Spain
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40
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Timmermann L, Butz M, Gross J, Kircheis G, Häussinger D, Schnitzler A. Neural synchronization in hepatic encephalopathy. Metab Brain Dis 2005; 20:337-46. [PMID: 16382344 DOI: 10.1007/s11011-005-7916-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatic encephalopathy (HE) is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. A number of pathological processes affecting glial and neuronal function have been identified, including hyper-ammonia, changes within the excitatory and inhibitory transmitter systems, as well as osmolytic changes with consecutive cell swelling. One explanation how these pathological processes result in neurological deficits in HE is the concept of pathologically synchronized oscillations within and between relevant brain regions. A number of studies suggest that the cognitive deficits and the reduced level of alertness in patients with HE can be attributed to a significantly slowed and pathologically synchronized spontaneous oscillatory brain activity, depending on the grade of HE. Moreover, HE motor symptoms, like postural tremor called"mini asterixis," have recently been shown to be associated with abnormal thalamo-cortical and cortico-muscular synchronization. Indirect evidence exists from studies of processing and recognition of flicker stimuli that in HE slowing of oscillations also occurs in the visual system. Taken together, pathological synchronization of neuronal activity may turn out to be a promising pathophysiological concept for linking neuronal dysfunction to the diversity of clinical deficits in HE.
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Affiliation(s)
- Lars Timmermann
- Department of Neurology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
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41
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Cauli O, Llansola M, Rodrigo R, El Mlili N, Errami M, Felipo V. Altered modulation of motor activity by group I metabotropic glutamate receptors in the nucleus accumbens in hyperammonemic rats. Metab Brain Dis 2005; 20:347-58. [PMID: 16382345 DOI: 10.1007/s11011-005-7918-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
One of the neurological complications in hepatic encephalopathy is the impairment of motor coordination and function. Clinical signs of basal ganglia, cortico-spinal and cerebellar dysfunction have been commonly detected in these patients. We are studying the molecular bases of the alterations in motor coordination and function in hepatic encephalopathy. Hyperammonemia is considered the main factor responsible for the neurological alterations in patients with hepatic encephalopathy. Activation of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAcc) induces locomotion in rats. Asa first step in our studies on the alterations in motor co-ordination and function in hyperammonemia and hepatic encephalopathy we studied whether the control of motor function by mGluRs in the NAcc is altered in hyperammonemic rats. The locomotor activity induced by injection into the nucleus accumbens (NAcc) of DHPG, an agonist of group I mGluRs was significantly increased in hyperammonemic rats. Injection of DHPG increased extracellular dopamine but not glutamate in the NAcc of control rats. In hyperammonemic rats DHPG-induced increase in dopamine was significantly reduced, and extracellular glutamate increased 6-fold. The content of mGluR 1 but not mGluR 5, is increased in the NAcc of hyperammonemic rats. Blockade of mGluR 1 completely prevented motor and neurochemical effects induced by DHPG. These results show that modulation of both motor function and extracellular concentration of neurotransmitters by mGluRs in the NAcc is altered in hyperammonemia. This may contribute to the alterations in motor function in hepatic encephalopathy.
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Affiliation(s)
- Omar Cauli
- Laboratory of Neurobiology, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
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Mechtcheriakov S, Graziadei IW, Kugener A, Schuster I, Mueller J, Hinterhuber H, Vogel W, Marksteiner J. Motor dysfunction in patients with liver cirrhosis: impairment of handwriting. J Neurol 2005; 253:349-56. [PMID: 16244813 DOI: 10.1007/s00415-005-0995-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2005] [Revised: 07/07/2005] [Accepted: 07/19/2005] [Indexed: 11/28/2022]
Abstract
Motor dysfunction is an important clinical finding in patients with liver cirrhosis and mild forms of hepatic encephalopathy. The mechanisms and clinical appearance of motor impairment in patients with liver cirrhosis are not completely understood. We studied fine motor control in forty four patients with advanced liver cirrhosis (excluding those with hepatic encephalopathy grade II) and 48 healthy controls using a kinematic analysis of standardized handwriting tests. We analysed parameters of velocity, the ability to coordinate and the level of automatisation of handwriting movements. Furthermore, we studied the association between impairment of handwriting and clinical neuro-psychiatric symptoms. As compared with control subjects, patients showed a statistically significant reduction of movement peak velocity in all handwriting tasks as well as a substantial increase of number of velocity inversions per stroke. Using a z-score based assessment we found impairment of handwriting in fourteen out of forty four patients (31.8 %). The deterioration of handwriting was associated with clinical symptoms of motor dysfunction, such as bradykinesia, adiadochokinesia, dysmetria of upper extremities and gait ataxia. This is the first study that quantitatively investigates impairment of handwriting in patients with liver cirrhosis. Our findings suggest the application of kinematic analysis of handwriting for diagnostics of motor dysfunction in patients with mild forms of hepatic encephalopathy.
