At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Alcohol abuse and its neurologic complications …
- Updated 08.18.2022
- Released 10.09.1997
- Expires For CME 08.18.2025
Alcohol abuse and its neurologic complications
The topic of alcohol abuse related to acute and chronic exposure covers a wide spectrum of neurologic syndromes involving the central and peripheral nervous system. Historical perspectives, clinical manifestations, clinical vignettes, etiology, pathogenesis, pathophysiology, epidemiology, prognosis, complications, and management are all discussed in this updated article. In addition, the authors discuss select mechanisms of cellular injury by alcohol.
• Alcohol intoxication has an acute and chronic symptomatology.
• The lethal dose of alcohol varies widely and depends on many external and internal factors. Tolerance develops with repeated exposures.
• Wernicke-Korsakoff syndrome is particularly found in the alcoholic population.
• Alcohol affects almost all areas of the nervous system.
• Alcohol affects the functioning of many systems in the body (heart, liver, muscle, nerve).
Historical note and terminology
Alcohol has been consumed by humans for thousands of years. Indeed, archaeologists have found evidence of nearly 11,000-year-old beer brewing troughs at a site in Turkey called Göbekli Tepe (68).
The term “alcoholism” was first used by a Swedish physician in 1849 to describe adverse systemic effects of alcohol. Also, early psychiatry texts described a syndrome of alcohol-related deterioration characterized by intellectual and behavioral abnormalities (11).
The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-Tr) defined alcoholism as “maladaptive pattern of drinking, leading to clinically significant impairment or distress” (12).
The definition of alcoholism by the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine is “a primary, chronic disease characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking” (192).
The role of alcoholism in the development of cognitive and functional decline was known in Ancient Greece (131) and has received serious study in Western medicine for more than 250 years.
In Greek mythology, Silenus was the frequently drunken companion and tutor of the wine god Dionysus. Artistic depictions of the drunken Silenus show him supported by satyrs or carried by a donkey.
Some Renaissance artistic depictions of the drunken Silenus show features of alcoholic cirrhosis, perhaps most fully in the painting Drunken Silenus (1626) by Spanish painter Jusepe de Ribera (1591-1652): evident signs of liver disease in this painting include parotid gland swelling, spider angioma (left parasternal area), gynecomastia, and ascites.
A clinic-pathologic description of hepatic encephalopathy from alcoholic cirrhosis was described by Italian anatomist and pathologist Giovanni Battista Morgagni (1682-1771), Professor of Anatomy at the University of Padua, in his De sedibus et causis morborum per anatomen indagatis (Seats and Causes of Diseases Investigated by Anatomy) (191).
Alcoholic neuropathy was documented at least as early as 1787 by English physician and philanthropist John Coakley Lettsom (1744-1815) (170), but other neurologic complications of alcoholism were probably not recognized until the end of the 19th century or later.
Alcohol-related deficits in memory and intellectual ability were reported in 1878 by British psychiatrist Robert Lawson (1846-1896) of the Wonford House Lunatic Asylum in Exeter (166; 165).
Subsequently, in a series of 3 articles from 1887 to 1889, Russian neuropsychiatrist Sergei Sergeievich Korsakoff (sometimes spelled Korsakov; 1853/1854-1900) gave a comprehensive description of the persistent amnestic confabulatory state now known as Korsakoff psychosis, occurring in conjunction with peripheral polyneuropathy, a combination he initially labeled either as “psychosis associated with polyneuritis” or “polyneuritic psychosis” (151; 150; 149; 305; 300; 301; 299; 158; 161; 162). Korsakoff based his conclusions on at least 46 patients, about two-thirds of whom were alcoholics, whereas the remainder suffered from a diverse group of disorders associated with protracted vomiting.
Korsakoff was apparently unaware of the syndrome incorporating a confusional state, ophthalmoparesis and other oculomotor findings, ataxia, and neuropathic features, which had been described by German neuropsychiatrist Carl Wernicke (1848-1905) in 1881 and labeled as “Die acute, hämorrhagische Poliencephalitis superior” (acute hemorrhagic superior polioencephalitis) and is now generally called Wernicke encephalopathy (310; 144; 145). The clinico-pathologic overlap between Wernicke encephalopathy and Korsakoff psychosis was ultimately recognized in the late 1920s and early 1930s (91; 133; 42), and the 2 terms became linked as Wernicke-Korsakoff syndrome.
The term “alcoholic hallucinosis” (also known as “alcohol hallucinosis” and “alcohol-related psychotic disorder”) refers to a disorder of acute onset, with a predominance of auditory hallucinations (although delusions and hallucinations in other sensory modalities may also be present), no disturbance of consciousness, and a history of heavy alcohol consumption (95).
This syndrome has often been attributed to Swiss psychiatrist Paul Eugen Bleuler (1857-1939), who labeled it alcoholic hallucinosis (Alkoholhalluzinose) and considered it as an alcoholic madness (Alkoholsahnsinn) (31); Bleuler was also responsible for other psychiatric terms, including schizophrenia, schizoid, and autism. However, in his textbook, Bleuler acknowledged the earlier description by Wernicke, who labeled the disorder as “chronic hallucinosis in alcoholism” (chronische Halluzinose beim Alkoholismus) (311). Even earlier, in 1847, the French author Claude-Nicolas- Séraphin Marcel described a similar symptom complex under the label of folie d'ivrogne (ie, drunken madness) (180).
L'alcool tue [Alcohol kills!] (circa 1900), after Eugène Burnand (1850-1921)Health propaganda poster showing an alcoholic man with delirium tremens on his deathbed, surrounded by his terrified family. A calendar on the back wall shows the date "24", possibly representing Christmas Eve. Color lithograph af...
Although alcoholic intoxication was long recognized in art, portrayals of delirium tremens in caricatures (273) and health propaganda posters became particularly prominent in the early 20th century, in the years before and during Prohibition (1920-1933) in the United States.
Marchiafava-Bignami disease is a progressive alcoholism-related neurologic disease characterized by corpus callosum demyelination and necrosis and subsequent atrophy. The disease was first described in 1903 by the Italian pathologists Ettore Marchiafava (1847-1935) and Amico Bignami (1862-1929) in an Italian Chianti drinker (181). In the autopsy of this patient, the middle two-thirds of the corpus callosum were necrotic.
In the last century, through careful observation and description, American neurologist and neuropathologist Raymond Delacy (“Ray”) Adams (1911-2008) made the most prodigious contributions in understanding the neurologic complications of alcohol abuse, in conjunction with various protégés, notably Boston-born neurologist Joseph Michael (“Joe”) Foley (1916-2012) and, subsequently, Canadian-American neurologist Maurice Victor (1920-2001) (01; 02; 03; 04; 85; 05; 302; 301; 303; 297; 304). Foley began to work with Adams on the neurologic manifestations of liver disease in the late 1940s after Foley returned from his military service during World War II (164; 159). In a series of reports from 1949 to 1953, Adams and Foley described the clinical (neurologic), electroencephalographic, and neuropathologic features of alcoholic liver disease, including the clinical and electrophysiologic features of asterixis (01; 02; 03; 04; 85).
Social commentary on the neurologic degeneration and social decay from alcoholism. The neurologic disorders and social decay resulting from alcoholism were targeted by social reformers in many countries since at least the 18th century.
English engraver, pictorial satirist, and social critic William Hogarth (1697-1764) depicted the effects of alcoholism in his famous engraving, Gin Lane (1751).
Hogarth's engraving, published according to Act of Parliament on February 1, 1751 in support of what would become the "Gin Act," shows a poor London street (the area depicted is St. Giles, London) strewn with hopeless drunka...
Hogarth's engraving, published according to Act of Parliament on 1 February 1751 in support of what would become the "Gin Act," shows a poor London street (the area depicted is St. Giles, London) strewn with hopeless drunkards and lined with gin shops and a flourishing pawnbroker. The inhabitants of Gin Lane are being destroyed by their addiction to the foreign spirit of gin, with the engraving illustrating shocking scenes of child neglect, starvation, madness, drunken brawls, and death. Hogarth's illustration is filled with satirical humor: the pawnbroker's shop depicted is "S. Gripe pawnbroker;" the distillery is "Kilman distillery;" a gin shop sign reads "drunk for a penny, dead drunk for two pence, clean straw for nothing;" and a drunkard's paper is headed "the downfall of Mdam. gin."
A poem below the engraving reads as follows:
Gin cursed Fiend, with Fury fraught,
Virtue and Truth, driv'n to Despair,
Damn'd Cup! that on the Vitals preys,
At that time, there was no quality control whatsoever, and gin was frequently adulterated (eg, with turpentine). When it became apparent that copious gin consumption was causing social problems, social reformers and the government made efforts to control the production of the spirit. The Spirit Duties Act (commonly known as the Gin Act of 1736) imposed high taxes on sales of gin, forbade the sale of gin in quantities of less than two gallons, and required an annual payment of £50 for a retail license. These measures had little effect beyond increasing smuggling and driving the distilling trade underground. The act was repealed by the Gin Act of 1743, which set much lower taxes and fees.
Similarly, the 4-part sequence of "A Drunkard's Progress" (1826) by American engraver and historian John Warner Barber (1798-1885) depicts the neurologic and social decay from alcoholism, complete with biblical admonitions. In the first image, "The Morning Dram," the father is drinking at 8 AM, ignoring his wife and children.
Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Wo unto them that rise up early in the morning that they may follow Strong Drink... Isa 5 C. 11v....
In the second image, "The Grog Shop," two men are drinking at a saloon, while two are brawling, one is vomiting, and one is unconscious on a bench.
Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Wo unto them that are mighty to drink wine, and men of strength to mingle Strong Drink... Isaiah ...
In the third image, "The Confirmed Drunkard," the father is intoxicated on the floor, while his wife and children are afraid, and the home is falling apart.
Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Who hath wo? Who hath sorrow? Who hath contentions? Who hath wounds without cause? ... They that ...
In the final image of the sequence, "Concluding Scene," there is an auction sign on the house, ordered by the sheriff. The family is evicted and departing with the wife in tears.
Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotations above the image: "The drunkard shall come to poverty. Proverbs 23 Chap. 21 v." [Proverbs 23:21] and "The wages of ...
Social critics and reformers blamed both the alcoholic and those that manufactured or sold alcohol for the adverse outcomes on individuals and society. The responsibility of purveyors of alcohol for the negative effects was portrayed in various ways, but often with religious overtones. For example, the engraving titled "Illustration of the Rumseller's just doom and final exit" (1835).
A Latin expression serves as an epigram: "Facilis descensus Averni: sed revocare gradum, Hoc opus, hic labor est." ("The descent to Perdition is easy—but to retrace one's steps—this is labor—this a task severe.") The engraving depicts a man, who is praying the rosary, about to be impaled by the devil, and struck by lightning bolts held in the hand of God. He is descending into Hell, portrayed by fire, smoke, a snake, and a fire-breathing serpent or dragon. A poem below the engraving reads as follows:
Behold! the soulless wretch—destroyer of his race—
Companion of the worm—the victim of despair—
Leading up to Prohibition in the United States, numerous forms of propaganda were used to convince people of the harms of alcohol (or of its relative safety by opponents of prohibition). One political cartoon of that era, "A sample room and its samples" (1902), for example, depicted a saloon keeper in front of a morbid saloon window display.
The window display sign says: "SHOW WINDOW EXHIBIT. WHAT OUR LIQUORS CAN DO. GENUINE SPECIMENS MADE ON THE PREMISES." The implications of this sign are displayed in the window in the form of 5 people damaged by alcohol, 4 of whom are labeled with their alcohol-induced problems: madman, tramp, convict, and idiot child (fetal alcohol syndrome). The fifth person, a woman, appears depressed or confused.
The 18th Amendment to the U.S. Constitution banned the manufacture, transportation, and sale of intoxicating liquors. The Volstead Act was ratified by the states on January 16, 1919 and went into effect on January 17, 1920, marking the beginning of the period in American history known as Prohibition. Despite an army of agents of the Bureau of Prohibition, Prohibition proved difficult to enforce; eventually, the illegal production and sale of liquor (“bootlegging”), the proliferation of illegal drinking spots ("speakeasies"), and the accompanying rise in gang violence and other crimes led to waning support for Prohibition by the end of the 1920s.
The 21st Amendment was ratified on December 5, 1933, repealing the 18th Amendment and ending Prohibition.
Presentation and course
• Based on the temporal relationship between alcohol abuse and onset of neurologic symptoms, the diverse neurologic manifestations of alcohol abuse may be subdivided into 3 main categories: (1) acute intoxication; (2) a withdrawal syndrome from sudden abstinence; and (3) a varied group of acute, subacute, or chronic disorders secondary to chronic alcohol abuse.
• In contrast to the acute and (usually) reversible pharmacological effects of ethanol intoxication, prolonged alcohol abuse leads to persistent and potentially irreversible neurologic deficits, potentially affecting any level of the nervous system.
• Alcohol withdrawal seizures usually occur on a background of years of alcohol abuse with a single generalized tonic-clonic seizure or a brief cluster of such seizures occurring 6 to 48 hours after the last drink.
• Alcohol withdrawal seizures typically occur as blood alcohol approaches zero, or shortly thereafter, and are rarely seen after more than 2 days of abstinence.
• The initial phase in Wernicke encephalopathy is classically characterized by the triad of mental confusion, oculomotor disturbance, and gait ataxia.
• Oculomotor disturbances in Wernicke encephalopathy can include nystagmus, abducens or conjugate gaze palsies, and ptosis.
• Wernicke encephalopathy may progress to hypotension, stupor, coma, hypothermia, and death if the underlying thiamine deficiency is unrecognized or untreated.
• Approximately 80% of untreated Wernicke encephalopathy patients subsequently evolve to a Korsakovian state.
• The Korsakoff syndrome is a memory disorder that typically emerges as the acute symptoms and signs of Wernicke encephalopathy subside; the amnesia is characterized by an inability to recall events for a period of a few years before the onset of illness (retrograde amnesia) and an inability to learn new information (anterograde amnesia).
• The common manifestations of alcoholic pellagra are encapsulated in “the 4 Ds”: diarrhea, dermatitis, dementia, and death.
• Most commonly, hepatic encephalopathy is a chronic disorder that occurs in the setting of alcoholic cirrhosis with portosystemic shunts.
• Hepatic encephalopathy has a wide range of presentations progressing successively through stages: (1) unimpaired cognitive function with intact consciousness; (2) lethargy and confusion or delirium; (3) somnolence and disorientation; and (4) coma.
• Alcoholic cerebellar degeneration is a disorder of progressive cerebellar degeneration that can be seen in patients with severe alcoholism; it preferentially affects the anterior and superior vermis, giving rise to a remarkably stereotypic syndrome of ataxic stance and gait.
• In acute alcoholic myopathy, massive muscle injury triggered by acute alcohol abuse may result in multiple organ failure and death, but alcoholic rhabdomyolysis generally has a good prognosis if renal failure is avoided or is aggressively treated.
• With chronic alcoholic myopathy only half of the sober patients recovered to normal strength over 5 years, indicating that chronic alcoholic myopathy is only partially reversible.
• Secondary disabilities (eg, school dropouts, criminal behavior, and substance or alcohol abuse problems) are common in young adults with fetal alcohol spectrum disorders.
The effects of alcohol on the central and peripheral nervous system are varied, and overuse of alcohol can have serious medical and neurologic consequences, even death.
Based on the temporal relationship between alcohol abuse and onset of neurologic symptoms, the diverse neurologic manifestations may be subdivided into 3 main categories: (1) acute intoxication; (2) a withdrawal syndrome from sudden abstinence; and (3) a varied group of acute, subacute, or chronic disorders secondary to chronic alcohol abuse.
Acute alcohol intoxication. Ethanol enters and distributes rapidly throughout the body after ingestion. Intoxication occurs because ethanol readily crosses the blood-brain barrier. It acts directly on neuronal membranes and interacts with numerous neurochemical receptors. Behavioral effects may include euphoria, dysphoria, social disinhibition, drowsiness, belligerence, and aggression. In nonalcoholic individuals, these may occur at serum concentrations as low as 50 to 150 mg per dL. Even a moderate dose of alcohol substantially impairs prospective memory function (72). Lethargy, stupor, coma, or death from respiratory depression and hypotension occur at progressively higher concentrations. The lethal dose varies widely because tolerance develops with repeated exposures. Some alcoholics may appear sober at a serum level as high as 500 mg per dL; whereas this same level can be fatal in nonalcoholic individuals.
Chronic alcohol abuse. In contrast to the acute and (usually) reversible pharmacological effects of ethanol intoxication, prolonged alcohol abuse leads to persistent and potentially irreversible neurologic deficits, potentially affecting any level of the nervous system (51; 67). The sites of neuronal injury and, hence, the clinical presentations, are governed by genetic, nutritional, and other environmental factors. Individuals with alcohol use disorder typically have impaired memory and smaller precentral frontal and hippocampal volumes (79). The neurologic disorders in individuals with chronic alcohol abuse may occur in isolation, or, more commonly, multiple syndromes may be present in a single patient.
Alcohol withdrawal. Sudden cessation of drinking in a chronic alcoholic typically produces a withdrawal syndrome of central nervous system hyperexcitability and may, if very severe, produce delirium tremens. The earliest symptom is a generalized tremulousness. Insomnia, agitation, delirium, hallucinations (auditory, visual, or tactile), or other perceptual disturbances may follow. The syndrome is also characterized by autonomic hyperactivity, such as tachycardia, profuse sweating, hypertension, and hyperthermia. Withdrawal symptoms commonly begin 6 to 8 hours after abstinence and are most pronounced at 24 to 72 hours after abstinence.
Alcohol withdrawal in a postsurgical setting may cause an increase in surgical complications, a situation demonstrated with elective spinal fusion surgery (106).
Alcohol withdrawal delirium. Alcohol withdrawal leads to a delirium syndrome that is short-lived and is usually easy to differentiate from the direct effects of alcohol on the brain. However, in some individuals, features of the delirium such as paranoia, auditory hallucinations, and attentional deficits persist for many months. The etiology for this prolonged and attenuated delirium syndrome is unknown. Benzodiazepines used in the treatment of alcohol withdrawal may also occasionally induce delirium (13).
Alcohol withdrawal seizures. Alcohol withdrawal may lead to tonic-clonic (grand mal) seizures, usually on a background of years of alcohol abuse (303). Convulsions occur typically 6 to 48 hours after the last drink and may occur singly or in a brief cluster. Alcohol withdrawal seizures typically occur as blood alcohol approaches zero, or shortly thereafter, and are rarely seen after more than 2 days of abstinence; however, a relative fall in blood alcohol levels during sustained drinking can also sometimes produce withdrawal seizures while blood alcohol levels are still at levels typically associated with intoxication. Unless an underlying neuropathology exists, the seizures are rarely focal. Generally, electroencephalograms on such patients are mildly abnormal and usually revert to normal within a few days. Status epilepticus is rare.
Seizures after an isolated episode of intoxication or after a short binge should suggest the possibility of an underlying seizure susceptibility (eg, from prior cortical trauma) or other contributing factor (additional toxic exposure, hypoxia, electrolyte abnormality, etc.). Similarly, seizures during active heavy drinking or after more than a week without alcohol raises the possibility of pathogenic mechanisms other than withdrawal per se (113).
