Characterization and quantification of alcohol-related polyneuropathy by magnetic resonance neurography.

BACKGROUND: We characterized and quantified peripheral nerve damage in alcohol-dependent patients (ADP) by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings. METHODS: Thirty-one adult patients with a history of excessive alcohol consumption and age-/sex-matched healthy controls were prospectively examined. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into ADP with alcohol-related polyneuropathy (ALN) and without ALN (Non-ALN). 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was performed using dual-echo 2-dimensional relaxometry sequences with spectral fat saturation. Detailed quantification of nerve injury by morphometric (cross-sectional area [CSA]) and microstructural MRN markers (proton spin density [ρ], apparent T2-relaxation-time [T2app ]) was conducted in all study participants. RESULTS: MRN detected nerve damage in ADP with and without ALN. A proximal-to-distal gradient was identified for nerve T2-weighted (T2w)-signal and T2app in ADP, indicating a proximal predominance of nerve lesions. While all MRN markers differentiated significantly between ADP and controls, microstructural markers were able to additionally differentiate between subgroups: tibial nerve ρ at thigh level was increased in ALN (p < 0.0001) and in Non-ALN (p = 0.0052) versus controls, and T2app was higher in ALN versus controls (p < 0.0001) and also in ALN versus Non-ALN (p = 0.0214). T2w-signal and CSA were only higher in ALN versus controls. CONCLUSIONS: MRN detects and quantifies peripheral nerve damage in ADP in vivo even in the absence of clinically overt ALN. Microstructural markers (T2app , ρ) are most suitable for differentiating between ADP with and without manifest ALN, and may help to elucidate the underlying pathomechanism in ALN.

Mechanical characteristics of BMSCs-intervened sciatic nerve in chronic alcohol-intoxicated animal model.

OBJECTIVE: To study the mechanical properties of sciatic nerve in rats with chronic alcoholism (CA) and intervened with bone marrow mesenchymal stem cells (BMSCs) and to provide biomechanical basis for clinical practice. METHODS: the serum of the BMSCs-intervened CA rats was sampled and determined the contents of malondialdehyde (MDA), metallothionein (CAS, MT), and Glutathione/r -glutamyl cysteinyl/glycine (GSH); meanwhile, the rats' sciatic nerve was tested the tensile and observed the histomorphological changes. RESULTS: The mechanical properties of sciatic nerve in BMSCs-intervened CA rats, as well as the serum levels of MT and GSH, were significantly different from those in the basic fibroblast growth factor (bFGF)-intervened CA rats (p < 0.05). CONCLUSIONS: BMSCs intervention can restore the levels of MT, GSH, MDA, histomorphology, and tensile mechanical properties in CA animal model, and its effects on repairing sciatic nerve are obvious.

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.

Acute nutritional axonal neuropathy.

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.

[EXPERIMENTAL MODELS OF ALCOHOLIC NEUROPATHY IN RATS.]

The aim of this work was to study the behavioral and histopathomorphological signs of peripheral neuropathy development in male Wistar rats on the model of alcoholic neuropathy. Chronic consumption of ethanol solution with concentration increasing from 7.47 to 26.2% (w/w) resulted in neuropathy (allodynia) de- velopment after 8 weeks of chronic alcohol administration. The behavioral signs of allodynia became significant on the 8th week and were retained up to the end of experiment (15 weeks of ethanol administration). The reference drug gabapentin effectively reduced the manifestation of allodinia. Histological exami- nation of sciatic nerve preparations from animals killed after ethanol consumption for 5, 10 and 15 weeks revealed the development of histopathomorphological pattern with increasing duration of chronic alcoholization. At the initial stage, the morphological basis of observed behavioral manifestations was provided by excess lipid deposition in peri/epineurium of nerve specimens). The further increase in treatment duration (up to 10 and 15 weeks) was associated with demye- lination and development of inflammation of the sciatic nerve. This experimental model allows one to investigate the efficacy of new neuroprotective and ana- lgesic substances - potential drugs for both prevention and management of neuropathy.

Small-fiber degeneration in alcohol-related peripheral neuropathy.