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Affiliation(s)
- Sergei Mechtcheriakov
- Department of General Psychiatry, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
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Mechtcheriakov S, Graziadei IW, Kugener A, Wiedemann J, Galbavy C, Hinterhuber H, Marksteiner J, Vogel W. Multidimensional assessment of neuro-psychiatric symptoms in patients with low-grade hepatic encephalopathy: A clinical rating scale. World J Gastroenterol 2005; 11:5893-8. [PMID: 16270405 PMCID: PMC4479696 DOI: 10.3748/wjg.v11.i37.5893] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the feasibility of a new clinical rating scale for a standardized assessment of cirrhosis-associated neuro-psychiatric symptoms.
METHODS: Forty patients with liver cirrhosis (LC, with or without low-grade hepatic encephalopathy) were invest-igated using a clinical neuro-psychiatric rating scale based on a comprehensive list of neurological, psychomotor, cognitive, affective, behavioral symptoms, and symptoms of disturbed bioregulation.
RESULTS: The analysis revealed that the majority of cirrhotic patients showed, besides characteristic neurological symptoms of hepatic encephalopathy, various psychomotor, affective and bioregulatory symptoms (disturbed sleep and sexual dysfunction). Patients were impaired in the following subscales: sleep and biorhythm disorder (75.0% of patients), Parkinsonoid symptoms (25.0%), affective symptoms (17.5%), and psychomotor retardation (12.5%). The increase of total neuro-psychiatric clinical score was significantly associated with the degree of hepatic enceph-alopathy.
CONCLUSION: This study suggests that a substantial number of patients with LC and low-grade hepatic encephalopathy manifest various clinical neuro-psychiatric symptoms. The use of a rating scale, which explores clinical dimensions of hepatic encephalopathy, would improve the management of patients with LC.
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Quero Guillén JC, Herrerías Gutiérrez JM. Diagnostic methods in hepatic encephalopathy. Clin Chim Acta 2005; 365:1-8. [PMID: 16168979 DOI: 10.1016/j.cca.2005.08.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2005] [Revised: 08/03/2005] [Accepted: 08/03/2005] [Indexed: 01/27/2023]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome in patients with liver disease and/or portosystemic shunting that affects quality of life and prognosis. The diagnosis is primarily based on clinical criteria that classify HE into 5 grades of severity ranging from normal mental status (grade 0) to coma (grade 4). As this clinical classification is rather subjective, additional diagnostic methods are required. Biochemical diagnostic tests can be used to confirm or exclude the diagnosis and to monitor the effect of treatment. An elevated ammonia level plays a central role in the pathogenesis of HE and can be determined in arterial, venous and capillary blood. Neuropsychological and neurophysiological tests are more sensitive and objective in diagnosing HE than the clinical criteria. Neuropsychological tests are especially of great value because of their high sensitivity for the detection of minimal HE and their low costs. The more sophisticated diagnostic tests such as magnetic resonance spectroscopy or positron emission tomography are mainly used for investigational purposes. This review will highlight these different diagnostic methods and comment on its pitfalls, clinical significance and overall applicability.