Wernicke-Korsakoff syndrome. Wernicke-Korsakoff syndrome is the best example of acquired nutritional deficiency in alcoholism (301). Wernicke encephalopathy and Korsakoff syndrome (or Korsakoff “psychosis”) are successive stages of thiamine (vitamin B1) deficiency. Increased metabolic demands, glucose infusion, and sudden resumption of dietary intake after a period of malnourishment are risk factors in precipitating acute symptoms.
The initial phase in Wernicke encephalopathy is classically characterized by the triad of mental confusion, oculomotor disturbance, and gait ataxia. Oculomotor disturbances can include nystagmus, abducens or conjugate gaze palsies, and ptosis (301; 41; 263). The encephalopathy may progress to hypotension, stupor, coma, hypothermia, and death if the underlying thiamine deficiency is unrecognized or untreated (263).
The classic triad is insensitive for the diagnosis of Wernicke encephalopathy (111; 194). In particular, the incidence of oculomotor findings is low in patients later shown to have had Wernicke encephalopathy. Consequently, modified diagnostic criteria have been developed to address the insensitivity of the classic triad. Modified diagnostic criteria for Wernicke encephalopathy require at least 2 of the following 4 signs: (1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment (41).
Unfortunately, Wernicke encephalopathy is frequently underrecognized by clinicians (111). In pathological series, there is a consistently high proportion of cases of Wernicke encephalopathy that never had a clinical diagnosis of that condition during life (111; 194; 283; 41): indeed, less than 20% of cases of Wernicke encephalopathy are diagnosed prior to death.
The Korsakoff syndrome is a memory disorder that typically emerges as the acute symptoms and signs of Wernicke encephalopathy subside. The amnesia is characterized by an inability to recall events for a period of a few years before the onset of illness (retrograde amnesia), and an inability to learn new information (anterograde amnesia, ie, loss of anterograde episodic memory) (41). Almost all patients have limited insight into their memory dysfunction. Other cognitive deficits may manifest themselves but are mild relative to the amnesia (147). Many, but not all, patients confabulate, a phenomenon that may be due to associated frontal lobe dysfunction (27); confabulation may resolve as frontal lobe function improves. Attention, language, and spatial navigation are usually normal. Although usually subacute in onset, Korsakoff syndrome can develop insidiously without evidence for the acute encephalopathy, ataxia, or oculomotor findings (297). Approximately 80% of untreated Wernicke encephalopathy patients subsequently evolve to a Korsakovian state (301).
Alcoholics with Wernicke-Korsakoff syndrome can be differentiated from those with Wernicke encephalopathy (without Korsakoff syndrome), but the severity and stability of memory loss, regardless of other cognitive deficits (41).
Wernicke-Korsakoff syndrome is generally diagnosed in younger patients rather than those diagnosed with alcohol-related dementia (41).
Alcoholic pellagra. Pellagra has been recognized among alcoholics for more than a century (138; 323). The common manifestations of this disorder are encapsulated in “the 4 Ds”: diarrhea, dermatitis, dementia, and death (158; 160). The typical cutaneous features of pellagra include peeling, redness, scaling, and thickening of sun-exposed areas (158; 160).
However, the dermatitis of pellagra ranges from obvious scaly erythema to more subtle changes that are often mistaken for the photodamage typically seen in the elderly (from a lifetime of cumulative exposure to solar irradiation). Neuropsychiatric features of pellagra include irritability, depressed mood, fatigue, neurasthenia, and poor attention and concentration (158; 160). In more advanced cases, lethargy, confusion, psychotic symptoms, spastic weakness of the limbs, and Babinski signs may be observed. Other findings may include aversion to bright light, glossitis, and dilated cardiomyopathy (114). A range of other less common medical and neurologic manifestations can also be seen as a result of alcoholic pellagra, either due to the pellagra or the chronic effects of alcohol, including, for example, black urine (from urobilinogen) (52), benign symmetrical lipomatosis (83), peripheral neuropathy (108), paratonia, and various forms of myoclonus (255; 256; 217).
Pellagrous encephalopathy in alcoholics is often overlooked, in part because it is frequently mistaken for alcohol withdrawal delirium or Wernicke encephalopathy (255; Oldham and Novic 2012; 176). Also, because the nutritional disorders of alcoholics are often mixed, alcoholic pellagra may be seen in combination with Wernicke encephalopathy or Marchiafava-Bignami disease, a situation likely to foster diagnostic confusion among clinicians (255; 218; 278).
Marchiafava-Bignami syndrome. Marchiafava-Bignami syndrome is a progressive alcoholism-associated neurologic syndrome of corpus callosum demyelination and necrosis and subsequent atrophy. The syndrome is thought to be due to a combination of vitamin B deficiency (including thiamine deficiency), malnutrition, and alcohol abuse (particularly large quantities of red wine) (118). The clinical presentation is varied, and premortem diagnosis was almost impossible before the era of modern neuroimaging (297; 259; 101). Some patients present with slowly progressive psychomotor slowing, incontinence, frontal release signs, and wide-based gait. Dysarthria, hemiparesis, apraxia, or aphasia may be present (143). Occasionally patients may present in stupor or coma. MRI or CT may reveal lesions in the corpus callosum, anterior commissure, and, less commonly, in the centrum semiovale (201) and lateral frontal cortex (129).
Alcoholic cognitive impairment (alcohol-related brain damage). Chronic alcohol abuse in the absence of nutritional deficiencies or organ failure has also been associated with changes in cognitive abilities in detoxified chronic alcoholics, with deficits in recent memory, visuospatial ability, abstract reasoning, speed of information processing, and novel problem solving (245; 152; 234). Commonly, neuropsychological testing shows a decline in performance IQ but not verbal IQ. Aphasia, apraxia, and agnosia are uncommon. Typically, the degree of impairment is mild-to-moderate, with most patients able to carry out daily activities. Widespread cognitive impairment is best encompassed within "alcohol-related brain damage" or "alcoholic cognitive impairment," with Korsakoff syndrome reserved for those with isolated or disproportionate memory impairment (147).
Alcoholic dementia. Alcohol-induced dementia is a syndrome characterized by deficits in memory and intellectual abilities severe enough to interfere with daily functioning. Although no formal diagnostic criteria have been established, Oslin and colleagues proposed that there must be a clinical diagnosis of dementia that remains at least 60 days after the last exposure to alcohol and a history of excessive alcohol consumption for greater than 5 years (212). This syndrome has multiple etiologies and presents with a range of clinical symptoms and abnormalities. Often, dementia attributed to alcoholism is actually dementia due to other etiologies present in an individual who drinks alcohol (222). There is evidence that extreme quantities of alcohol can cause dementia (36) and that low levels may be somewhat protective against dementia (28; 244) and death (73).
Hepatic encephalopathy. Hepatic encephalopathy is a metabolic disturbance associated with liver disease or portosystemic shunting. It is characterized by disturbances of consciousness. Most commonly, hepatic encephalopathy is a chronic disorder that occurs in the setting of alcoholic cirrhosis with portosystemic shunts. There is a wide range of presentations progressing successively through stages: (1) unimpaired cognitive function with intact consciousness; (2) lethargy and confusion/ delirium; (3) somnolence and disorientation; and (4) coma. In the early stages, mood disorders, sleep disturbances, and personality changes can be seen. Asterixis (ie, negative myoclonus, flapping tremor, liver flap) is a typical feature of presomnolent hepatic encephalopathy (01; 02; 03; 04; 257; 197). Various forms of intercurrent illness (eg, infections, gastrointestinal bleeding from esophageal varices, hypoxia, electrolyte disturbances, etc.) and some medications can precipitate abrupt worsening of hepatic encephalopathy.
Several scales have been proposed for assessing or staging hepatic encephalopathy (309). The most commonly used are the West Haven criteria to differentiate between 4 grades of clinically overt hepatic encephalopathy (306), often augmented by addition of minimal hepatic encephalopathy (Table 1).
Table 1. Grading Hepatic Encephalopathy
• No encephalopathy
• Psychometric or neuropsychological alterations (eg, psychomotor speed, executive function)
West Haven criteria grade
• Trivial lack of awareness
• Lethargy or apathy
• Somnolence to semi-stupor
Alcoholic cerebellar degeneration. Alcoholic cerebellar degeneration is a disorder of progressive cerebellar degeneration, sometimes seen in patients with severe alcoholism (302). The rate of progression is variable. The anterior and superior vermis are preferentially affected, giving rise to a remarkably stereotypic syndrome of ataxic stance and gait. A wide-based gait and an inability to tandem walk are the most prominent signs. Limb ataxia, if present, occurs primarily in the legs. Arms are involved only to a slight extent, if at all. The gait disturbance usually develops over several weeks. Sometimes, a mild gait instability may be present for some time and then deteriorate suddenly after a bout of binge drinking or an intercurrent illness. The pathogenesis of this disorder is multifactorial and likely includes thiamine deficiency and the toxic effects of alcohol. The disorder predominantly affects middle-aged men (141). In autopsy series of decedents with a history of chronic ethyl alcohol abuse, alcoholic cerebellar degeneration was diagnosed in anywhere from 11% to 27% of cases (285; 316).
Results of brain trauma during alcohol intoxication. Alcoholic patients are prone to traumatic injuries of the brain and the peripheral nerves. Well-recognized central nervous system complications include subdural and epidural hematoma, cerebral contusion, and posttraumatic epilepsy. Compressive neuropathies may appear after a period of prolonged unconsciousness. These may involve the radial nerve at the spiral groove (Saturday night palsy), the peroneal nerve at the fibular head, or the sciatic nerve in the gluteal region.
