The clinical symptoms of alcoholic peripheral neuropathy were described more than 200 years ago. The descriptions by Lettsom (1787)[1] and Jackson (1822)[2] have led to the recognition and association of peripheral nerve disease with excessive ethanol use. Several terms connote alcohol neuropathy, including neuritic beriberi, neuropathic beriberi, and alcoholic neuritis. In patients with alcoholic neuropathy, nutritional deficiency goes hand in hand with alcohol abuse.
The similarity between beriberi, which is caused by deficiency of thiamine (vitamin B 1), and alcoholic neuropathy had long been noted, but in 1928, Shattuck was the first to seriously discuss the relationship.[3] He suggested that polyneuritis of chronic alcoholism was caused chiefly by failure to take or assimilate food containing a sufficient quantity of vitamin B complex and might properly be regarded as true beriberi. However, this theory may be only partially true. Independently of thiamine deficiency, ethanol now appears to have a direct toxic effect on peripheral nerves.
The precise pathogenesis of alcohol neuropathy remains unclear. Separating ethanol use from nutritional and vitamin deficiencies, especially thiamine, has always been difficult and a source of long-standing debate. Nutritional deficiency (frequently associated with alcohol neuropathy) and/or the direct toxic effect of alcohol or both have been implicated and studied.[4, 5] In Wernicke-Korsakoff syndrome, a clear association between reduction of thiamine levels or thiamine-mediated enzyme activity (transketolase) has been established, though this has not been conclusively established in the case of peripheral neuropathy.
It is widely assumed that alcohol-related peripheral neuropathy is primarily a consequence of nutritional deficiency. This was largely based on observations made more than eight decades ago demonstrating that thiamine deficiency (beriberi) neuropathy was clinically similar to ALN. In recent studies, failure of thiamine treatment to reverse ALN, together with new information demonstrating clinical and electrophysiological distinctions between ALN and nutritional deficiency neuropathies, suggests that alcohol itself may significantly predispose and enhance development of neuropathy in the appropriate clinical setting. The authors reviewed the evidence on both sides and conclude that ALN should be regarded as a toxic rather than nutritional neuropathy.[6] In their comparison of patients with alcoholism and nonalcoholic control subjects, Behse and Buchthal concluded that nutritional deficiencies alone did not produce the neuropathy.[7]
Monforte et al. concluded that alcohol appears to be toxic to autonomic and peripheral nerves in a dose-dependent manner, based on heart rate, blood pressure, and electrophysiologic examination.[8]
In a study of macaque monkeys, Hallett et al. failed to produce clinical and electrophysiologic signs of neuropathy in monkeys that were given a certain amount of alcohol for 3–5 years.[9] Studies in rats also failed to demonstrate a direct toxic effect of alcohol on the peripheral nerves.
Most studies of peripheral neuropathy in humans and animals implicate nutritional deficiency as an etiology as opposed to the direct toxic effect of alcohol.
Independent of thiamine deficiency, ethanol now appears to have a direct toxic effect on the peripheral nerves. Dina et al suggest that catecholamines in nociceptors are metabolized to neurotoxic products by monoamine oxidase-A (MAO-A). This can cause neuronal dysfunction, which leads to neuropathic pain.[10]
Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status is well known. The clinicopathologic features of painful symptoms and small axon loss are distinct from those of beriberi neuropathy. This supports the view of direct neurotoxic effect by alcohol or its metabolites.[11]
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.[12]
In utero alcohol exposure predisposes to a major risk factor for lifelong aberrant neuroimmune function. Behavioral and physiological sequelae occur throughout life and include cognitive developmental disabilities as well as disease susceptibility related to aberrant immune and neuroimmune actions, in particular significant alterations in the neuroimmune axis occur.[13, 14]
Depending on criteria and patient selection, incidence of peripheral neuropathy ranging from 10% to 50% has been reported. These studies included alcoholics hospitalized for other reasons or for detoxification. Neuropathy is more prevalent in frequent, heavy, and continuous drinkers compared to more episodic drinkers.[8]
Mortality/Morbidity
Johnson and Robinson studied the mortality rate of individuals with alcoholism who had autonomic neuropathy.[13]
Their findings suggested that evidence of vagal neuropathy in long-term alcoholics is associated with a significantly higher mortality rate than in the general population (a reported 88% survival rate at 7 years in alcoholics with autonomic neuropathy as compared to 94% in the general population).
Deaths due to cardiovascular disease are a major factor.
Many deaths were attributed to strokes, since heavy alcohol consumption is a significant risk factor for stroke.
Sex
A high incidence of alcoholic polyneuropathy has been observed in women and men. Women, when compared to men, are more predisposed to alcohol-induced damage, and the susceptibility extends to hepatic, cardiac, cerebral, and muscular changes. Also, there appears to be a greater sensitivity of females to the toxic effects of alcohol on peripheral nerve fibers unrelated to malnutrition.
