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Miliano C, Dong Y, Proffit M, Corvalan N, Natividad LA, Gregus AM, Buczynski MW. Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice. Neuropharmacology 2025:110502. [PMID: 40360036 DOI: 10.1016/j.neuropharm.2025.110502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025]
Abstract
Alcohol use disorder (AUD) affects millions of people and represents a significant health and economic burden. Pain is a frequently under-treated aspect of hyperkatifeia during alcohol withdrawal, yet to date no drugs have received FDA approval for the treatment of this indication in AUD patients. This study aims to evaluate the potential of targeting bioactive lipid signaling pathways as a therapeutic approach for treating alcohol withdrawal-related pain hypersensitivity. We utilized a chronic intermittent ethanol (CIE) vapor exposure model in C57BL/6J mice of both sexes to establish alcohol dependence and demonstrated that CIE produced robust tactile allodynia and thermal hyperalgesia during withdrawal that was independent of prior blood alcohol levels. Next, we evaluated four drugs for their efficacy in reversing tactile allodynia during abstinence from CIE using a cross-over treatment design that included FDA-approved naltrexone as well as commercially available inhibitors targeting the inflammatory lipid signaling enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and 15-Lipoxygenase (LOX). None of these compounds produced significant therapeutic benefit in reversing established CIE-induced tactile allodynia, despite attenuating pain-like behaviors at these doses in other chronic pain models. Additionally, we assessed plasma endocannabinoid levels in both sexes during withdrawal. We found that there was an inherent sex difference in the endogenous anti-inflammatory endocannabinoid tone in naive mice and that CIE treatment affected endocannabinoids levels in female mice only. These findings underscore the need to better understand the underlying causes of AUD-induced allodynia and to develop novel therapeutic approaches to mitigate pain hypersensitivity in AUD patients.
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Affiliation(s)
- C Miliano
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061
| | - Y Dong
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061
| | - M Proffit
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061
| | - N Corvalan
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061
| | - L A Natividad
- College of Pharmacy, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, Texas, USA
| | - A M Gregus
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061.
| | - M W Buczynski
- School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Blacksburg, VA 24061.
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2
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Sahu P, Verma HK, Bhaskar LVKS. Alcohol and alcoholism associated neurological disorders: Current updates in a global perspective and recent recommendations. World J Exp Med 2025; 15:100402. [PMID: 40115759 PMCID: PMC11718584 DOI: 10.5493/wjem.v15.i1.100402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 11/27/2024] [Accepted: 12/16/2024] [Indexed: 12/26/2024] Open
Abstract
Alcohol use disorder (AUD) is a medical condition that impairs a person's ability to stop or manage their drinking in the face of negative social, occupational, or health consequences. AUD is defined by the National Institute on Alcohol Abuse and Alcoholism as a "severe problem". The central nervous system is the primary target of alcohol's adverse effects. It is crucial to identify various neurological disorders associated with AUD, including alcohol withdrawal syndrome, Wernicke-Korsakoff syndrome, Marchiafava-Bignami disease, dementia, and neuropathy. To gain a better understanding of the neurological environment of alcoholism and to shed light on the role of various neurotransmitters in the phenomenon of alcoholism. A comprehensive search of online databases, including PubMed, EMBASE, Web of Science, and Google Scholar, was conducted to identify relevant articles. Several neurotransmitters (dopamine, gamma-aminobutyric acid, serotonin, and glutamate) have been linked to alcoholism due to a brain imbalance. Alcoholism appears to be a complex genetic disorder, with variations in many genes influencing risk. Some of these genes have been identified, including two alcohol metabolism genes, alcohol dehydrogenase 1B gene and aldehyde dehydrogenase 2 gene, which have the most potent known effects on the risk of alcoholism. Neuronal degeneration and demyelination in people with AUD may be caused by neuronal damage, nutrient deficiencies, and blood brain barrier dysfunction; however, the underlying mechanism is unknown. This review will provide a detailed overview of the neurobiology of alcohol addiction, followed by recent studies published in the genetics of alcohol addiction, molecular mechanism and detailed information on the various acute and chronic neurological manifestations of alcoholism for the Future research.
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Affiliation(s)
- Prashanti Sahu
- Department of Zoology, GGU Bilaspur, Bilaspur 495009, Chhattīsgarh, India
| | - Henu Kumar Verma
- Department of Lung Health and Immunity, Helmholtz Zentrum Munich, Munich 85764, Bayren, Germany
| | - LVKS Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattīsgarh, India
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Fernandez A, Graf G, Lasserre A, Daeppen JB, Chu Sin Chung P, Berna C, Suter MR. Somatosensory profiling of patients undergoing alcohol withdrawal: Do neuropathic pain and sensory loss represent a problem? J Peripher Nerv Syst 2023; 28:490-499. [PMID: 37419872 DOI: 10.1111/jns.12578] [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: 03/31/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023]
Abstract
INTRODUCTION Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. METHODS In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. RESULTS Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. DISCUSSION Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention.
