Alcohol-related peripheral neuropathy: Clinico-neurophysiological characteristics and diagnostic utility of the neuropathy symptoms score and the neuropathy impairment score.

Alcohol overconsumption is well known to cause damage to the peripheral nervous system, affecting both small and large nerve fibers. The aim of this descriptive study was to investigate peripheral nerve damage, and to correlate clinical, epidemiological and neurophysiological findings, in patients diagnosed with Alcohol Use Disorder (AUD). Ninety alcohol-dependent subjects on inpatient basis were enrolled in this prospective study over a 3-year period. Every subject was assessed by the Neuropathy Symptoms Score (NSS) questionnaire and the Neuropathy Impairment Score (NIS) clinical examination grading scale, followed by Nerve Conduction Studies, Quantitative Sensory Testing and Sympathetic Skin Response (SSR) testing. Peripheral neuropathy was diagnosed in 54 subjects (60%), by abnormal neurophysiological tests and presence of clinical signs or symptoms. Among them, pure large fiber neuropathy (LFN) was found in 18 subjects, pure small fiber neuropathy (SFN) in 12 subjects, and both large and small fiber neuropathy was diagnosed in 24 subjects. Using linear regression, we found that higher NSS and NIS scores correlated with lower amplitudes of the sural sensory nerve action potential and of the SSR. We also found a significant longer duration of alcohol abuse in subjects with neuropathy, using Student's t-test (p = 0.024). Additionally, applying NIS abnormal cut-off score ≥4, using ROC analysis, we predicted the majority of subjects with LFN, confirming 95.23% sensitivity and 93.75% specificity. Our study confirmed that peripheral neuropathy involving large and small nerve fibers, with a symmetrical length-dependent pattern, is common between patients with AUD and related to the duration of the disorder. We suggest that NSS and NIS scales could be used for the assessment of neuropathy in clinical practice, when the essential neurophysiological testing is not available.

Alcohol-related peripheral neuropathy: a systematic review and meta-analysis.

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.

Chronic Neurologic Effects of Alcohol.

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.

Chronic alcoholics retain dyspeptic symptoms, pan-enteric dysmotility, and autonomic neuropathy before and after abstinence.

OBJECTIVE: To carry out a comprehensive study on gastrointestinal symptoms, motility and autonomic neuropathy in chronic alcoholics before and one year after abstinence. METHODS: Dyspeptic symptoms (questionnaires), fasting and postprandial gallbladder and gastric motility (ultrasonography), oro-cecal transit time (lactulose H2 -breath test), stool form score (indirect marker of colonic transit), and autonomic neuropathy (sweat spot test, R-R ratio) were assessed at baseline in 268 subjects (136 chronic alcoholics and 132 healthy controls). A subgroup of 39 patients was re-evaluated after 12 months of abstinence. RESULTS: Chronic alcoholics had increased dyspepsia, delayed gastric emptying and oro-cecal transit time but faster gallbladder emptying, with slightly accelerated colonic transit. Sympathetic, but not parasympathetic, autonomic dysfunction was found. Dyspeptic symptoms and functional alterations of gastric emptying and oro-cecal transit tests were still present after 12-month abstinence, whereas gallbladder motility, stool form score and sympathetic function improved. CONCLUSIONS: Chronic alcoholics exhibit combined and interdependent presence of dyspeptic symptoms, impaired motility at different levels of the gastrointestinal tract, with sympathetic dysfunction. Only a few of these abnormalities improve after one year of abstinence from alcohol.

Experimental model of alcohol-related peripheral neuropathy.

INTRODUCTION: The aim of this work was to determine the effect of chronic alcohol exposure on peripheral nerves in a nutritionally balanced rat model of alcoholism. METHODS: Three different strains of adult male rats were pair-fed for 8 weeks with isocaloric liquid diets containing 0% or 37% ethanol. Nerve conduction studies (NCS) were performed. Peripheral nerve and muscle were examined histologically with morphometrics. RESULTS: Ethanol exposure significantly slowed velocity in tibial and fibular nerves, but not in the plantar nerve in all 3 strains. Studies of the sciatic nerve revealed decreased fiber diameters and increased regenerative sprouts in peripheral nerves. There was muscle denervation of ethanol-exposed rats in all 3 strains. CONCLUSIONS: Chronic ethanol exposure caused a polyneuropathy characterized by axonal degeneration despite adequate nutrition. These results suggest that ethanol exposure has direct neurotoxic effects on peripheral nerves. This model may be useful in understanding the underlying mechanism(s) of alcohol-related peripheral neuropathy.