Clinical manifestations of alcoholic neuropathy can be summarized as slowly progressive (over months) abnormalities in sensory, motor, autonomic, and gait function. Patients might ignore early symptoms, and seek help only when significant complications develop. Symptoms are often indistinguishable from other forms of sensory motor axonal neuropathy.
Sensory symptoms include early numbness of the soles, followed by dysesthesias of feet and legs, especially at night. "Pins and needles" sensation, which is reported commonly, progresses to severe pain that is described as burning or lancinating. Symptoms typically start distally and progress slowly to proximal involvement (dying-back neuropathy). When symptoms extend above the ankle level, the fingertips often get similarly affected, giving rise to the well-known stocking and glove pattern. Paresthesia might become unpleasant, even painful.
Motor manifestations include distal weakness and muscle wasting.[15]
When proprioception becomes involved, sensory ataxia will occur giving rise to gait difficulty, independent of alcoholic cerebellar degeneration.
Autonomic disturbances are seen less commonly than in other neuropathic conditions (eg, diabetes).
Dysphagia and dysphonia are prominent secondary to degeneration of the vagus nerve. Other parasympathetic abnormalities include depressed reflex heart rate responses, abnormal pupillary function, sexual impotence, and sleep apnea.
Sympathetic dysfunction is rare but if present can produce orthostatic hypotension and hypothermia.
Frequent falls and accidents are common. These are secondary to gait unsteadiness and ataxia that are caused by cerebellar degeneration, sensory ataxia, or distal weakness.
Examination shows distal sensory loss in the lower extremities. In severe cases, the hands may be involved.
In addition to distal atrophy and weakness, deep tendon reflexes usually are decreased or absent.
Stasis dermatitis, glossiness, and thinness of skin of the lower legs are common findings.
Hyperesthesia and hyperalgesia may be seen along with hyperpathia.
Excessive sweating of the soles and dorsal aspects of the feet and of the palms and fingers is a common manifestation of alcoholic neuropathy and is indicative of involvement of the peripheral (postganglionic) sympathetic nerve fibers.
Occurrence of trophic ulcers is rare.
Charcot arthropathy, also known as neuroarthropathy, is most commonly associated with diabetes mellitus, despite a variety of other etiologies. It has also been associated with chronic alcoholism in nondiabetic individuals.
Rare cases have been reported of severe acute or subacute neuropathy mimicking Guillain-Barré syndrome.
Pressure palsies include radial neuropathy (Saturday night palsy), which is radial nerve compression at the spiral groove that yields wrist drop, in addition to compression neuropathy at many additional sites. Ulnar neuropathy at the elbow, radial or axillary nerve injury in the axilla (crutch-type compression), peroneal neuropathy at the fibular head, and superficial radial nerve are just a few of the potential sites of nerve injury.
Rare cases of acute or subacute alcoholic peripheral neuropathy have been described. They mimic Guillain-Barré syndrome, although biopsy and electrodiagnostic studies have revealed an axonal neuropathy, with normal CSF parameters. A causal association with ethanol has been proposed.
Pressure palsies: Alcoholics with generalized axonal peripheral neuropathy are prone to pressure palsies at multiple sites. Associated nutritional deficiency and weight loss might potentiate the same. Neurapraxia is more common than axonotmesis, and recovery is often the rule, although elderly patients do poorly.
The diagnosis is based on accurate history of prolonged and excessive alcohol intake, clinical signs and symptoms, and electrophysiologic testing. Behse and Buchtal suggested that a minimum of 100 mL of ethyl alcohol (3 L of beer or 300 mL of spirits) per day for 3 years will precipitate the neuropathy.
Electrophysiologic findings primarily reveal evidence of primary axonal sensory motor polyneuropathy. Electrodiagnosis might detect a subclinical peripheral neuropathy.
Sensory conduction studies may be abnormal even before the advent of clinical symptoms.
Sural nerve sensory action potentials (SNAP) are reduced slightly to moderately in conduction velocity and SNAP amplitudes also are reduced.
As the condition worsens, the sensory potentials may become unobtainable. The median, radial, and ulnar nerves show the same response as the disease progresses.
Motor conduction studies of the lower extremities (tibial and peroneal nerves) may reveal a slight reduction in conduction velocity (not to exceed 70-80% of the lower limit of normal), with diminution of the compound muscle action potential (CMAP) amplitude with a slight prolongation in distal latency. The upper extremity nerves follow the same pattern as time progresses.
The tibial H reflex latency is prolonged and becomes unobtainable if the condition continues to progress. The F waves are obtained more easily but reveal slight to moderate prolongation of latency.
Needle electromyography (EMG) examination of the distal muscles of the lower extremities shows active denervation as well as chronic changes in the form of re-innervation patterns.
Spontaneous activity (positive sharp waves and fibrillation) is seen in the tibialis anterior and gastrocnemius.
The motor unit action potentials are reduced in recruitment pattern, with high-amplitude, long-duration, and polyphasic motor units.