BACKGROUND: Alcohol-related peripheral neuropathy (ALN) is generally characterized as an axonal large-fiber polyneuropathy caused by thiamine deficiency. We hypothesized, based on clinical observations, that ALN is associated with a small-fiber polyneuropathy that can be diagnosed with skin biopsy in heavy alcohol drinking subjects with normal thiamine status. METHODS: Eighteen individuals (9 heavy alcohol drinking subjects and 9 healthy control subjects) were assessed for the potential utility of skin biopsies in detecting ALN-associated small nerve fiber degeneration. Heavy drinking was defined as greater than 4 drinks/d and 5 drinks/d in women and men, respectively, as determined by the Timeline Follow-Back and lifetime drinking history. All subjects underwent neurological examination, nerve conduction studies, and skin biopsies to quantify end nerve fiber densities (ENFD). Other causes of neuropathy were excluded and thiamine status was assessed. RESULTS: Average ENFD were significantly decreased at the calf in the alcohol group as compared with control group (p < 0.0001). Histological sections demonstrated striking attrition and architectural simplification of intraepidermal nerve fibers in the heavy alcohol drinking subjects. There were no significant intergroup differences with respect to clinical assessments of neuropathy or thiamine status. CONCLUSIONS: ALN is associated with a small-fiber neuropathy that can be detected with skin biopsy in heavy alcohol drinking individuals with normal thiamine status. Skin biopsy is a useful, minimally invasive biomarker that could extend studies to understand the effect of alcohol on the peripheral nerves and to evaluate potential therapeutic agents in larger clinical trials.

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.

Muscle pain in models of chemotherapy-induced and alcohol-induced peripheral neuropathy.

OBJECTIVE: While inflammatory pain is well described in skeletal muscle, neuropathic muscle pain remains to be clarified. We used 3 well-established rodent models of peripheral neuropathy to evaluate for muscle pain. METHODS: In rats exposed to either of 2 neurotoxic cancer chemotherapies, paclitaxel or oxaliplatin, or to alcohol consumption, we assessed the evolution of mechanical hyperalgesia in skeletal muscle and skin, in the same animal. To explore the involvement of protein kinase C epsilon (PKCε), a second messenger implicated in some forms of neuropathic pain, antisense oligodeoxynucleotides (AS-ODNs) or mismatch ODNs (MM-ODNs) for PKCε were administered intrathecally. RESULTS: Rats submitted to models of chemotherapy-induced and alcohol-induced neuropathy developed persistent muscle hyperalgesia, which evolved in parallel in muscle and skin. The administration of PKCε AS, which has been shown to mediate cutaneous hyperalgesia in paclitaxel and ethanol models of neuropathic pain, also inhibited muscle hyperalgesia induced by these agents. Stopping AS-ODN was associated with the reappearance of hyperalgesia at both sites. The AS-ODN to PKCε treatment was devoid of effect in both muscle and skin in the oxaliplatin neuropathy model. INTERPRETATION: Our results support the suggestion that neuropathic muscle pain may be a greater clinical problem than generally appreciated.

Peripheral nerve size in normals and patients with polyneuropathy: an ultrasound study.

Ultrasound has been used for visualizing peripheral nerve pathology. Our goal was to use ultrasound to quantitate the sizes of upper extremity nerves along their length in control subjects and patients with neuropathy. We measured median and ulnar nerve cross-sectional areas (NCSA) in the arms of 190 subjects, including 100 with neuropathies and 90 controls. We found that NCSAs in healthy child and adult controls were greater with increasing height, at proximal sites, and at sites of entrapment. Nerves were enlarged in all Charcot-Marie-Tooth 1A (CMT-1A) (11 of 11; 100%), most chronic inflammatory demyelinating polyneuropathy (CIDP) (31 of 36; 86%), half of Guillain-Barré syndrome (GBS) (8 of 17; 47%), but few axonal neuropathy (7 of 36, 19%) subjects. In GBS, nerve enlargement occurred early and with minimal electrodiagnostic abnormalities in some patients. We conclude that NCSA measured by ultrasound is a quantifiable marker of nerve features that should be corrected for patient characteristics and nerve site. NCSA is generally larger in demyelinating than it is in axonal polyneuropathies.