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Affiliation(s)
- Aurore Fernandez
- Pain Center, Department of Anesthesiology, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Center for Integrative and Complementary Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Guillaume Graf
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Aurélie Lasserre
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry-Addiction Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Jean-Bernard Daeppen
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry-Addiction Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Paul Chu Sin Chung
- Pain Center, Department of Anesthesiology, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Chantal Berna
- Pain Center, Department of Anesthesiology, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Center for Integrative and Complementary Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - Marc R Suter
- Pain Center, Department of Anesthesiology, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
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Borgonetti V, Roberts AJ, Bajo M, Galeotti N, Roberto M. Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: A mouse model of alcohol-evoked neuropathic pain. Br J Pharmacol 2023; 180:2377-2392. [PMID: 37050867 PMCID: PMC10898491 DOI: 10.1111/bph.16091] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND AND PURPOSE Chronic pain is considered a key factor contributing to alcohol use disorder (AUD). The mechanisms responsible for chronic pain associated with chronic alcohol consumption are unknown. We evaluated the development of chronic pain in a mouse model of alcohol dependence and investigate the role of neuroinflammation. EXPERIMENTAL APPROACH The chronic-intermittent ethanol two-bottle choice CIE-2BC paradigm generates three groups: alcohol-dependent with escalating alcohol intake, nondependent (moderate drinking) and alcohol-naïve control male and female mice. We measured mechanical allodynia during withdrawal and after the last voluntary drinking. Immunoblotting was used to evaluate the protein levels of IBA-1, CSFR, IL-6, p38 and ERK2/1 in spinal cord tissue of dependent and non-dependent animals. KEY RESULTS We found significant escalation of drinking in the dependent group in male and female compared with the non-dependent group. The dependent group developed mechanical allodynia during 72 h of withdrawal, which was completely reversed after voluntary drinking. We observed an increased pain hypersensitivity compared with the naïve in 50% of non-dependent group. Increased IBA-1 and CSFR expression was observed in spinal cord tissue of both hypersensitivity-abstinence related and neuropathy-alcohol mice, and increased IL-6 expression and ERK1/2 activation in mice with hypersensitivity-related to abstinence, but not in mice with alcohol-evoked neuropathic pain. CONCLUSIONS AND IMPLICATIONS The CIE-2BC model induces two distinct pain conditions specific to the type of ethanol exposure: abstinence-related hypersensitivity in dependent mice and alcohol-evoked neuropathic pain in about a half of the non-dependent mice.
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Affiliation(s)
- Vittoria Borgonetti
- Department of Neuroscience, Psychology, Drug Research, and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, Florence, 50139, Italy
- Department of Molecular Medicine and Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Amanda J. Roberts
- Animal Models Core, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Michal Bajo
- Department of Molecular Medicine and Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Nicoletta Galeotti
- Department of Neuroscience, Psychology, Drug Research, and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, Florence, 50139, Italy
| | - Marisa Roberto
- Department of Molecular Medicine and Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA
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Kokotis P, Papantoniou M, Schmelz M, Buntziouka C, Tzavellas E, Paparrigopoulos T. Pure small fiber neuropathy in alcohol dependency detected by skin biopsy. Alcohol 2023; 111:67-73. [PMID: 37295567 DOI: 10.1016/j.alcohol.2023.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/10/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023]
Abstract
BACKGROUND Alcohol overconsumption is well known to cause damage to the peripheral nervous system. The aim of this study was the functional and structural evaluation of the small nerve fibers in alcohol-dependent subjects, with or without symptoms of peripheral neuropathy. METHODS Twenty-six consecutive alcohol-dependent subjects treated for detoxification voluntarily in the specialized unit of the Athens University Psychiatric Clinic were enrolled in this prospective study over 18 months. Every subject was assessed by peripheral nerve evaluation using the Neuropathy Symptoms Score (NSS) and Neuropathy Impairment Score (NIS), followed by nerve conduction studies (NCS), quantitative sensory testing (QST), and skin biopsy. Twenty-nine normal subjects, age- and gender-matched, constituted the control group. RESULTS Peripheral neuropathy was diagnosed in 16 subjects (61.5%). Among these 16 subjects, pure large fiber neuropathy (LFN) was found in two subjects (12.5%), pure small fiber neuropathy (SFN) was found in eight subjects (50%), and both large and small fiber neuropathy was diagnosed in six patients (37.5%). The intraepidermal nerve fiber density (IENFD) of the patients' skin biopsy was significantly lower than that of the control group. Additionally, QST results showed a statistically significant sensory impairment in the patients. CONCLUSIONS Our study confirms small fiber neuropathy due to alcohol abuse with a high prevalence of pure SFN that might have remained undetected without QST and IENFD.