Osmotic demyelination syndrome. Central pontine myelinolysis/extrapontine myelinolysis (CPM/EPM) and its association with alcoholic and malnourished patients was reported by Adams and colleagues in 1959 (05). They found that rapid changes in electrolyte concentration, most commonly of sodium, are associated with CPM/EPM. Today, these entities are also referred to as the osmotic demyelination syndrome (235). Central pontine myelinolysis is a neurobehavioral disorder associated with rapid onset of quadriparesis, pseudobulbar palsy, pupillary abnormalities, behavioral changes, and sometimes coma.
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). Tobacco-alcohol optic neuropathy—part of the large group of nutritional and toxic optic neuropathies—is a rare disorder of decreased central vision associated with nutritional deficiencies and tobacco smoking (63; 265). Tobacco-alcohol optic neuropathy is characterized by bilateral visual disturbances with grossly diminished visual acuity, papillomacular bundle damage, symmetric scotomas, acquired disturbances of color vision, and mostly normal fundi (250; 155; 88; 25). In a series of 40 cases, central scotomas were present in 80%, whereas centrocecal scotomas (ie, located between the central point of fixation and the blind spot with a roughly horizontal oval shape) prevailed in the rest (155). The acquired disturbances of color vision usually involve the red-green sense (84%) (155). The amplitudes of the visual evoked potentials are typically reduced and deformed (155).
Alcoholic neuropathy. Among the most prevalent neurologic syndromes in alcoholism is a distal, predominantly sensory or sensorimotor polyneuropathy (26; 55; 189). Tingling or burning pain is often the symptom that brings the patient to medical attention. Dysesthesias are most prominent over the soles and toes and may be severe enough to interfere with walking. As the disease progresses, loss of sensation becomes more pronounced, and neuropathic pain often paradoxically lessens in severity. Neurologic examination reveals abnormally elevated sensory thresholds to vibration, temperature, and pinprick. Distal muscle atrophy and mild weakness are sometimes seen. Ankle tendon reflexes are diminished or absent. Romberg sign, gait disturbances, and more widespread areflexia, weakness, and sensory loss may be seen in advanced cases. Autonomic disturbances (eg, impotence, sweating abnormalities, and orthostatic hypotension) are common, but often overlooked (189; 40). Rare, neuropathic "Charcot" joints may develop from deafferentation, and hoarseness may develop if the neuropathy involves the recurrent laryngeal nerves.
Pressure-induced focal neuropathies can also be linked to the development of myopathy (be considered as a secondary alcoholic neuropathy). The most common is a radial nerve palsy (ie, the so-called “Saturday night palsy” as it typically followed the carousing of a Saturday night) that resulted from radial nerve compression between the humerus and a hard object (eg, the arm of a park bench) during a drunken stupor.
Alcohol-induced (dry) beriberi. Some nutritionally compromised alcoholics may develop a subacute neuropathy due to thiamine deficiency—dry beriberi. Symptoms may evolve over a period of weeks or months. The most common presentation is flaccid weakness and at nadir, many cannot walk independently (193; 49; 120; 248; 66; 276). Other features include numbness/paresthesia, dysautonomia, vocal cord dysfunction, dysphagia, and nystagmus. Some may have concomitant Wernicke-Korsakoff syndrome (69).
Alcoholic myopathy. Alcohol can produce several myopathic disorders, including acute alcoholic myopathy with or without myoglobinuria, hypokalemic myopathy, chronic atrophic myopathy, and cardiomyopathy (219; 182; 298; 157; 163; 290; 81; 142). Acute alcoholic myopathy (also termed “alcoholic rhabdomyolysis and acute alcoholic necrotizing myopathy”) is an uncommon syndrome of abrupt muscle injury that typically occurs in malnourished chronic alcoholics following a binge or in the first days of alcohol withdrawal; experimental studies have demonstrated that both alcohol and nutritional factors are necessary to produce this syndrome (23; 157; 163). Severity ranges from asymptomatic transient elevation of creatine kinase to frank rhabdomyolysis with myoglobinuria. Although in most instances full recovery occurs within days to weeks, death may occur in the setting of acute renal failure and hyperkalemia. Chronic alcoholic myopathy is a gradually evolving syndrome of proximal weakness, atrophy, and gait disturbance that frequently complicates years of alcohol abuse. Muscle strength correlates with lifetime consumption of ethanol. Recovery occurs if alcohol is avoided, but the timeframe of improvement is weeks to months, in contrast to the rapid recovery typical of acute alcoholic myopathy. Pathogenic mechanisms include impaired gene expression and protein synthesis as well as increased oxidative damage and apoptosis.
Traumatic or pressure-induced rhabdomyolysis resulting from a drunken stupor can also be considered as a secondary alcoholic myopathy.
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Prenatal exposure to high levels of alcohol at critical periods of fetal development can impact neural crest development, disrupting the normal processes of facial and brain development, and potentially inducing birth defects that combine morphological stigmata (eg, facial dysmorphism) with neurologic and neuropsychological deficits (272; 199; 35; 156; 167; 172; 247; 267). The range of facial dysmorphism and neurologic and neuropsychologic disorders is called fetal alcohol spectrum disorder, of which fetal alcohol syndrome is the most severe form. The following table details the different fetal alcohol spectrum disorders.
Table 2. Fetal Alcohol Spectrum Disorders
• Small head circumference
• Aversion to social/eye contact
• Mental retardation
Diagnosis of fetal alcohol syndrome requires identification of a specific pattern of craniofacial dysmorphology (ie, short palpebral fissures; severe midfacial hypoplasia causing a “flat” midface; long flat or “deficient” philtrum; and a thin, elongated upper lip), but most individuals with behavioral and neurologic sequelae of heavy prenatal ethanol exposure do not exhibit defining facial characteristics (172; 267). Minor dysmorphic features can include ptosis, abnormal ear helices, “railroad track” ears, “hockey stick” palmar creases, and a turned-up nose. Short stature and microcephaly are common and may persist into adulthood. Almost half of affected children have significant learning disabilities, and most others have mild intellectual impairment. Speech delay and hyperactivity are common. Nonspecific mild neurologic deficits may include odor and taste abnormalities, fine motor control deficits, and hearing loss.
Brain malformations related to prenatal exposure to ethanol include microcephaly, agenesis/dysgenesis of the corpus callosum, cerebellar hypoplasia, a smaller hippocampus and basal ganglia, neuronal migration errors, holoprosencephaly, myelomeningocele, optic nerve hypoplasia, and hydrocephalus (241; 128; 179).
Children with fetal alcohol syndrome have a higher incidence of vision problems and eye pathology than normal children, including amblyopia, strabismus, hyperopia, anisometropia, and astigmatism (188; 296; 102). Compared with nonaffected children, children with fetal alcohol spectrum disorders showed an amblyopia-like pattern of vision deficit, including deficits in visual acuity, contrast sensitivity, and stereoacuity, in the absence of the optical and oculomotor disruptions of early visual experience that usually precede this condition (296). Evidence from animal models suggests that the deficits in spatial vision may be due to alterations in the functional architecture of the neocortex that occurs following prenatal alcohol exposure (296). Eyelid abnormalities are also more common in children with fetal alcohol syndrome, including blepharophimosis (a congenital anomaly in which the eyelids are underdeveloped such that they cannot open as far as usual and permanently cover part of the eyes), epicanthus (rounded, downward-directed fold of skin covering the caruncular area of the eye), telecanthus (an abnormally increased distance between the medial canthi), and ptosis (188; 102).
Prognosis and complications
Alcohol-related central and peripheral nervous system dysfunction may improve with abstinence from alcohol and correction of malnutrition. The degree of recovery depends on the type of damage as well as the severity and chronicity of the disorder.
Alcohol withdrawal. Alcohol withdrawal is associated with increased cost, longer hospitalizations, and higher risk of medical complications and in-hospital mortality after acute ischemic stroke (06).
Wernicke-Korsakoff syndrome. With early recognition and rapid treatment with intravenous thiamine, Wernicke syndrome may resolve with mild or no sequelae. However, without prompt treatment, many survivors are left with a severe amnesia (Korsakoff syndrome) (146). Among those with longstanding or recurrent encephalopathy, persistent cognitive dysfunction or the Korsakoff syndrome eventually emerges. In addition, untreated patients with Wernicke encephalopathy have a significantly increased risk of death, and most patients who succumb are still drinking at the time of death (41).
The prognosis of Korsakoff syndrome (and more specifically of Korsakoff disease) is generally bleak, and most patients are left with a permanent and devastating memory disorder, even if other neurologic features (eg, nystagmus, ataxia, and neuropathy) may improve markedly or even recover completely (80; 279; 177). Some limited recovery of the amnestic disorder may occur within 1 to 3 months and may continue for up to 1 year or more (279). Only about 20% of patients make a substantial recovery (301). Patients' lack of insight further complicates their behavioral management. Most patients with Korsakoff syndrome require institutionalization in some form because of the profound memory impairment (41). Patients may survive for many years, and their death is typically unrelated to the original neurologic disease. Cognitive test performance of detoxified alcoholic Korsakoff patients remains stable over at least 2 years; neither accelerated cognitive decline nor onset of dementia-like symptoms is observed (90).
Alcoholic pellagra. Alcoholic pellagra has a good prognosis for short-term recovery if promptly recognized and treated, but the issues that led to development of the condition in the first place (ie, severe alcoholism and malnutrition) are associated with significant long-term morbidity and mortality.
Marchiafava-Bignami syndrome. Marchiafava-Bignami syndrome has a high mortality rate, and survivors frequently have significant disability, though limited improvement is possible (118).
Alcoholic cognitive impairment. Perhaps the best prognosis is associated with the milder cognitive changes seen in chronic alcoholics with good nutrition. Several studies have shown that with months and years of abstinence, improvements in visuospatial ability and memory can occur, although older alcoholics are less likely to reach the performance levels of their nonalcoholic age cohort. Partial or complete reversal of the brain shrinkage seen on neuroimaging may also occur.
Alcoholic dementia. With alcohol-related dementias, prognosis varies according to the extent to which permanent brain damage has occurred.