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.

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.

Alcoholic neuropathy.

PURPOSE OF REVIEW: The concept of alcoholic neuropathy has been obscured because of an often undetected or overestimated influence of thiamine deficiency. We describe clinicopathologic features of alcoholic neuropathy, taking the effect of thiamine status into consideration, and recent progress associated with the pathogenesis. RECENT FINDINGS: Clinical features of alcoholic neuropathy without thiamine deficiency are characterized by slowly progressive, sensory-dominant symptoms. Superficial sensation is predominantly impaired and painful symptoms are the major complaint. Pathologic features are characterized by small-fiber-predominant axonal loss. In contrast, the clinicopathologic features of alcoholic neuropathy with concomitant thiamine deficiency are variable, constituting a spectrum ranging from a picture of a pure form of alcoholic neuropathy to a presentation of nonalcoholic thiamine-deficiency neuropathy. One possible mediator of the direct neurotoxic effects among the metabolites of ethanol is acetaldehyde. Axonal transport and cytoskeletal properties are impaired by ethanol exposure. Protein kinase A and protein kinase C may also play a role in the pathogenesis, especially in association with painful symptoms. SUMMARY: Nutritional deficiency as well as the direct neurotoxic effects of ethanol or its metabolites can cause alcoholic neuropathy. Although clinicopathologic features of the pure form of alcoholic neuropathy are uniform, they show extensive variation when thiamine deficiency is present.

[Peripheral and optical myeloneuropathy in a folic acid deficient alcoholic patient]. / Mieloneuropatía periférica y óptica en un paciente alcohólico deficiente en ácido fólico.

INTRODUCTION: In Western countries, neurological disorders secondary to toxic nutritional problems usually present as isolated cases that are generally associated to identifiable causes (alcoholism, eating disorders, absorption disorders, use of medicines) that reduce the availability of basic nutrients, especially B group vitamins, but also folic acid (FA). The optic nerves and the peripheral axons are frequent target organs in this type of pathology, but leukoencephalopathy and spinal cord involvement may also appear, often in combination. CASE REPORT: We describe the case of a 38-year-old female smoker with a heavy alcohol habit, who developed a subacute clinical pattern of, predominantly axonal, sensitive peripheral polyneuropathy, with vegetative fibre involvement. She also presented involvement of the posterior spinal cord, which gave rise to an ataxic disorder in the gait, as well as a severe bilateral retrobulbar optic neuropathy. Likewise, she presented macrocytosis (MCV: 118) due to megaloblastosis. She was also found to have a FA deficit but a normal vitamin B12 metabolism. With the help of supplementary vitamins, stopping drinking and the regularisation of her diet, the patient presented progressive clinical improvement, and was able to walk without support at 3 months and almost completely recovered her sight, which was corroborated by an improvement in the studies of both visual and somatosensorial evoked potentials. CONCLUSIONS: In our community, alcoholism is a frequent cause of nutritional deficiencies, which lead to neurological problems. FA is one of the nutrients that become deficient in alcoholics. More and more descriptions are being reported of peripheral polyneuropathy, retrobulbular optic neuropathy, myelopathy or leukoencephalopathy associated to FA deficiency, above all in patients with a history of alcoholism.

Neurocognitive impairment associated with alcohol use disorders: implications for treatment.

Between 50% and 80% of individuals with alcohol use disorders experience mild to severe neurocognitive impairment. There is a strong clinical rationale that neurocognitive impairment is an important source of individual difference affecting many aspects of addiction treatment, but empirical tests of the direct influence of impairment on treatment outcome have yielded weak and inconsistent results. The authors address the schism between applied-theoretical perspectives and research evidence by suggesting alternative conceptual models of the relationship between neurocognitive impairment and addiction treatment outcome. Methods to promote neurocognitive recovery and ways in which addiction treatments may be modified to improve psychosocial adaptation are suggested. Specific suggestions for future research that may help clarify the complex relations between neurocognitive impairment and addiction treatment are outlined.

[Alcohol polyneuropathy]. / Alkoholpolyneuropathie.