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Affiliation(s)
- Panagiotis Kokotis
- Laboratory of Clinical Neurophysiology, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
| | - Michail Papantoniou
- Laboratory of Clinical Neurophysiology, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Martin Schmelz
- Department of Experimental Pain Research, MCTN Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Chrysanthi Buntziouka
- Laboratory of Clinical Neurophysiology, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Elias Tzavellas
- First Department of Psychiatry, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Thomas Paparrigopoulos
- First Department of Psychiatry, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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de la Monte SM. Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes). J Alzheimers Dis 2023; 95:1301-1337. [PMID: 37718817 PMCID: PMC10896181 DOI: 10.3233/jad-230555] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.
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Affiliation(s)
- Suzanne M. de la Monte
- Departments of Pathology and Laboratory Medicine, Medicine, Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA
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7
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Alcoholic neuropathy associated with chronic alcohol intake. IBRO Neurosci Rep 2022; 13:177-186. [PMID: 36065406 PMCID: PMC9440385 DOI: 10.1016/j.ibneur.2022.08.004] [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: 12/13/2021] [Accepted: 08/12/2022] [Indexed: 11/22/2022] Open
Abstract
Alcoholic neuropathy (AN), a debilitating condition that mainly affects chronic alcohol drinkers, is thought to cause lesions in the peripheral nervous system leading to sensory, autonomic, and motor dysfunctions. Despite many studies, the pathogenesis of these lesions is still not completely understood. We investigated few aspects on the development of alcohol-induced peripheral neuropathy, by assessing sensory, motor and autonomic functions, as well as stereological analysis of axonal fibers and myelin sheath of the sciatic nerve. Twelve male Wistar rats were divided into Control group and Alcohol group that was submitted to Two Bottle-Choice Paradigm of intermittent and voluntary alcohol solution intake (20%; v/v) during eight weeks. At the end of treatment, three different sensorium-motor tests were applied - Tactile Sensitivity, Thermal Sensitivity, and Functional Observational Battery (FOB). Quantitative morphometric analysis of sciatic nerve structures was performed by stereological method. Alcohol concentration in the blood was measured to analyze possible correlation between availability of alcohol in the blood and the magnitude of the peripheral nerve lesion. Our data showed a peripheral effect of chronic alcohol intake associated with hyperalgesia and a process of demyelination with a strong correlation with alcohol consumption. This process was associated with increased tactile sensitivity, with behavioral reflexes such as locomotor hyperactivity, changes in gait and balance, and autonomic reflexes such as piloerection.
Alcoholic neuropathy and its consequences. Neuropathy and sensitive and motor alterations. Alcoholic neuropathy and thinner myelin sheath thickness.
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Baj J, Forma A, Kobak J, Tyczyńska M, Dudek I, Maani A, Teresiński G, Buszewicz G, Januszewski J, Flieger J. Toxic and Nutritional Optic Neuropathies—An Updated Mini-Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19053092. [PMID: 35270784 PMCID: PMC8910489 DOI: 10.3390/ijerph19053092] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/27/2022] [Accepted: 03/03/2022] [Indexed: 12/20/2022]
Abstract
Optic neuropathies constitute a group of conditions with various etiologies and might be caused by different factors; we can distinguish the genetic and acquired causes of optic neuropathies. Even though the symptoms are not highly specific, this condition is primarily characterized by unilateral or bilateral vision loss with worsening color detection. The loss may be acute or gradual depending on the causation. In this article, we included a specification of toxic optic neuropathy (TON) mainly triggered by alcohol abuse and also the usage of other substances, including drugs or methanol, as well as intoxication by metals, organic solvents, or carbon dioxide. Nutritional deficiencies, vitamin absorption disorder, and anemia, which usually appear during excessive alcohol intake, and their effect on the etiology of the optic neuropathy have been likewise discussed.
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Affiliation(s)
- Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (A.M.)
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
- Correspondence:
| | - Joanna Kobak
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Magdalena Tyczyńska
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Iga Dudek
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Amr Maani
- Department of Human Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (A.M.)
| | - Grzegorz Teresiński
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Jacek Januszewski
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (J.K.); (M.T.); (I.D.); (G.T.); (G.B.); (J.J.)
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
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Wiśniewski P, Maurage P, Jakubczyk A, Trucco EM, Suszek H, Kopera M. Alcohol use and interoception - A narrative review. Prog Neuropsychopharmacol Biol Psychiatry 2021; 111:110397. [PMID: 34224795 PMCID: PMC8380667 DOI: 10.1016/j.pnpbp.2021.110397] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/31/2021] [Accepted: 06/29/2021] [Indexed: 01/29/2023]
Abstract
Interoception, defined as the ability to perceive and interpret body signals, may play an important role in alcohol use disorder (AUD). Earlier studies suggested an association between interoception impairment and known risk factors for AUD (e.g., alexithymia, emotion dysregulation, impulsivity, pain). Neurobiological studies show that the neurotoxicity of alcohol affects various elements of the interoceptive system (especially the insula) at structural and functional levels, with differential short/long term impacts. Conversely, primary interoceptive impairments may promote alcohol consumption and foster the evolution towards addiction. Despite convincing evidence demonstrating that interoception impairment may be an important contributor to the development and course of AUD, only a few studies directly evaluated interoceptive abilities in AUD. The research shows that interoceptive accuracy, the objective component of interoception, is lower in AUD individuals, and is correlated with craving and emotion dysregulation. Interoceptive sensibility is in turn higher in AUD individuals compared to healthy controls. Moreover, there is evidence that therapy focused on improving the ability to sense signals from the body in addiction treatment is effective. However, important methodological limitations in interoceptive measures persist, and it is therefore necessary to further investigate the associations between interoception and AUD.