Hepatic encephalopathy. The overall prognosis for recovery is poor in patients with alcoholic hepatic encephalopathy. Mortality is commonly due to sepsis, gastrointestinal hemorrhage, or raised intracranial pressure (41).
Alcoholic cerebellar degeneration. Alcoholic cerebellar degeneration causes irreversible damage, mostly involving the vermis, but also in other areas of the cerebellum (14).
Osmotic demyelination syndrome. The outcome in osmotic demyelination syndrome (CPM/EPM) is variable, and some cases may be asymptomatic: in an autopsy series of 220 consecutive decedents with chronic liver disease, 21 had CPM that was not clinically evident prior to death (264).
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). The outcome is variable and unpredictable.
Alcoholic neuropathy. In patients with peripheral neuropathy, dysesthesia often persists years after the initial manifestation, even with alcohol cessation. Unfortunately, tobacco-alcohol optic neuropathy is often underdiagnosed or only detected at a stage when the full recovery of vision is not possible (53).
Alcohol-induced (dry) beriberi. The prognosis of alcohol-induced dry beriberi is variable. Some recover promptly with thiamine (49), whereas others, with more advanced disease, may recover slowly and incompletely over a period of months to years (193; 120; 69; 66). Deaths may occur from acute heart failure (Shoshin beriberi) or pulmonary embolism (248).
Alcoholic myopathy. In acute alcoholic myopathy, massive muscle injury triggered by acute alcohol abuse may result in multiple organ failure and death. However, alcoholic rhabdomyolysis generally has a good prognosis if renal failure is avoided or is aggressively treated (15). Muscle has a remarkable capacity to regenerate, and most patients with alcoholic rhabdomyolysis recover full muscle function. Even patients who have had multiple episodes of myoglobinuria may have no lasting skeletal muscle effects. In patients with chronic alcoholic myopathy, improvement also is usual when ethanol is avoided.
Individuals with acute alcoholic muscular syndrome with muscle cramps recover within 2 to 4 weeks if they remain abstinent (220).
A 5-year study of the natural history of chronic alcoholic myopathy showed that only half of the sober patients recovered to normal strength, indicating that chronic alcoholic myopathy is only partially reversible. In some alcoholics even a substantial reduction in alcohol consumption may be as effective as complete abstinence in improving muscle strength or preventing its deterioration (78).
Loss of paraspinal muscle mass is a male gender-specific consequence of cirrhosis that predicts complications and death (77). Loss of paraspinal muscle mass was an independent predictor of the occurrence of bacterial infections, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal syndrome (77).
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Secondary disabilities (eg, school dropouts, criminal behavior, and substance/alcohol abuse problems) are common in young adults with fetal alcohol spectrum disorders (190).
Case 1. Wernicke-Korsakoff syndrome. A 48-year-old man with chronic alcoholism was brought to the emergency room after being found at home in a confused state. He was awake, but disoriented. Examination showed a partial right abducens palsy and nystagmus in all directions of gaze. Tendon reflexes were normal in both arms and at both knees, but absent at the ankles. Babinski sign was absent bilaterally. He was unable to walk independently and fell easily to either side. Brain CT showed mild atrophy of the cerebellar and cerebral hemispheres. Routine blood studies were notable for a serum sodium of 130 mg/dL. He was treated with intravenous fluids, thiamine, and multivitamins.
Repeat examination 2 weeks later showed an alert and coherent patient; however, he thought the year was 1978 and the president was Ronald Reagan. He was unable to recall events of the last several days, but seemed undisturbed by his difficulties. His eye movements were full, with prominent end-gaze nystagmus. He had normal strength in the limbs. Finger-to-nose testing was performed normally, but there was mild dysmetria with heel-to-shin testing. He walked with a wide-based gait, and tandem gait was impossible. Sensory examination revealed severe impairment of vibratory sensation in the toes, normal joint position sensation, and mild dysesthesias to light touch distal to both ankles. Ankle jerks continued to be absent.
With abstinence from alcohol and resumption of a normal diet, his gait improved slowly over a year. He continued to have significant memory deficits and remained unable to function independently. He also complained of burning and tingling pain in the distal lower extremities and received only partial relief from amitriptyline.
Case 2. Cognitive and behavioral changes accompanied by a history of alcohol abuse. A 76-year-old right-handed man presented with a 4-year history of erratic behavior and memory difficulties. Prior to our evaluation, he had a 15-year history of heavy alcohol abuse that persisted after inpatient rehabilitation and participation in Alcoholics Anonymous. Approximately 1 year prior to examination, he began to have difficulty learning his new area code and dialing phone numbers. Both his drive and interest in life were diminished. Although previously easygoing, he became explosive and irritable, often frightening his wife. Unexpectedly, he converted from a liberal Democrat to a fanatical follower of a right-wing political sect and spent much of his time associating with followers of this group. A few months prior to evaluation he had been caught having an extramarital affair. There was no history of stroke, head injury, or psychiatric disorder. His medications were nifedipine and enalapril.
On examination, the patient was noted to be bright and alert, but had no insight into his problems and blamed his wife for making the doctor’s appointment. He was irritable, disinhibited, and somewhat explosive. Mini-Mental State Exam score was 23/30. On memory testing, he had a slow rate of acquisition and a rapid rate of forgetfulness. Remote memory was good with cues. He interpreted proverbs concretely and made several perseverations when asked to perform frontal executive tasks. He had normal language and perfect naming but impaired word-list generation. There were mild visuospatial difficulties. Cranial nerves II through XII were normal, as were motor bulk, power, and tone. Sensory exam showed severe loss of position and vibration sense distal to the elbows and knees. Reflexes were decreased. Babinski signs were present bilaterally. Gait was normal. MRI scan of the brain showed mild to moderate ventricular dilatation and severe cortical atrophy without acute hemorrhage, midline shift, or focal lesions. SPECT scan demonstrated extensive bilateral frontal hypoperfusion and bilateral temporal hypoperfusion.
The patient’s memory loss was relatively mild but was consistent with early Alzheimer disease. Yet, his disinhibition and profound difficulty on frontal systems tasks, along with a SPECT scan with marked frontal involvement, were atypical for early Alzheimer disease and brought up the possibility of either an alcohol-induced frontal syndrome, or a degenerative frontotemporal dementia.
Subsequently, the patient’s course was remarkable for progressive cognitive and behavioral difficulties and unrelenting alcohol consumption. Eventually, he became incontinent and required placement in a nursing home where he died. Autopsy revealed severe frontal and hippocampal atrophy and moderate temporal atrophy in the neocortex. On microscopic examination, moderate numbers of neuritic and diffuse plaques in the neocortex and moderate numbers of plaques in the hippocampus and entorhinal cortex, primarily on the right, were found. There was a marked loss of neurons in the CA-1 and subiculum of the hippocampus but no neurofibrillary tangles and no Pick bodies. Cerebellar structures were normal. Unfortunately, the mammillary bodies were not available for analysis. The patient’s plaque score was sufficient for a diagnosis of probable Alzheimer disease using CERAD criteria, despite atypical features like the absence of neurofibrillary tangles in the cortex and severe neuron loss in frontal cortex.
In retrospect, this gentleman suffered from a mixed disorder with Alzheimer disease leading to the progressive memory loss and dementia. The alcohol abuse seems to have exacerbated the memory disturbance. The profound neuronal loss in the frontal lobes was not consistent with Alzheimer disease and may have been secondary to this patient’s chronic alcoholism (109). Hence, the behavioral deficits exhibited by this gentleman may truly represent the ongoing effects of alcohol abuse.
• In alcohol intoxication, ethanol fleetingly and weakly binds or interacts with receptor sites on various proteins in a manner similar to that of inhaled anesthetic agents, and it can also change or stabilize ion channels.
• Alcohol ingestion impairs cellular and molecular processes causing neurodegenerative change through excitotoxicity, free radical formation, and neuroinflammatory damage.
• Alcohol dependence is a complex disorder of the brain, and its etiology encompasses a vast array of physiologic, immunologic, genetic, hereditary, social, and behavioral factors.
• Alcohol use disorder is a psychiatric diagnosis comprising both dependence and abuse; over 50% of patients treated for alcohol use disorders carry 1 or more additional psychiatric disorders.
• Tolerance develops with frequent or prolonged alcohol intoxication through both metabolic and functional mechanisms: metabolic tolerance refers to changes in the efficiency or capacity to metabolize ethanol, whereas functional tolerance refers to a lessened response to alcohol independent of the rate of alcohol metabolism.
• In contrast to prior notions that ethanol and other alcohols exerted their effects on the CNS by nonselectively disrupting the lipid bilayers of neurons, modern evidence has demonstrated that ligand-gated ion channels are primarily responsible for mediating the effects of ethanol.
• Wernicke-Korsakoff syndrome is due to thiamine deficiency.
• Korsakoff disease is most commonly associated with chronic alcohol abuse, in which case low dietary intake of thiamine is compounded by alcohol-induced impairments in thiamine absorption and metabolism.
• At autopsy, the major gross pathologic changes in Wernicke encephalopathy include petechial hemorrhages, grayish and reddish discoloration, and slight softening of the tissues in structures surrounding the third and fourth ventricles.
• The neuropathologic changes in Korsakoff syndrome are identical in distribution and histologic character to those of Wernicke encephalopathy, showing only the more chronic findings of the earlier pathologic processes.
• Alcoholic pellagra is caused by a deficiency of either nicotinic acid (ie, niacin/vitamin B3) or tryptophan, usually in combination with lack of other amino acids and micronutrients.
• Chronic alcoholism is a risk factor for liver disease, particularly alcoholic cirrhosis with portosystemic shunting, which can result in hepatic encephalopathy.