Elucidation of molecular mechanism involved in neuroprotective effect of Coenzyme Q10 in alcohol-induced neuropathic pain.

The aim of the present investigation was to evaluate the effect of Coenzyme Q10 and its combination with vitamin E in alcohol-induced chronic neuropathic pain. Male Wistar rats were orally treated with alcohol (10 g/kg, 35% v/v, b.i.d.) for 10 weeks. Coenzyme Q10 (25, 50, and 100 mg/kg) and vitamin E (100 mg/kg) were coadministered orally for 1 h after ethanol administration for 10 weeks. Various nerve functions, biochemical, and molecular parameters were assessed. Chronic administration of ethanol for 10 weeks resulted significant development of neuropathic pain. Treatment with Coenzyme Q10 (50 and 100 mg/kg) for 10 weeks showed significant and dose dependently increased in level of nociceptive threshold, endogenous antioxidant, and Na,K-ATPase enzyme. Coenzyme Q10 (50 and 100 mg/kg) significantly restored the levels of motor nerve conduction velocity and sensory nerve conduction velocity. It also showed significant decrease in levels of endogenous calcium, oxidative-nitrosative stress, TNF-α, IL-1ß, and IL-4 level. Alteration in protein expression of polymerase gamma (pol γ) was significantly restored the Coenzyme Q10 treatment. The important finding of the study is that, Coenzyme Q10 (100 mg/kg) and α-tocopherol (100 mg/kg) combination-treated rats showed more significant prevention of behavioral, biochemical, and molecular neurotoxic effect of alcohol administration than Coenzyme Q10 or α-tocopherol alone treated group. It is evident from the finding of present investigation that plethora of mechanism including inhibition of oxido-nitrosative stress, release of pro-inflammatory cytokine, modulation of endogenous biomarker, and protection of pol γ protein expression simultaneously orchestrate to exhibits neuroprotective effect of Coenzyme Q10, vitamin E and their combination.

Therapeutic role of curcumin in prevention of biochemical and behavioral aberration induced by alcoholic neuropathy in laboratory animals.

Painful peripheral neuropathy induced by chronic ethanol consumption is a major medico-socioeconomical problem. The objective of present investigation was to study the effect of curcumin (20, 40 and 80mg/kg; p.o.) in alcohol-induced neuropathy in rats. Ethanol (35% v/v, 10g/kg; p.o.) was administered for 10 weeks which showed a significant decrease in thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocity. It caused enhanced malondialdehyde, oxidative-nitrosative stress, total calcium levels, inflammatory mediators (TNF-α and IL-1ß levels) along with DNA damage. Co-administration of curcumin and α-tocopherol for 10 weeks significantly and dose-dependently improved nerve functions, biochemical as well as molecular parameters and DNA damage in sciatic nerve of ethanol treated rats. Hence, it was concluded that curcumin is of potent therapeutic value in the amelioration of alcoholic neuropathy in rats and acts by inhibition of pro-inflammatory mediators like TNF-α and IL-1ß.

Amelioration of functional, biochemical and molecular deficits by epigallocatechin gallate in experimental model of alcoholic neuropathy.

Long term alcohol consumption leads to decreased nociceptive threshold characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism involved in this pain includes increased oxidative-nitrosative stress, release of pro-inflammatory cytokines and neuronal apoptosis. The present study was designed to explore the protective effect of epigallocatechin-3-gallate against alcoholic neuropathic pain in rats. Rats fed with alcohol (35%) for 10 weeks showed markedly decreased tail flick latency in tail-immersion test (thermal hyperalgesia), vocalization threshold in Randall-Sellito test (mechanical hyperalgesia) and paw-withdrawal threshold in von-Frey hair test (mechanical allodynia) along with enhanced oxidative-nitrosative stress and inflammatory mediators (TNF-α, IL-1ß and TGF-ß1 levels). Co-administration of epigallocatechin-3-gallate (25-100 mg/kg) significantly and dose-dependently prevented functional, biochemical and molecular changes associated with alcoholic neuropathy. In conclusion, the current findings suggest the neuroprotective potential of epigallocatechin-3-gallate in attenuating the functional, biochemical and molecular alterations associated with alcoholic neuropathy through modulation of oxido-inflammatory cascade.