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Affiliation(s)
- Paweł Wiśniewski
- Department of Psychiatry, Medical University of Warsaw, Warsaw, Poland.
| | - Pierre Maurage
- Louvain Experimental Psychopathology research group (LEP), Psychological Sciences Research Institute, UCLouvain, Louvain-la-Neuve, Belgium
| | - Andrzej Jakubczyk
- Department of Psychiatry, Medical University of Warsaw, Warsaw, Poland
| | - Elisa M Trucco
- Department of Psychology, Center for Children and Families, Florida International University, Miami, FL, USA; Department of Psychiatry, Addiction Center, University of Michigan, Ann Arbor, MI, USA
| | - Hubert Suszek
- Department of Psychology, University of Warsaw, Warsaw, Poland
| | - Maciej Kopera
- Department of Psychiatry, Medical University of Warsaw, Warsaw, Poland
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10
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Abstract
Small fiber neuropathy is common and prevalent in the elderly. The disease can be associated with many medical conditions. It often has a negative impact on quality of life due to painful paresthesia, dizziness, and sedative side effects of pain medications. Skin biopsy is the gold standard diagnostic test. Screening for associated conditions is important, because etiology-specific treatment can slow down disease progression and ameliorate symptoms. Adequate pain control can be challenging due to safety and tolerability of pain medications in the elderly. Treatment should be individualized with the goals of controlling underlying causes, alleviating pain, and optimizing daily function.
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Affiliation(s)
- Lan Zhou
- Department of Neurology, Boston Medical Center Cutaneous Nerve Laboratory, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
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11
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Raasing LR, Vogels OJ, Veltkamp M, van Swol CF, Grutters JC. Current View of Diagnosing Small Fiber Neuropathy. J Neuromuscul Dis 2021; 8:185-207. [PMID: 33337383 PMCID: PMC8075405 DOI: 10.3233/jnd-200490] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated C-fibers [5, 6]. SFN might affect small sensory fibers, autonomic fibers or both, resulting in sensory changes, autonomic dysfunction or combined symptoms [7]. As a consequence, the symptoms are potentially numerous and have a large impact on quality of life [8]. Since diagnostic methods for SFN are numerous and its pathophysiology complex, this extensive review focusses on categorizing all aspects of SFN as disease and its diagnosis. In this review, sensitivity in combination with specificity of different diagnostic methods are described using the areas under the curve. In the end, a diagnostic work-flow is suggested based on different phenotypes of SFN.
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Affiliation(s)
- Lisette R.M. Raasing
- ILD Center of Excellence, Department of Pulmonology,St Antonius Hospital, CM, Nieuwegein, The Netherlands
| | - Oscar J.M. Vogels
- Department of Neurology, St Antonius Hospital, CM, Nieuwegein, The Netherlands
| | - Marcel Veltkamp
- ILD Center of Excellence, Department of Pulmonology,St Antonius Hospital, CM, Nieuwegein, The Netherlands
- Division of Heart and Lungs, University Medical Center Utrecht, CX, Utrecht, The Netherlands
| | | | - Jan C. Grutters
- ILD Center of Excellence, Department of Pulmonology,St Antonius Hospital, CM, Nieuwegein, The Netherlands
- Division of Heart and Lungs, University Medical Center Utrecht, CX, Utrecht, The Netherlands
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12
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Alcohol-Induced Neuropathy in Chronic Alcoholism: Causes, Pathophysiology, Diagnosis, and Treatment Options. CURRENT PATHOBIOLOGY REPORTS 2020. [DOI: 10.1007/s40139-020-00214-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Abstract
Purpose of the Review
Alcohol abuse causes a wide range of disorders that affect the nervous system. These include confusion, cerebellar ataxia, peripheral neuropathy, and cognitive impairment. Chronic and excessive alcohol consumption is the primary cause of peripheral neuropathy. It is worth noting that peripheral neuropathy has no reliable treatment due to the poor understanding of its pathology.