• Various pathogenic mechanisms have been proposed for hepatic encephalopathy, including those that involve hyperammonemia, neuroinflammation, false neurotransmitters, and increased GABA neurotransmission.
• Malnutrition is probably not a significant factor in alcoholic cerebellar degeneration; instead, direct neurotoxicity of ethanol is suspected to be the cause of this disorder.
• Acute alcoholic myopathy is caused by severe alcoholic binges, usually in drinkers of long duration; in contrast, chronic alcoholic myopathy is caused by prolonged, consistent alcohol abuse, rather than by binge drinking.
Etiology and pathogenesis
Alcohol intoxication. Ethanol fleetingly and weakly binds or interacts with receptor sites on various proteins in a manner similar to that of inhaled anesthetic agents, and it can also change or stabilize ion channels.
Inhibitory GABA and glycine receptor subunits are promising candidate genes associated with alcohol dependence, and these subunits, along with a group of ligand-gated ion channels, may be the target site responsible for acute intoxication. Over time, with chronic intake, various physiologic adaptations occur (112; 288).
Excessive ethanol is toxic to the nervous system (51; 67). Moderate alcohol exposure can induce angiogenesis through induction of vascular endothelial growth factor (100). This may explain the cardiovascular-protective effects of modest alcohol consumption. Ethanol, under experimental conditions, has wide-ranging effects on gene expression (204) and various neuronal constituents, including lipid membranes, receptors for GABA N-methyl-D-aspartate (260; 315) and 5-hydroxytryptamine (319), ion channels, G-proteins (46; 261), and second messengers.
Alcohol ingestion impairs cellular and molecular processes causing neurodegenerative change through excitotoxicity, free radical formation, and neuroinflammatory damage. These neurodegenerative changes may involve membrane proteins, neurotransmitters, ion channels, and signaling pathways (07; 58). Alcohol-induced dysfunction or dysregulation of microglia (which play a major role in immune responses to cerebral insults) may induce or exacerbate neurotoxicity (115).
Thirty ounces of an 86-proof alcoholic beverage contain 2250 calories, or approximately 100% of the daily caloric requirement. These are empty calories, as a typical alcoholic beverage contains a negligible amount of protein, vitamins, and minerals; therefore, serious malnutrition is prevalent in people with alcoholism. On the other hand, adequate diet or even nutritional supplements do not prevent many neurologic complications of alcoholism.
Except for acute alcohol intoxication and alcohol-withdrawal syndrome, neurologic complications of alcoholism are likely due to either nutritional deficiency, a direct toxic effect of ethanol, or secondary effects from prior metabolic derangement or cumulative neurologic trauma acquired during bouts of alcohol intoxication (51; 67).
The majority of ingested ethyl alcohol is oxidized to acetaldehyde in the liver. Acetaldehyde is further metabolized to acetic acid, subsequently forming acetyl coenzyme A. During this process, via the cytosolic oxidative pathway of ethyl alcohol metabolism, NAD is reduced to NADH via alcohol dehydrogenase. NADH, the reduced form of NAD, accumulates in mitochondria, hindering mitochondrial metabolism.
Alcohol dependence. Alcohol dependence is a complex disorder of the brain, and its etiology encompasses a vast array of physiologic, immunologic, genetic, hereditary, social, and behavioral factors. A spectrum of use and abuse exists, and progression to more severe levels does not always occur. Habitual intake can lead to abuse, resulting in conflicts in a person’s work and social environments. Abuse can wax and wane over time. Chronic severe abuse can lead to health, legal, and financial problems. Addiction is the end result.
Alcohol use disorder. Alcohol use disorder is a psychiatric diagnosis comprising both dependence and abuse; over 50% of patients treated for alcohol use disorders carry 1 or more additional psychiatric disorders (271). Two of the genes most strongly suspected of engendering a decreased risk of abusing alcohol are alcohol dehydrogenase types 2 and 1B (71). Thus far, genome-wide association studies have yielded inconsistent results, reinforcing the genetic complexity of alcohol use disorder. A 2015 meta-analysis of twin and adoption studies reported a heritability of approximately 50% (295).
Alcohol withdrawal. Tolerance develops with frequent or prolonged alcohol intoxication though both metabolic or functional mechanisms: metabolic tolerance refers to changes in the efficiency or capacity to metabolize ethanol, whereas functional tolerance refers to a lessened response to alcohol independent of the rate of alcohol metabolism.
In contrast to the prior notions that ethanol and other alcohols exerted their effects on the CNS by nonselectively disrupting the lipid bilayers of neurons, modern evidence has demonstrated that ligand-gated ion channels are primarily responsible for mediating the effects of ethanol (64).
In particular, γ-aminobutyric acid type A (GABAA) receptors occupy a central role in mediating the effects of ethanol on the CNS. GABA is the primary inhibitory neurotransmitter in the mammalian CNS; consequently, activation of GABAA receptors by GABA decreases neuronal excitability. Ethanol produces both short- and long-term modulation of GABAA receptors (64). Not only does ethanol enhance inhibitory GABAergic neurotransmission (174), it also suppresses excitatory glutamate release by inhibiting NMDA receptors (76; 44).
Chronic alcohol ingestion leads to increased release of endogenous opiates, activation of GABAA receptors, up-regulation of NMDA-type glutamate receptors (125; 287), increased dopaminergic transmission, and increased serotonin release. When chronic consumption suddenly ceases, GABAA inhibitory actions are decreased and NMDA excitatory actions are increased, resulting in increased neurotransmitter excitotoxicity effects that can result in hallucinations, tremor, seizures, delirium, and increased body temperature, heart rate, and blood pressure.
In addition to alcohol (ethanol), other positive allosteric modulators of GABAA receptors include benzodiazepines, barbiturates, meprobamate, methaqualone, zolpidem, and propofol. In particular, the ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs.
Because they act through similar mechanisms, alcohol (ethanol), benzodiazepines, barbiturates, and other CNS “depressants” can produce cross tolerance. Withdrawal from these substances can produce similar withdrawal syndromes.
Wernicke-Korsakoff syndrome. Wernicke-Korsakoff syndrome is due to thiamine deficiency. Korsakoff disease is most commonly associated with chronic alcohol abuse, in which case low dietary intake of thiamine is compounded by alcohol-induced impairments in thiamine absorption and metabolism (269; 254; 320). There may also be a contribution from an age-related vulnerability to diencephalic amnesia produced by thiamine deficiency (225).
At autopsy, the major gross pathologic changes in Wernicke encephalopathy include petechial hemorrhages, grayish and reddish discoloration, and slight softening of the tissues with neuronal loss, gliosis, and vascular damage in structures surrounding the third and fourth ventricles and the cerebral aqueduct (285; 153). This anatomically localized capillary dysfunction is due to thiamine deficiency and is not a direct toxic effect of alcohol (14). Regions most prominently affected are the mammillary bodies, dorsal medial nucleus of the thalamus, periaqueductal region, and the tegmentum of the pons. The encephalopathic component of Wernicke encephalopathy is associated with leakage of capillaries around the third ventricle, whereas the ophthalmoplegia and ataxia are secondary to hemorrhages around the aqueduct of Sylvius in the midbrain and the fourth ventricle in the medulla. Cortical changes are frequently, but not universally, reported and are seen as ventricular enlargement and sulci widening, especially in the frontal lobe (297). These pathological changes may occur rapidly, with the onset of clinically apparent Wernicke encephalopathy, or insidiously, without clinically apparent signs of Wernicke encephalopathy.
The neuropathologic changes in Korsakoff syndrome are identical in distribution and histologic character to those of Wernicke encephalopathy, showing only the more chronic findings of the earlier pathologic processes. Bilateral, symmetrically placed, punctate lesions in the area of the third ventricle, fourth ventricle, and aqueduct are the hallmarks of Korsakoff disease. Lesions in the midbrain and cerebellum are responsible for the neurologic symptoms of the Wernicke stage, whereas lesions in the diencephalon (including the mammillothalamic tract) are critical for the amnesia that characterizes Korsakoff disease (317). The characteristic neuropathology of Korsakoff disease includes neuronal loss, microhemorrhages, and gliosis in the paraventricular and periaqueductal grey matter. Interactions involving the thalamus, mammillary bodies, hippocampus, frontal lobes, and cerebellum are important for new memory formation and executive function; the impairment of these circuits significantly contribute to the cognitive defects found in Korsakoff disease (132; 224). However, the minimal lesion(s) necessary for severe amnesia has not been resolved. The mammillary bodies are affected in approximately 80% of cases; however, shrinkage of the mammillary bodies and frontal lobes is visible on MRI for both Korsakoff disease patients and non-Korsakoff alcoholics (127; 75), even if it tends to be more severe in those with Korsakoff disease. Victor and colleagues suggested that damage to the dorsomedial nucleus of the thalamus is essential in the causation of memory deficits of Korsakoff disease (301), whereas others have implicated both the mammillary bodies and other thalamic nuclei in the anterior and midline areas, including the preretinal nucleus (178; 39; 107; 292; 146; 154). Neurodegeneration of the anterior thalamic nuclei is apparently a characteristic and specific feature in alcoholics with Korsakoff syndrome (107; 292).
Alcoholic pellagra. Alcoholic pellagra is caused by a deficiency of either nicotinic acid (ie, niacin/vitamin B3) and/or tryptophan, usually in combination with lack of other amino acids and micronutrients (255; 297; 158; 160). Inadequate intake of either niacin or tryptophan was historically most common in areas where corn or millet (with a high leucine content) was the primary foodstuff, but endemic pellagra is now rare because cereals and bread are supplemented with niacin. Secondary deficiency may occur due to certain medications, diarrhea, alcoholism, cirrhosis, or some combination of these. Alcoholics with pellagra have a higher prevalence of protein malnutrition than nonpellagrous alcoholics, as reflected in greater frequencies of anemia and hypoalbuminemia, and in lower serum potassium levels (61). Depression in pellagrins may be due to a serotonin deficiency caused by decreased tryptophan availability to the brain (19). Alcoholism can induce or aggravate pellagra by: (1) inducing malnutrition, gastrointestinal disturbances, and B vitamin deficiencies; (2) inhibiting the conversion of tryptophan to niacin; and (3) promoting the accumulation of the heme precursor 5-aminolaevulinic acid and porphyrins (136; 19).