Dry beriberi mimicking the Guillain-Barre syndrome.

A 44-year-old man is described with severe flaccid quadriparesis that evolved over 3 weeks. He had regularly binged on alcohol-up to 20 cans of beer per day with occasional consumption of spirits-for more than 15 years but had balanced this with regular food intake. However, for a week prior to the current episode he had not eaten anything of significance. Nerve conduction studies revealed a background peripheral, mainly sensory, neuropathy with a superimposed acute motor axonopathy. CSF was normal. He improved with high dose vitamin replacement and physiotherapy but remains dependent on a Zimmer frame for mobility and a splint for wrist drop.

Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy.

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliable successful therapy, which is mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy is characterized by spontaneous burning pain, hyperalgesia (an exaggerated pain in response to painful stimuli) and allodynia (a pain evoked by normally innocuous stimuli). Chronic alcohol intake is known to decrease the nociceptive threshold with increased oxidative-nitrosative stress and release of proinflammatory cytokines coupled with activation of protein kinase C. The aim of the present study is to investigate the effect of both isoforms of vitamin E, alpha-tocopherol (100mg/kg; oral gavage) and tocotrienol (50, 100 and 200mg/kg; oral gavage) against alcohol-induced neuropathic pain in rats. Male Wistar rats, were administered 35% v/v ethanol (10 g/kg; oral gavage) for 10 weeks, and were treated with alpha-tocopherol and tocotrienol for the same duration. Ethanol-treated animals showed a significant decrease in nociceptive threshold as evident from decreased tail flick latency (thermal hyperalgesia) and decreased paw-withdrawal threshold in Randall-Sellito test (mechanical hyperalgesia) and von-Frey hair test (mechanical allodynia) along with the reduction in nerve glutathione and superoxide dismutase levels. TNF-alpha and IL-1beta levels were also significantly increased in both serum and sciatic nerve of ethanol-treated rats. Treatment with alpha-tocopherol and tocotrienol for 10 weeks significantly improved all the above-stated functional and biochemical deficits in a dose-dependent manner with more potent effects observed with tocotrienol. The study demonstrates the effectiveness of tocotrienol in attenuation of alcoholic neuropathy.

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy.

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

Strength-duration properties of sensory and motor axons in alcoholic polyneuropathy.

OBJECTIVE: The strength-duration time constant (SDTC) is a measure of axonal excitability and depends on the biophysical properties of the axonal membrane. The strength-duration time constant can provide information about Na+ channel function. We aimed to examine changes in the SDTCs of motor and sensory fibers in the median nerves in patients with alcoholic polyneuropathy. METHODS AND RESULTS: We measured the SDTCs of motor and sensory fibers in 17 patients with alcoholic polyneuropathy (15 men and two women) after stimulating the right median nerve at the wrist. The results were compared with ten healthy age-matched subjects (six men and four women). In patients, the SDTC and rheobase for the motor fibers were 370.8+/-97.4 micros and 3.9+/-1.7 mA; for the sensory fibers, the SDTC and rheobase were 464.7+/-104.3 micros and 3.3+/-1.9 mA. In controls, the SDTC and rheobase for the motor fibers were 359.3+/-103.5 micros and 3.5+/-1.9 mA; for the sensory fibers, the SDTC and rheobase were 478.9+/-113.9 micros and 2.1+/-1.5 mA. Sensory fibers had significantly longer SDTCs and lower rheobase than motor fibers in patients and controls. However, when the values of the patients and controls were compared, a statistically significant difference was only found for the rheobase of sensory fibers (p=0.037). CONCLUSIONS: Although alcoholic neuropathy corresponds to the pattern of axonopathy, it did not act on the SDTC of the median nerve, which depends on the biophysical properties of the axonal membrane at the node of Ranvier. The process causing axonal degeneration in alcoholic neuropathy may affect internodal channels other than nodal channels or the Na+ -K+ ATP pump.

[Metabolic and nutritional neuropathy].