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Affiliation(s)
- Juan C Quero Guillén
- Department of Digestive Diseases, University Hospital Virgen Macarena, Avda. Dr. Fedriani 3, 41007 Seville, Spain.
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Jover R, Compañy L, Gutiérrez A, Lorente M, Zapater P, Poveda MJ, Such J, Pascual S, Palazón JM, Carnicer F, Ferrandis F, Pérez-Mateo M. Clinical significance of extrapyramidal signs in patients with cirrhosis. J Hepatol 2005; 42:659-65. [PMID: 15826714 DOI: 10.1016/j.jhep.2004.12.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2004] [Revised: 11/25/2004] [Accepted: 12/01/2004] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIMS Extrapyramidal signs have been described in cirrhosis and there is little information about their clinical significance. The aims of this study have been to investigate the relationship between extrapyramidal signs and cognitive impairment, and what is their influence on quality of life. METHODS 46 patients with cirrhosis were evaluated for cognitive impairment with psychometric tests (Trail-Making Test part A, Grooved-Pegboard, Block-Design, Oral Symbol Digit and Stroop Test) and cognitive evoked potentials (P300). Extrapyramidal signs were evaluated using the UPDRS scale. Health-related quality of life (HRQL) was measured using SF-36 scale and the Chronic Liver Disease Questionnaire (CLDQ). RESULTS Twenty-two patients had extrapyramidal signs, and these patients scored worse in all psychometric tests, except Block-Design. Patients with extrapyramidal signs also showed a longer P300 latency. Moreover, patients with extrapyramidal signs had the worst score in all the HRQL scales used. A multivariate analysis disclosed that the only variable showing an independent relationship to the mental component summary of SF-36 and with CLDQ was UPDRS score. CONCLUSIONS We have found a clear relationship between the presence of extrapyramidal signs and cognitive impairment. Moreover, patients with extrapyramidal signs have worse scores in quality of life scales.
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Affiliation(s)
- Rodrigo Jover
- Department of Gastroenterology-Liver Unit, Hospital General Universitario de Alicante, C/Pintor Baeza, sn, E-03010 Alicante, Spain.
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Abstract
BACKGROUND Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy. OBJECTIVES To evaluate the beneficial and harmful effects of dopaminergic agonists for patients with hepatic encephalopathy. SEARCH STRATEGY Trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2004), The Cochrane Central Register of Controlled Trials (Issue 3, 2004), MEDLINE (1966-2004/07), EMBASE (1980-2004/07), manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies. SELECTION CRITERIA All randomised trials comparing dopaminergic agonists versus placebo or no intervention for hepatic encephalopathy. DATA COLLECTION AND ANALYSIS Trial inclusion and data extraction were made independently by two reviewers. Binary outcomes are reported as odds ratios (OR) with 95% confidence intervals (CI) based on a random effects model. The presence of statistical heterogeneity was explored by the chi-squared test with significance set at P < 0.1. Potential sources of heterogeneity were explored through subgroup analyses with regard to the type of hepatic encephalopathy and type of dopaminergic agonist. MAIN RESULTS Five trials were included. Four trials had low methodological quality. Compared with placebo or no treatment, dopaminergic agonists had no significant effect on the risk of no improvement (OR 0.33, 95% CI 0.01 to 11.25, two trials, 80 patients) or mortality (OR 1.11, 95% CI 0.34 to 3.54, four trials, 139 patients). There was significant heterogeneity (P = 0.09) among trial results on the risk of no improvement, but not on mortality (P = 0.19). The treatment response was not significantly different with regard to the type of hepatic encephalopathy or dopaminergic agonist, but the analyses had very low power to detect potential differences. There was a nonsignificant trend that dopaminergic agonists may be associated with adverse events (OR 8.33, 95% CI 0.37 to 187.74, 2 trials, 13 patients). All adverse events (n = 7) occurred in the experimental group. REVIEWERS' CONCLUSIONS This review does not provide evidence that dopaminergic agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure. The review is limited by the small number of trials performed within this field, the low number of patients randomised in each trial, and the low methodological quality of included trials. Accordingly, there is also insufficient evidence to exclude a potential beneficial effect. Dopaminergic agonists should not be used for hepatic encephalopathy, but may be assessed in future randomised clinical trials.