Marchiafava-Bignami disease. In Marchiafava-Bignami disease, there is demyelination of the corpus callosum. The pathogenesis of Marchiafava-Bignami disease is unknown, but the underlying pathologic changes in the corpus callosum resemble those of central pontine myelinolysis with selective destruction of white matter; in addition, Marchiafava-Bignami disease has rarely been seen in reported alcohol abstainers, suggesting that other factors (eg, nutritional) may play a role. A link between abuse of red wine and the disorder has been suggested (195).
Alcoholic dementia. Chronic and excessive alcohol use has both direct and indirect effects on central nervous system function. A small study suggested a possible association between reduced brain glucose metabolism and cortical thickness in alcohol use disorder (282). Whether or not the direct effects of alcohol abuse can independently produce a dementia syndrome continues to be debated (173). If an alcohol dementia truly exists, it is often mild enough that the ability to perform activities of daily living is retained. There is a much stronger consensus that indirect effects of alcoholism produce dementia. These indirect etiologies include metabolic thiamine or niacin deficiency. Marchiafava-Bignami disease, which is associated with degeneration of the corpus callosum, is also considered a complication of alcohol, possibly red wine.
The biological bases for alcohol-induced dementia vary. Alcohol quickly crosses the blood-brain barrier, and both alcohol and its major metabolite, acetaldehyde, can be neurotoxic. Prolonged use seems to lead to neuronal loss, neuroglial proliferation, dendritic simplification, and reduction in synaptic complexity. The frontal and parietal lobes may be particularly sensitive to the effects of alcohol, although this is far from proven. Studies using well-nourished animals have shown ethanol-induced reductions in choline acetyltransferase, cell loss in the nucleus basalis, and altered dendritic spines in the hippocampus (50). In humans, these effects are observable on CT and MRI as enlargement of the lateral and third ventricles and mild to moderate sulcal widening. The fact that the atrophy is reversible after sustained periods of abstinence argues that some of these changes are due to shrinkage rather than outright cell death. Cerebellar degeneration, particularly in the region of the anterior and superior vermis, is also commonly seen in chronic alcoholics (284).
Hepatic encephalopathy. Chronic alcoholism is a risk factor for liver disease, and particularly alcoholic cirrhosis with portosystemic shunting, which can result in hepatic encephalopathy. Various pathogenic mechanisms have been proposed for hepatic encephalopathy, including those that involve hyperammonemia, neuroinflammation, false neurotransmitters, and increased GABA neurotransmission. Arterial blood ammonia concentrations are typically elevated in hepatic encephalopathy, with fluctuating ammonia levels roughly correlating with the severity of clinical disease, although a small proportion of patients develops symptoms with normal blood ammonia levels. Moreover, measures that act to reduce ammonia levels are helpful in treating hepatic encephalopathy.
There are no gross abnormalities in the brains of patients who die due to hepatic coma. Microscopic examination shows diffuse hyperplasia of Alzheimer type 2 astrocytes of the cerebral cortex and subcortical grey matter structures (eg, basal ganglia, thalamus, dentate nuclei, and brain stem nuclei).
These pathologic cells have a large vacuolated nucleus with chromatin displaced to 1 side.
Alcoholic cerebellar degeneration. Malnutrition is probably not a significant factor in alcoholic cerebellar degeneration; instead, direct neurotoxicity of ethanol is suspected to be the cause of this disorder. Pathologic changes in alcoholic cortical cerebellar degeneration involve particularly the anterior and superior portions of the cerebellar vermis and hemispheres.
Osmotic demyelination syndrome. Central and extrapontine myelinolysis, disorders of the osmotic demyelination syndrome, are uncommon demyelinating disorders most frequently involving the pons, midbrain, cerebellum, and lateral geniculate body. CPM/EPM is almost always associated with comorbid chronic conditions, including chronic alcoholism, various causes of hypo- and hypernatremia, liver transplantation, lung infections, malignancies, hemodialysis, and central nervous system dysfunction (140). The underlying etiology of these disorders is complex and not yet clearly delineated; however, there is a strong association with osmotic stress, with the most common predisposing factor being hyponatremia in 78% of cases (235; 122; 262). The aquaporin water channels have also been implicated (226).
Neuroimaging most commonly reveals symmetric demyelinating lesions in the base of the pons, midbrain, cerebellum, lateral geniculate nucleus, deep gray nuclei, spinal cord, and cerebral cortex (289). Neuropathologic features include relatively well-preserved cell bodies with demyelinated axons in the pons and occasionally lesions in the striatum, thalamus, cerebellum, and cerebral white matter (50). Rojiani and colleagues described the following types of lesions: spongy (early demyelination), vacuolar (reactive), and hypercellular (239).
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). Tobacco-alcohol optic neuropathy typically occurs in nutritionally deficient patients who abuse both tobacco and alcohol (25; 97; 20). The pathogenesis of tobacco-alcohol amblyopia has been controversial but may involve alterations of methionine and S-adenosyl-L-methionine metabolism, with contributions from cyanide in tobacco smoke, vitamin deficiencies (eg, folate, B12, thiamine), and other nutritional deficiencies (63; 98; 99).
Many have subsumed the outdated term tobacco-alcohol optic neuropathy under the larger group of nutritional amblyopia (265), and more recently the improved terms nutritional optic neuropathy (97; 277; 98) or toxic-nutritional optic neuropathy (25; 20). Indeed, some have argued that tobacco-alcohol is a misnomer, because the condition is primarily mediated by nutritional deficits and not ethanol toxicity per se (45; 97), even though the same argument could be leveled at other nutritional neurologic disorders resulting from alcohol abuse combined with a nutritionally deficient diet (eg, Wernicke-Korsakoff syndrome and alcoholic pellagra). Identified nutritional defects in patients with tobacco-alcohol optic neuropathy include deficiencies of folate (vitamin B9), cobalamin (vitamin B12), and thiamine (vitamin B1) (87; 308; 63; 88). The role of cyanide in tobacco smoke is unclear, because serum thiocyanate levels in "tobacco amblyopes" are relatively reduced compared with healthy smokers (86); therefore, if cyanide derived from tobacco smoke is indeed a causative factor in the development of tobacco-alcohol optic neuropathy, the biochemical defect may be a failure of conversion of cyanide to thiocyanate, its chief detoxification product (266; 86).
Although an optic neuropathy is generally assumed in such cases, there is little evidence to suggest that the locus of pathology is restricted to the optic nerve. MRI of the optic nerve is typically normal (135), and electrophysiological evidence indicates that some affected people likely have retinal dysfunction involving the macula (25). Moreover, histopathological studies in animal models showed lesions in the retina, optic nerve and tract, and the maculopapillary bundle (237; 265).
Alcoholic neuropathy. The etiology of alcoholic polyneuropathy is unresolved, but the clinical-pathologic similarity to beriberi (neuropathy due to thiamine deficiency) suggests that nutritional factors, and particularly thiamine deficiency, play a role (62; 207).
Alcohol-induced (dry) beriberi. Alcohol-induced dry beriberi is due to thiamine deficiency, resulting from nutritional compromise in an alcoholic patient.
Alcoholic myopathy. Acute alcoholic myopathy is caused by severe alcoholic binges, usually in drinkers of long duration. Chronic alcoholic myopathy is caused by prolonged, consistent alcohol abuse, rather than by binge drinking. Although myopathy and neuropathy are frequently both present in chronic alcoholics, the pathogenetic mechanisms involved in each of these forms of tissue damage are presumably not identical because histologic and clinical evidence of myopathy may occur in the absence of symptoms or electrophysiologic signs of neuropathy or of malnutrition (182; 290). Nutritional factors may contribute to the pathogenesis of chronic alcoholic myopathy because muscle weakness and histologic myopathy among alcoholics are both more severe in the presence of malnutrition (202).
The pathogenesis of alcoholic myopathy involves multiple interrelated pathways (228; 227; 229). First, impaired gene expression and protein synthesis, as well as increased oxidative damage, act together to reduce the formation of myofibrillar proteins (228; 229). Second, impaired gene expression, increased oxidative damage, and the pro-apoptotic properties of alcohol act to increase apoptosis. Third, additional muscle damage comes from alterations in ion channels and cell membrane permeability, impaired energy metabolism, protein adduct formation, and the toxicity of fatty acid ethyl esters. All of these processes contribute to the death and loss of myocytes and, hence, to progressive myopathy (82).
Fetal alcohol spectrum disorder. Structural alterations associated with prenatal alcohol exposure include decrements in global and regional brain volume, isocortical volume, isocortical thickness, and isocortical surface area with prenatal exposure to alcohol, along with alterations in brain shape and symmetry, and disruption of interhemispheric functional connectivity (184; 268; 313; 167; 242; 168). Prenatal alcohol exposure can also produce structural brain abnormalities that involve specific structures in the cerebellum, basal ganglia, and midline corpus callosum (236; 34; 184). Prenatal alcohol exposure is also a risk factor for development of more severe brain abnormalities, including holoprosencephaly (32; 241; 57; 293; 119). Malnutrition is probably not a significant factor in fetal alcohol spectrum disorder; instead, direct neurotoxicity of ethanol is the suspected cause of this disorder.