We assessed whether postgastrectomy polyneuropathy associated with thiamine deficiency is clinicopathologically identical to beriberi neuropathy, including a biochemical determination of thiamine status. The typical presentation for the two etiologies was as a symmetric sensorimotor polyneuropathy predominantly involving the lower limbs. In both groups, the main electrophysiologic findings were those of axonal neuropathy, most prominently in the lower limbs. Sural nerve biopsy specimens also indicated axonal degeneration in both groups. Subperineurial edema was commonly observed. Thiamine-deficiency neuropathies due to gastrectomy and dietary imbalance are identical despite variability in their clinicopathologic features and suggested that thiamine deficiency can be a major cause of postgastrectomy polyneuropathy. Characteristics of alcoholic neuropathy have been obscured by difficulty in isolating them from features of thiamine-deficiency neuropathy. We assessed 64 patients with alcoholic neuropathy including subgroups without and with coexisting thiamine deficiency. Thirty-two patients with nonalcoholic thiamine-deficiency neuropathy also were investigated for comparison. We concluded that pure-form of alcoholic neuropathy was distinct from pure-form of thiamine-deficiency neuropathy, supporting the view that alcoholic neuropathy can be caused by direct toxic effect of ethanol or its metabolites. However, features of alcoholic neuropathy is influenced by concomitant thiamine-deficiency state, having so far caused the obscure clinicopathological entity of alcoholic neuropathy.

A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization.

Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.

mGlu5 receptor and protein kinase C implicated in the development and induction of neuropathic pain following chronic ethanol consumption.

The central mechanisms of neuropathic pain following chronic ethanol consumption are poorly understood. We previously reported that the levels of metabotropic glutamate 5 (mGlu5) receptor and phosphorylated-protein kinase C (PKC) were significantly increased in the spinal cord following chronic ethanol consumption. The aim of this study was to investigate whether mGlu5 receptor and PKC inhibitors directly attenuate the neuropathic pain-like state induced by chronic ethanol treatment in rats. A significant decrease in the mechanical nociceptive threshold was observed 5 weeks of chronic ethanol consumption. This hyperalgesia was significantly attenuated by repeated i.p. injection of (S)-2,6-diamino-N-[[1-(oxotridecyl)-2-piperidinyl]methyl] hexanamide dihydrochloride (NPC15437), a selective PKC inhibitor, once a day for a week after 4 weeks of ethanol treatment. Furthermore, this hyperalgesia was also significantly attenuated by repeated i.p. injection of 6-methyl-2-[phenylethynyl]-pyridine (MPEP), a selective mGlu5 receptor inhibitor, once a day for a week after 4 weeks of ethanol treatment. Furthermore, the hyperalgesia that developed after 5 weeks of ethanol treatment was significantly suppressed by a single i.p. post-injection with either NPC15437 or MPEP. These findings constitute direct evidence that spinal mGlu5 receptor and PKC play substantial roles in the development and maintenance of an ethanol-dependent neuropathic pain-like state in rats.

Involvement of microglia in the ethanol-induced neuropathic pain-like state in the rat.

Central mechanisms of neuropathy induced by chronic ethanol treatment are almost unknown. In this study, rats were treated with ethanol-diet for 72 days. Mechanical hyperalgesia was observed during ethanol consumption, even after ethanol withdrawal. Under these conditions, a microglial marker ionized calcium-binding adaptor molecule 1-, but not a neuron marker microtuble associated protein-2-, like immunoreactivies were increased in the rat spinal cord. Furthermore, hypertrophy of microglia was clearly observed following chronic ethanol consumption. These findings support the idea that the activation and hypertrophy of microglia in the spinal cord may be, at least in part, associated with in the induction of ethanol-dependent neuropathic pain-like state.

Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat.

While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. We compared changes in mechanically-evoked C-fiber activity, in models of painful peripheral neuropathy induced by drinking ethanol (alcohol) or administering 2',3'-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor for AIDS therapy, two co-morbid conditions in which pain is thought to be mediated by different second messenger signaling pathways. In C-fiber afferents, ddC decreased conduction velocity. In contrast, alcohol but not ddC caused enhanced response to mechanical stimulation (i.e., decrease in threshold and increase in response to sustained threshold and supra-threshold stimulation) and changes in pattern of evoked activity (interspike interval and action potential variability analyses). These marked differences in primary afferent nociceptor function, in two different forms of neuropathy that produce mechanical hyperalgesia of similar magnitude, suggest that optimal treatment of neuropathic pain may differ depending on the nature of the causative insult to the peripheral nervous system, and emphasize the value of studying co-morbid conditions that produce painful peripheral neuropathy by different mechanisms.