Recent Findings
Coasting is a major feature of alcoholic neuropathy, largely due to chronic alcohol abuse. Its major features are hyperalgesia, allodynia, and burning pain. Even though much research was done in this area, still we do not have a full understanding of the mechanism of alcoholic neuropathy. However, some theories have been proposed. These include direct or indirect effects of alcohol metabolites, impaired axonal transport, suppressed excitatory nerve pathway activity, or imbalance in neurotransmitters. Activation of spinal cord microglia, mGlu5 spinal cord receptors, and hypothalamic-pituitary-adrenal axis also seem to be implicated in the pathophysiology of this alcoholic neuropathy. The goal of treatment is to impede further damage to the peripheral nerves while also restoring their normal physiology. Alcohol abstinence, intake of balanced diets, and treatment with medications are suggested including benfotiamine, alpha-lipoic acid, acetyl-l-carnitine, vitamin E, methylcobalamin, myo-inositol, N-acetylcysteine, capsaicin, tricyclic antidepressants, or antiepileptic drugs.
Summary
This review focuses on the many pathways that play a role in the onset and development of alcohol-induced neuropathy, as well as present the possible treatment strategies of this disorder, providing insights into a further search of new treatment modalities.
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Crocetto F, Coppola N, Barone B, Leuci S, Imbimbo C, Mignogna MD. The association between burning mouth syndrome and urologic chronic pelvic pain syndrome: A case-control study. J Oral Pathol Med 2020; 49:829-834. [PMID: 32797728 DOI: 10.1111/jop.13097] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/13/2020] [Accepted: 07/29/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND The overlap between some painful conditions is widespread. The aim of this study was to evaluate the overlap between burning mouth syndrome (BMS) and urological chronic pelvic pain syndrome (UCPPS) in an outpatient clinic of a university hospital. METHODS A controlled clinical study was performed. BMS patients and healthy controls were enrolled in the study. Patients were screened through laboratory test and a complete urological examination. Two validated questionnaires were submitted to all the patients: National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and International Prostatic Symptom Score (IPSS). RESULTS A total of 50 BMS patients and 50 healthy controls were enrolled in the study. Statistically significant differences between the two groups regarding the items of the IPSS questionnaire of Incomplete Emptying (U = 750, P < .001), Intermittency (U = 768.5, P < .001), QoL (U = 848, P < .002), and Total Symptom score (U = 1040, P = .05) were found. Moreover, the responses of NIH-CPSI showed statistically significant differences regarding Pain subscale (U = 714, P < .001), QoL Impact subscale (U = 1016.500, P = .05), and NIH-CPSI total score (U = 953.500, P = .002). CONCLUSION To the best our knowledge, the reported data demonstrate for the first time an association between BMS and UCPPS. Further studies with a larger sample are needed to confirm the co-occurrence of urological symptoms in patients with burning mouth syndrome.
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Affiliation(s)
- Felice Crocetto
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Urology and Andrology Unit, University of Naples Federico II, Naples, Italy
| | - Noemi Coppola
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Oral Medicine Unit, University of Naples Federico II, Naples, Italy
| | - Biagio Barone
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Urology and Andrology Unit, University of Naples Federico II, Naples, Italy
| | - Stefania Leuci
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Oral Medicine Unit, University of Naples Federico II, Naples, Italy
| | - Ciro Imbimbo
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Urology and Andrology Unit, University of Naples Federico II, Naples, Italy
| | - Michele Davide Mignogna
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, Oral Medicine Unit, University of Naples Federico II, Naples, Italy
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Orum MH, Kalenderoglu A. Decreases in retinal nerve fiber layer thickness correlates with cumulative alcohol intake. J Addict Dis 2020; 38:400-410. [DOI: 10.1080/10550887.2020.1776083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
| | - Aysun Kalenderoglu
- Department of Psychiatry, Adiyaman University, Faculty of Medicine, Adiyaman, Turkey
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De Logu F, Li Puma S, Landini L, Portelli F, Innocenti A, de Araujo DSM, Janal MN, Patacchini R, Bunnett NW, Geppetti P, Nassini R. Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice. J Clin Invest 2019; 129:5424-5441. [PMID: 31487269 PMCID: PMC6877331 DOI: 10.1172/jci128022] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/29/2019] [Indexed: 12/15/2022] Open
Abstract
Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia, and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1-dependent (NOX1-dependent) production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1-/- or Plp1-Cre Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small-fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.
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Affiliation(s)
- Francesco De Logu
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Simone Li Puma
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Lorenzo Landini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Francesca Portelli
- Histopathology and Molecular Diagnostics, Department of Health Sciences, University of Florence, Florence, Italy
| | - Alessandro Innocenti
- Plastic and Reconstructive Microsurgery, Careggi University Hospital, Florence, Italy
| | - Daniel Souza Monteiro de Araujo
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil
| | - Malvin N. Janal
- Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, New York, USA
| | - Riccardo Patacchini
- Department of Corporate Drug Development, Chiesi Farmaceutici SpA, Parma, Italy
| | - Nigel W. Bunnett
- Department of Surgery and
- Department of Pharmacology, Columbia University in the City of New York, New York, New York, USA
| | - Pierangelo Geppetti
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Romina Nassini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
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Zahr NM, Pohl KM, Pfefferbaum A, Sullivan EV. Central Nervous System Correlates of "Objective" Neuropathy in Alcohol Use Disorder. Alcohol Clin Exp Res 2019; 43:2144-2152. [PMID: 31386216 PMCID: PMC6779503 DOI: 10.1111/acer.14162] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 07/24/2019] [Indexed: 01/11/2023]
Abstract
BACKGROUND Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes-related neuropathies, neuropathy associated with alcohol use disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy. METHODS In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ-glutamyltransferase), were evaluated. RESULTS The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors. CONCLUSIONS This study supports CNS involvement in objective signs of neuropathy in AUD.