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Affiliation(s)
- B Als-Nielsen
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Department 7102, H:S Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Romero-Gómez M, Ramos-Guerrero R, Grande L, de Terán LC, Corpas R, Camacho I, Bautista JD. Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 2004; 41:49-54. [PMID: 15246207 DOI: 10.1016/j.jhep.2004.03.021] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2003] [Revised: 02/08/2004] [Accepted: 03/26/2004] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS We performed the current study to assess the intestinal activity of enterocyte phosphate-activated glutaminase (PAG) in cirrhosis. METHODS Forty-nine cirrhotic patients and 36 control subjects underwent endoscopic duodenal biopsies. Minimal hepatic encephalopathy (MHE) was evaluated using three psychometric tests. Oral glutamine challenge (OGC) was performed and MELD, Child-Pugh and the presence of esophageal varices were recorded. PAG was measured by enzymatic methods. Cerebral magnetic resonance spectroscopy was performed in 10 cirrhotics. RESULTS PAG was found to be higher in cirrhotics than control subjects 2.4+/-1.51 vs. 0.68+/-0.57IU/mg protein (P<0.001). PAG was also increased in patients with MHE and correlated with MELD, INR, esophageal varices and serum bile acids. A negative correlation was observed between PAG activity and intra-cerebral choline/creatine ratio (r=-0.67; P=0.035) and a positive correlation with glutamine plus glutamate/creatine ratio (r=0.78; P=0.007). In multivariate analysis using backward logistic regression, presence of MHE was the only variable independently related to altered enterocyte PAG. CONCLUSIONS Enterocyte PAG is increased in cirrhotic patients and correlates with MHE. These data support a possible role for intestinal glutaminase in the pathogenesis of hepatic encephalopathy (HE) and could be a new target for future therapies.
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Affiliation(s)
- Manuel Romero-Gómez
- Hepatology Unit, Hospital Universitario de Valme, Ctra Cádiz s/n, 41014 Sevilla, Spain.
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Shah NJ, Neeb H, Zaitsev M, Steinhoff S, Kircheis G, Amunts K, Häussinger D, Zilles K. Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging. Hepatology 2003; 38:1219-26. [PMID: 14578860 DOI: 10.1053/jhep.2003.50477] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Changes are shown in the spin-lattice (T1) relaxation time caused by the putative deposition of manganese in various brain regions of hepatic encephalopathy (HE) patients using a novel and fast magnetic resonance imaging (MRI) method for quantitative relaxation time mapping. A new method, T1 mapping with partial inversion recovery (TAPIR), was used to obtain a series of T1-weighted images to produce T1 maps. Imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI scanner. The measurement time per patient with this technique, including adjustments, was approximately 5 minutes. Regions of interest in the globus pallidus, the caudate nucleus, the posterior and anterior limbs of the internal capsule, the putamen, the frontal and occipital white matter, the white matter of the corona radiata, the occipital visual and frontal cortices, and the thalamus were interactively defined in the left hemisphere and analyzed with respect to their T1 values. T1 changes in the brains of HE patients can be determined quantitatively with TAPIR in short, clinically relevant measurement times. Significant correlations between the change in T1 and HE severity have been shown in the globus pallidus, the caudate nucleus, and the posterior limb of the internal capsule. No significant correlation of T1 with grade of HE was found in the putamen, frontal white matter, white matter of the corona radiata, white matter in the occipital lobe, the anterior limb of the internal capsule, visual cortex, thalamus, or frontal cortex. In conclusion, these measurements show that T1 mapping is feasible in short, clinically relevant acquisition times.
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Affiliation(s)
- Nadim Joni Shah
- Institut für Medizin, Forschungszentrum Jülich GmbH, Jülich, Germany.
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Affiliation(s)
- M Lewis
- Academic Unit of Medicine, St James's University Hospital, Leeds, UK.
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