The Alcoholic Polyneuropathy occurs in about 10-30% of alcoholics. It is the second most frequent type of polyneuropathies after the diabetic form. The clinical pattern is a symmetric sensory or symmetric motor sensory manifestation type. In almost all cases there is a pressure pain of the calves. In the beginning the disturbance of the proprioceptive sensation is predominant. Disturbances of the autonomic nervous system deal with the sympathetic as well as the parasympathetic nervous system. Morphologically there is a primary axonal degeneration. A direct toxic influence of the alcohol itself is discussed as the prevailing pathomechanism.

[Therapy of polyneuropathies. Causal and symptomatic]. / Therapie von Polyneuropathien. Kausal und symptomatisch.

In the first instance, polyneuropathies are treated causally. The most common underlying cause is diabetes mellitus or alcohol abuse. In a large number of patients with polyneuropathy, however, the underlying cause cannot be definitively identified. For these--but equally for patients with etiologically clear polyneuropathy--a stock-taking of clinical symptoms should be carried out and, where indicated, symptomatic treatment initiated. In addition to medication aimed at combating pain, muscular spasm, autonomic functional disorders, and for the prevention of thrombosis, physical measures (physiotherapy, foot care, orthopedic shoes) are of primary importance.

Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status.

BACKGROUND: Although polyneuropathy related to chronic alcoholism has been reported frequently, its clinical features and pathogenesis remain to be clarified. OBJECTIVE: To determine the clinicopathologic features and pathogenesis of alcoholic polyneuropathy associated with pain in patients with normal thiamine status, particularly in comparison to beriberi neuropathy. PATIENTS AND METHODS: Clinical, electrophysiologic, and histopathologic findings were assessed in 18 patients with painful alcoholic polyneuropathy and normal thiamine status. RESULTS: Symmetric sensory-dominant polyneuropathy predominantly involving the lower limbs was the major clinical pattern. Painful sensations with or without burning quality represented the initial and major symptom. Progression of symptoms usually was gradual, continuing over months or years. Electrophysiologic and pathologic findings mainly indicated an axonal neuropathy. Densities of small myelinated fibers and unmyelinated fibers were more severely reduced than the density of large myelinated fibers, except in patients with a long history of neuropathic symptoms and marked axonal sprouting. CONCLUSIONS: The clinicopathologic features of painful symptoms and small axon loss are distinct from those of beriberi neuropathy. Sensory-dominant involvement with prominent neuropathic pain is characteristic of alcoholic neuropathy when thiamine deficiency is not involved, supporting the view of direct neurotoxic effect by alcohol or its metabolites.

Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis.

Alcohol misusers frequently have difficulties in gait, and various muscle symptoms such as cramps, local pain and reduced muscle mass. These symptoms are common in alcoholic patients and have previously been ascribed as neuropathological in origin. However, biochemical lesions and/or the presence of a defined myopathy occur in alcoholics as a direct consequence of alcohol misuse. The myopathy occurs independently of peripheral neuropathy, malnutrition and overt liver disease. Chronic alcoholic myopathy is characterized by selective atrophy of Type II fibres and the entire muscle mass may be reduced by up to 30%. This myopathy is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere and occurs in approximately 50% of alcohol misusers. Alcohol and acetaldehyde are potent inhibitors of muscle protein synthesis, and both contractile and non-contractile proteins are affected by acute and chronic alcohol dosage. Muscle RNA is also reduced by mechanisms involving increased RNase activities. In general, muscle protease activities are either reduced or unaltered, although markers of muscle membrane damage are increased which may be related to injury by reactive oxygen species. This supposition is supported by the observation that in the UK, alpha-tocopherol status is poor in myopathic alcoholics. Reduced alpha-tocopherol may pre-dispose the muscle to metabolic injury. However, experimental alpha-tocopherol supplementation is ineffective in preventing ethanol-induced lesions in muscle as defined by reduced rates of protein synthesis and in Spanish alcoholics with myopathy, there is no evidence of impaired alpha-tocopherol status. In conclusion, by a complex series of mechanisms, alcohol adversely affects skeletal muscle. In addition to the mechanical changes to muscle, there are important metabolic consequences, by virtue of the fact that skeletal muscle is 40% of body mass and an important contributor to whole-body protein turnover.