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Affiliation(s)
- Natalie M Zahr
- Neuroscience Program, (NMZ, KMP, AP), SRI International, Menlo Park, California
- Department of Psychiatry and Behavioral Sciences, (NMZ, KMP, AP, EVS), Stanford University School of Medicine, Stanford, California
| | - Kilian M Pohl
- Neuroscience Program, (NMZ, KMP, AP), SRI International, Menlo Park, California
- Department of Psychiatry and Behavioral Sciences, (NMZ, KMP, AP, EVS), Stanford University School of Medicine, Stanford, California
| | - Adolf Pfefferbaum
- Neuroscience Program, (NMZ, KMP, AP), SRI International, Menlo Park, California
- Department of Psychiatry and Behavioral Sciences, (NMZ, KMP, AP, EVS), Stanford University School of Medicine, Stanford, California
| | - Edith V Sullivan
- Department of Psychiatry and Behavioral Sciences, (NMZ, KMP, AP, EVS), Stanford University School of Medicine, Stanford, California
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Nakamura M, Namiki T, Munetsugu T, Hashimoto T, Fujimoto T, Yokozeki H. Image Gallery: Acquired anhidrosis associated with alcohol-related peripheral neuropathy, a potential cause of anhidrosis due to reduced innervation of eccrine glands. Br J Dermatol 2019; 180:e35. [PMID: 30714116 DOI: 10.1111/bjd.17247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- M Nakamura
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - T Namiki
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - T Munetsugu
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - T Hashimoto
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - T Fujimoto
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - H Yokozeki
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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Julian T, Glascow N, Syeed R, Zis P. Alcohol-related peripheral neuropathy: a systematic review and meta-analysis. J Neurol 2018; 266:2907-2919. [PMID: 30467601 PMCID: PMC6851213 DOI: 10.1007/s00415-018-9123-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/09/2018] [Accepted: 11/12/2018] [Indexed: 12/20/2022]
Abstract
The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to identify the most appropriate management strategies. In this review, possible pathogenetic mechanisms are also discussed. A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. 87 articles were included in this review, 29 case–control studies, 52 prospective/retrospective cohort studies and 2 randomised control trials, 1 cross sectional study, and 3 population-based studies. The prevalence of peripheral neuropathy amongst chronic alcohol abusers is 46.3% (CI 35.7– 57.3%) when confirmed via nerve conduction studies. Alcohol-related peripheral neuropathy generally presents as a progressive, predominantly sensory axonal length-dependent neuropathy. The most important risk factor for alcohol-related peripheral neuropathy is the total lifetime dose of ethanol, although other risk factors have been identified including genetic, male gender, and type of alcohol consumed. At present, it is unclear what the pathogenetic mechanisms for the development of neuropathy amongst those who chronically abuse alcohol are, and therefore, it is unknown whether it is attributed to the direct toxic effects of ethanol or another currently unidentified factor. There is presently sparse data to support a particular management strategy in alcohol-related peripheral neuropathy, but the limited data available appears to support the use of vitamin supplementation, particularly of B-vitamin regimens inclusive of thiamine.
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Affiliation(s)
- Thomas Julian
- The Medical School, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK
| | - Nicholas Glascow
- The Medical School, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK
| | - Rubiya Syeed
- The Medical School, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK
| | - Panagiotis Zis
- Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK. .,Medical School, University of Cyprus, Nicosia, Cyprus.
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de Greef BTA, Hoeijmakers JGJ, Gorissen‐Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. Eur J Neurol 2018; 25:348-355. [PMID: 29112785 PMCID: PMC5814938 DOI: 10.1111/ene.13508] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 11/02/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND PURPOSE Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.