Avaria et al demonstrated that prenatal alcohol exposure is associated with abnormalities in nerve electrical properties and that the pattern is different from that seen in adults, showing conduction slowing and decrease in proximal and distal amplitude.[16]
Chronic ethanolism-associated liver involvement[17] and nutritional deficiency may be inferred by abnormal liver function test results and macrocytic anemia. Thiamine levels are not consistently reduced, but the thiamine-mediated enzyme transketolase estimation is often abnormal.
Cerebrospinal fluid (CSF) is typically normal or might show a mildly elevated total protein level.
Patients have an increased risk of compression neuropathy, and electrodiagnostic findings can be complicated by superimposed mononeuropathies that are present. Recent methods of demonstrating small-diameter fiber neuropathy, such as quantitative sensory testing and intraepidermal nerve fiber density, have been applied but need to be applied in large scale.
Sural nerve biopsy often shows evidence of generalized distal axonal loss affecting both large and small fibers but without distinctive pathologic features.
Autonomic testing of parasympathetic and sympathetic reflexes is often abnormal (25% in one study), including analysis of heart rate variability, Valsalva maneuver, handgrip, tilt table, and standing maneuvers.[18] The pattern of abnormalities often resembles the changes in diabetes and other causes of autonomic failure.
Pathologic findings of the peripheral nerve in alcoholic neuropathy generally are agreed to consist of axonal degeneration with secondary segmental demyelination.
Alcohol-related peripheral neuropathy (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.[19, 20]
Treatment is directed toward stopping further damage to the peripheral nerves and returning to normal functioning. These can be achieved by alcohol abstinence, a nutritionally balanced diet supplemented by all B vitamins, and rehabilitation. However, in the setting of ongoing ethanol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients.
According to Dina et al, adrenal medullectomy and administration of glucocorticoid receptor antagonist mifepristone (RU 38486) prevented and reversed a model of painful peripheral neuropathy in alcohol binge-drinking rats. Their results suggest a convergence of the effects of mediators of the hypothalamic-pituitary-adrenal axis and the sympathoadrenal-stress axis on sensory neurons in the induction and maintenance of alcohol-induced painful peripheral neuropathy .[19]
The prognosis of alcoholic neuropathy generally is good, as reported by Hillbom and Wennberg in their series of 10 patients.[21]
Provided that alcohol intake is discontinued and other causes of neuropathy (eg, malignancy, diabetes, nerve trauma) are carefully excluded, clinical and electrophysiologic examinations returned to normal or near normal. This is independent of age.
Prognosis is generally better in patients who are healthy and well nourished. Recovery is presumed to be due to regeneration and collateral sprouting of damaged axons.
Studies have shown that patients with mild-to-moderate neuropathy can significantly improve, but the improvement is usually incomplete in those with severe findings.
Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS, Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Charles Gellido, MD, Laboratory Director, Assistant Professor, Department of Neurology, Jacobi Medical Center, Albert Einstein College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Neil A Busis, MD, Chief of Neurology and Director of Neurodiagnostic Laboratory, UPMC Shadyside; Clinical Professor of Neurology and Director of Community Neurology, Department of Neurology, University of Pittsburgh Physicians
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Academy of Neurology<br/>Serve(d) as a speaker or a member of a speakers bureau for: American Academy of Neurology<br/>Received income in an amount equal to or greater than $250 from: American Academy of Neurology.
Chief Editor
Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Jonathan S Rutchik, MD, MPH, FACOEM, Associate Clinical Professor, Division of Occupational Medicine, Department of Medicine, University of California, San Francisco, School of Medicine; Neurology, Environmental and Occupational Medicine Associates (www.neoma.com)
Disclosure: Nothing to disclose.
References
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Jackson J. On a peculiar disease resulting from the use of ardent spirits. N Engl J Med Surg. 1822. 11:351.
Shattuck GC. The relation of beri-beri to polyneuritis from other causes. Am J Tropical Med. 1928. 83539-43:
Mellion M1, Gilchrist JM, de la Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic, or both?. Muscle Nerve. 2011 Mar;. 43(3):309-16.:309-16.
Behse F, Buchthal F. Alcohol Neuropathy: Clinical, Electrophysiological and Biopsy Findings. Ann Neurol. 1977. 2:95-110.
Mellion ML, Silbermann E, Gilchrist JM, Machan JT, Leggio L, de la Monte S. Small-fiber degeneration in alcohol-related peripheral neuropathy. Alcohol Clin Exp Res. 2014 Jul. 38(7):1965-72.
Victor M. Polyneuropathy due to nutritional deficiency and alcoholism. Dyck P, Thomas P, Lambert E, Bunge R, eds. Peripheral Neuropathy. Philadelphia: 1984. 1899.
Windebank AJ. Polyneuropathy due to nutritional deficiency and alcoholism. Dyck P, Thomas P, Lambert E, Bunge R, eds. Peripheral Neuropathy. Philadelphia: 1993. 1310.