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Affiliation(s)
- B. T. A. de Greef
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
| | - J. G. J. Hoeijmakers
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
| | - C. M. L. Gorissen‐Brouwers
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
| | - M. Geerts
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
| | - C. G. Faber
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
| | - I. S. J. Merkies
- Department of NeurologySchool of Mental Health and NeuroscienceMaastricht University Medical Center+MaastrichtThe Netherlands
- Department of NeurologySt Elisabeth HospitalWillemstadCuraçao
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Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol 2017; 16:934-944. [DOI: 10.1016/s1474-4422(17)30329-0] [Citation(s) in RCA: 205] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 07/31/2017] [Accepted: 08/09/2017] [Indexed: 12/15/2022]
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22
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Seitz J, Sawyer KS, Papadimitriou G, Oscar-Berman M, Ng I, Kubicki A, Mouradian P, Ruiz SM, Kubicki M, Harris GJ, Makris N. Alcoholism and sexual dimorphism in the middle longitudinal fascicle: a pilot study. Brain Imaging Behav 2017; 11:1006-1017. [PMID: 27448160 PMCID: PMC5253343 DOI: 10.1007/s11682-016-9579-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alcoholism can lead to a complex mixture of cognitive and emotional deficits associated with abnormalities in fronto-cortico-striatal-limbic brain circuitries. Given the broad variety of neurobehavioral symptoms, one would also expect alterations of postrolandic neocortical systems. Thus, we used diffusion tensor imaging (DTI) to study the integrity of the middle longitudinal fascicle (MdLF), a major postrolandic association white matter tract that extends from the superior temporal gyrus to the parietal and occipital lobes, in individuals with a history of chronic alcohol abuse. DTI data were acquired on a 3 Tesla scanner in 30 abstinent alcoholics (AL; 9 men) and 25 nonalcoholic controls (NC; 8 men). The MdLF was determined using DTI-based tractography. Volume of the tract, fractional anisotropy (FA), radial (RD), and axial (AD) diffusivity, were compared between AL and NC, with sex and hemispheric laterality as independent variables. The association of DTI measures with neuropsychological performance was evaluated. Men showed bilateral reduction of MdLF volume and abnormal diffusion measurements of the left MdLF. Analyses also indicated that the left MdLF diffusion measurements in AL men were negatively associated with Verbal IQ and verbal fluency test scores. Abstinent alcoholic men display macrostructural abnormalities in the MdLF bilaterally, indicating an overall white matter deficit. Additionally, microstructural deficits of the left MdLF suggest more specific alterations associated with verbal skills in men.
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Affiliation(s)
- Johanna Seitz
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kayle S Sawyer
- Behavioral Neuroscience and Departments of Psychiatry and Neurology, Boston University School of Medicine, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - George Papadimitriou
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Marlene Oscar-Berman
- Behavioral Neuroscience and Departments of Psychiatry and Neurology, Boston University School of Medicine, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Isaac Ng
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Antoni Kubicki
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Palig Mouradian
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Susan M Ruiz
- Behavioral Neuroscience and Departments of Psychiatry and Neurology, Boston University School of Medicine, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
| | - Marek Kubicki
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Gordon J Harris
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA
- Radiology Computer Aided Diagnostics Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Nikos Makris
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Departments of Psychiatry, Neurology and Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA.
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Didriksen M, Rigas AS, Allen RP, Burchell BJ, Di Angelantonio E, Nielsen MH, Jennum P, Werge T, Erikstrup C, Pedersen OB, Bruun MT, Burgdorf KS, Sørensen E, Ullum H. Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: results from the Danish Blood Donor Study. Sleep Med 2017; 36:55-61. [DOI: 10.1016/j.sleep.2017.04.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/03/2017] [Accepted: 04/04/2017] [Indexed: 12/27/2022]
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Hamel J, Logigian EL. Acute nutritional axonal neuropathy. Muscle Nerve 2017; 57:33-39. [PMID: 28556429 DOI: 10.1002/mus.25702] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 05/21/2017] [Accepted: 05/23/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. METHODS Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. RESULTS Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. DISCUSSION We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018.
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Affiliation(s)
- Johanna Hamel
- University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York, 14642, USA
| | - Eric L Logigian
- University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York, 14642, USA
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Chan ACY, Wilder-Smith EP. Small fiber neuropathy: Getting bigger! Muscle Nerve 2016; 53:671-82. [PMID: 26872938 DOI: 10.1002/mus.25082] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2016] [Indexed: 12/13/2022]
Abstract
Etiological and clinical heterogeneity of small fiber neuropathy (SFN) precludes a unifying approach and necessitates reliance on recognizable clinical syndromes. Symptoms of SFN arise from dysfunction in nociception, temperature, and autonomic modalities. This review focuses on SFN involving nociception and temperature, examining epidemiology, etiology, clinical presentation, diagnosis, pathophysiology, and management. Prevalence of SFN is 52.95 per 100,000 population, and diabetes and idiopathic are the most common etiologies. Dysesthesia, allodynia, pain, burning, and coldness sensations frequently present in a length-dependent pattern. Additional autonomic features in gastrointestinal, urinary, or cardiovascular systems are frequent but poorly objectified. SFN is diagnosed by intraepidermal nerve fiber density and quantitative sensory and autonomic tests in combination with normal nerve conduction. Pathophysiological understanding centers on sodium channel dysfunction, and genetic forms are beginning to be understood. Treatment is directed at the underlying etiology supported by symptomatic treatment using antidepressants and anticonvulsants. Little is known about long-term outcomes, and systematic cohort studies are needed.
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Affiliation(s)
- Amanda C Y Chan
- Division of Neurology, National University Hospital, Level 10 Tower Block, University Medicine Cluster, 1E Kent Ridge Road, 119228, Singapore
| | - Einar P Wilder-Smith
- Division of Neurology, National University Hospital, Level 10 Tower Block, University Medicine Cluster, 1E Kent Ridge Road, 119228, Singapore.,Neurology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Seger S, Stritt M, Doppler K, Frank S, Panaite A, Kuntzer T, Steck A, Pagenstecher A, Sommer C, Stalder AK. A semi-automated method to assess intraepidermal nerve fibre density in human skin biopsies. Histopathology 2015; 68:657-65. [PMID: 26249211 DOI: 10.1111/his.12794] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 07/30/2015] [Indexed: 11/30/2022]
Abstract
AIMS Evaluation of intraepidermal nerve fibres (IENFs) in skin biopsies is used in the diagnosis of small-fibre neuropathies. The number of IENFs is assessed manually under a microscope, with an inter-rater variability of ~25%. Unless the images are digitized, there is no documentation. Our aim was to develop a method for standardized semi-automated quantification (SAQ) and documentation of IENF density. METHODS AND RESULTS We analysed samples from four different university centres that were immunostained according to local protocols. Images were acquired through the Z-plane with a whole slide scanner. orbit image analysis software was used to create an analysable image and develop a reliable algorithm for IENF detection. Rebuilt images revealed well-contrasted nerves, allowing detection of IENFs (automated). The software presented the detected nerves for confirmation by the operator (manual). As compared with the conventional microscopy count, the SAQ achieved correlation coefficients of 0.99 and 0.96 and interfacility variabilities of 19% and 23%, respectively. We found better reproducibility with fluorescence-stained specimens than with bright-field images. CONCLUSIONS The new semi-automated method has high experimenter-independent reproducibility when based on nerve detection by fluorescence and is easy to perform, even by untrained users. The IENF counting is electronically well documented.
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Affiliation(s)
- Shanon Seger
- Department of Translational Science, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Manuel Stritt
- Department of Information Management Drug Discovery, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Kathrin Doppler
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Stephan Frank
- Department of Neuropathology, University Hospital Basel, Basel, Switzerland
| | - Adrian Panaite
- Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - Thierry Kuntzer
- Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - Andreas Steck
- Department of Neurology, University Hospital Basel, Basel, Switzerland
| | - Axel Pagenstecher
- Department of Neuropathology, University Hospital Giessen and Marburg, Marburg, Germany
| | - Claudia Sommer
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Anna K Stalder
- Department of Translational Science, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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28
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Lakritz JR, Bodair A, Shah N, O'Donnell R, Polydefkis MJ, Miller AD, Burdo TH. Monocyte Traffic, Dorsal Root Ganglion Histopathology, and Loss of Intraepidermal Nerve Fiber Density in SIV Peripheral Neuropathy. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1912-23. [PMID: 25956030 PMCID: PMC4484219 DOI: 10.1016/j.ajpath.2015.03.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 02/26/2015] [Accepted: 03/03/2015] [Indexed: 12/16/2022]
Abstract
HIV-associated sensory neuropathy remains the most common neurological complication of HIV infection and is characterized by dorsal root ganglion (DRG) inflammation and intraepidermal nerve fiber density (IENFD) loss. Chronic peripheral immune cell activation and accumulation may cause damage to the DRG, but has not been fully investigated yet. By using an SIV-infected, CD8-lymphocyte-depleted rhesus macaque model, we defined immune cells surrounding DRG neurons and their role in DRG pathology, measured cell traffic from the bone marrow to the DRGs using 5-bromo-2-deoxyuridine (BrdU) pulse, and serially measured IENFD. We found an increase in CD68(+) and CD163(+) macrophages in DRGs of SIV-infected animals. MAC387(+) recently recruited monocytes/macrophages were increased, along with BrdU(+) cells, in the DRGs of SIV-infected macaques. We demonstrated that 78.1% of all BrdU(+) cells in DRGs were also MAC387(+). The number of BrdU(+) monocytes correlated with severe DRG histopathology, which included neuronophagia, neuronal loss, and Nageotte nodules. These data demonstrate that newly recruited MAC387(+)BrdU(+) macrophages may play a significant role in DRG pathogenesis. IENFD decreased early (day 21), consistent with the development of sensory neuropathy in SIV-infected macaques. Decreased IENFD was associated with elevated BrdU(+) cells in the DRG. These data suggest that increased recruitment of macrophages to DRG is associated with severe DRG histopathology and IENFD loss.
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Affiliation(s)
| | - Ayman Bodair
- Department of Biology, Boston College, Chestnut Hill, Massachusetts
| | - Neal Shah
- Department of Biology, Boston College, Chestnut Hill, Massachusetts
| | - Ryan O'Donnell
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael J Polydefkis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew D Miller
- Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, New York
| | - Tricia H Burdo
- Department of Biology, Boston College, Chestnut Hill, Massachusetts.
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