The developmental neurotoxicity of ethanol may be due to disruption of L1 cell adhesion molecule signal cascades. Cell adhesion molecules (CAMs) are critical for guiding neural development. Most cell adhesion molecules have been grouped into 3 families, all of which participate in differential adhesion, signal transduction, and physical/mechanical effects: (1) cadherins; (2) integrins; and (3) members of the immunoglobulin superfamily, including the cell surface transmembrane glycoprotein L1 (L1CAM) (24; 321). L1 mediates adhesion, neurite extension, neuronal migration, and fasciculations that are necessary for proper development of synaptic connections (196). Mutations in the L1 gene on the X chromosome are responsible for multiple allelic X-linked neurologic conditions: (1) X-linked hydrocephalus (hydrocephalus due to stenosis of aqueduct of Sylvius or HSAS) (215); (2) MASA syndrome (The acronym "MASA" stands for 4 of the signs and symptoms associated with the syndrome: (a) mental retardation, (b) "aphasia" [speech delay], (c) shuffling gait, and (d) adducted thumbs [with cleft palate, microcephaly, dysmyelination, and possibly hydrocephalus]) (Fitch and Levy 1975); (3) complicated spastic paraplegia type 1 (SP-1); (4) X-linked agenesis of the corpus callosum; and (5) "CRASH syndrome": corpus callosum hypoplasia, mental retardation, adducted thumbs (or "aphasia" [speech delay]), spastic paraparesis, and hydrocephalus (196; 215; 321).
The observation that patients with fetal alcohol syndrome share similar features to patients with the CRASH syndrome led to the investigation of the effects of ethanol on L1, and ultimately to recognition that alcohol inhibits cell-cell adhesion mediated by L1 (232; 24; 252). For example, concentrations of ethanol achieved in blood and brain after ingesting a single alcoholic beverage are sufficient to inhibit L1-mediated neurite outgrowth in cerebellar granule neurons (232). Such inhibition of L1-mediated neurite outgrowth may result from decreased expression, altered cell surface distribution, impaired signal transduction, or impaired interaction with the cytoskeleton (24).
• A genetic predisposition for alcohol abuse has been demonstrated by adoption studies, studies of identical twins, and families of individuals with early-onset alcoholism.
• The low concordance between clinical and pathological diagnosis of Wernicke-Korsakoff syndrome may result from a combination of factors: (1) under-recognition of the disorder by clinicians; (2) pathological changes occurring with subclinical disease.
• Approximately half of chronic alcoholics have loss of lean body mass due to loss of muscle tissue, decreased muscle strength, and associated gait abnormalities.
• Between one- and two-thirds of chronic alcoholics have skeletal muscle myopathies, making alcoholic myopathies the most prevalent type of myopathy.
• Alcoholic rhabdomyolysis predominates in men by a greater than 4-to-1 ratio, whereas in chronic alcoholic myopathy, males and females are equally affected.
• After exposure to heavy alcohol consumption during pregnancy, 80% of children exhibit abnormalities associated with alcohol exposure.
About 19 million Americans may be problem drinkers. A genetic predisposition has been demonstrated by adoption studies, studies of identical twins, and families of individuals with early-onset alcoholism (304). First-degree relatives of alcoholics are 7 times more likely to develop alcoholism than the general population.
Alcoholism affects all socioeconomic levels of society and appears to have a strong genetic predisposition (230), although environmental and cultural influences also clearly play a role (304). Adolescents are at increased risk for alcohol abuse disorders and other neuropsychiatric disorders during the adult years when they participate in binge drinking (60).
In a 9-year study of 750 children admitted with coma, the etiology of toxic coma was dominated by alcohol and other abuse substances (270).
Alcoholism is an independent risk factor for recurrent hypertensive intracerebral hemorrhage (322).
Alcohol-related seizures. Alcohol withdrawal is the most common cause of acute symptomatic seizures seen in an emergency room setting, accounting for about three quarters of such cases (233). Chronic alcoholism and alcohol consumption are risk factors for developing a first generalized tonic-clonic seizure (169). The risk of seizures increases with increasing (current) alcohol use, independent of alcohol withdrawal (200): for unprovoked seizures, the risk of seizures increases in a dose-dependent manner with daily alcohol intake (200).
Wernicke-Korsakoff disease. Alcoholism and alcohol-related nutritional deficiency accounts for approximately 80% of the cases of Wernicke encephalopathy seen in a hospital setting (187). The incidence of Korsakoff disease has been estimated at approximately 10 per million first psychiatric admissions (48). However, several large autopsy studies have found neuropathological changes consistent with Wernicke-Korsakoff syndrome in 2% to 3% of postmortem examinations, suggesting a much higher prevalence of this syndrome (284; 111; 213). Most of these cases had not received a clinical diagnosis of Wernicke-Korsakoff syndrome during life. The low concordance between clinical and pathological diagnosis of Wernicke-Korsakoff syndrome may result from a combination of factors: (1) underrecognition of the disorder by clinicians; (2) pathological changes occurring with subclinical disease (294); and (3) Wernicke-Korsakoff encephalopathy superimposed on a more general dementia picture.
Alcoholic pellagra. Alcoholism is a risk factor for nutritional disorders, including pellagra and Wernicke encephalopathy (37). Contributing factors to the development of pellagra in alcoholics include homelessness, failure to eat regularly, and some medications (eg, isoniazid for tuberculosis) (136; 223; 280; 171).
Alcohol-related dementia. In alcohol-dementia, the frequency of alcohol-related problems varies according to how the problem is defined and which group is being studied. For the elderly, the group most likely to develop a dementia, the prevalence of alcohol problems ranges between 1% and 6% of all community residents, between 10% and 15% of elderly seeking medical attention, and between 28% and 44% of elderly admitted to psychiatric units (84). However, the incidence and prevalence of alcohol-related dementia syndromes have not been clearly established. Heavy alcohol use is reported in 21% to 24% of patients with dementia, but in many of these cases, the primary diagnosis is Alzheimer disease and the role of alcohol abuse is equivocal. However, alcohol use may increase the risk or severity of a dementia as is noted in the clinical vignette (Case 2) above and in the study of Saunders and colleagues (251). Within an elderly population, moderate drinkers have an odds ratio of 1.8 for incident dementia and 2.8 for an Alzheimer diagnosis relative to nondrinkers (211). A lifetime history of heavy drinking is associated with a 4-fold increase in dementia diagnoses (212), although moderate drinking may diminish one’s chances of cognitive decline in late life (92).
Alcohol-induced (dry) beriberi. Alcohol abuse is a significant risk factor for developing dry beriberi (49; 203).
Alcoholic myopathy. Approximately half of chronic alcoholics have loss of lean body mass due to loss of muscle tissue, decreased muscle strength, and associated gait abnormalities (240). Between one- and two-thirds of chronic alcoholics have skeletal muscle myopathies, making alcoholic myopathies the most prevalent type of myopathy (229).
Heavy alcohol consumption and sedentary lifestyle are independently associated with reduced skeletal mass index in cirrhotic patients (56). The skeletal mass index is commonly used for diagnostic purposes because it includes central skeletal muscles whose mass is independent of activity and water retention, and it corresponds best to the patient’s total muscle mass (56; 240). The skeletal mass index, or more precisely the L3 skeletal muscle index, is determined with the use of abdominal CT scans. On these, the transverse area of the abdominal and paraspinal wall muscles (psoas, erector spinae, quadratus lumborum, transversus abdominis, internal and external oblique muscles and rectus abdominis) is measured at the level of the third lumbar vertebra; this measurement in square centimeters is then divided by the patient’s height squared to obtain the index result.
Alcohol is a common cause of nontraumatic myoglobinuria. Alcoholic rhabdomyolysis predominates in men by a greater than 4-to-1 ratio and usually occurs in the fourth to sixth decades of life. Recurrent episodes are reported in about 30% of cases following an initial episode of rhabdomyolysis. The incidence and prevalence of alcoholic rhabdomyolysis has varied considerably in different studies, probably at least in part due to variations in the intensity and chronicity of drinking, and coexistent nutritional disorders, among the subjects studied. Most studies suggest that alcoholic rhabdomyolysis is infrequent in alcoholics, occurring in less than 5% of chronic alcoholics. Nevertheless, the rhabdomyolytic variant of acute alcoholic myopathy represents the most common nontraumatic cause of rhabdomyolysis in hospitalized patients.
In chronic alcoholic myopathy, males and females are equally affected. Quantitative strength testing and histologic studies indicate that muscle abnormalities consistent with chronic alcoholic myopathy are common in habitual drinkers, affecting 40% to 60% of patients who chronically abuse alcohol (198).
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Assessment of the effects attributable to prenatal exposure to alcohol is complicated by the difficulties in verifying and quantitating exposure from a group of mothers who almost universally smoked tobacco, often abused other substances, and had poor or nonexistent prenatal care (128); thus, fetal alcohol spectrum disorder in humans is not a monotoxic disorder (128).
After exposure to heavy alcohol consumption during pregnancy, 80% of children exhibit abnormalities associated with alcohol exposure (156); maternal binge drinking and high total weekly intake of alcohol pose the greatest risk of adverse fetal outcomes (156).
• Abstinence from alcohol or treatment of alcoholism are the only effective preventive measures for the neurologic complications of alcohol abuse.
• The means by which alcohol abstinence is achieved in the alcoholic population includes medications (eg, disulfiram, calcium carbimide, naltrexone), support groups (eg, "Alcoholics Anonymous"), specialized addiction treatment programs, and more controversial programs stressing moderation versus total abstinence.
• Thiamine supplementation of some staple food products (eg, flour) is an easy and safe measure that can potentially improve the thiamine reserve of different human groups and function as a means of primary prevention of thiamine-deficiency disorders.
• In patients with Wernicke encephalopathy, rapid and aggressive treatment with parenteral thiamine is critical to prevent progression to Korsakoff disease and also to prevent fatal outcomes; this should be done prior to administration of glucose-enriched fluids.
• Niacin supplementation of some staple food products (eg, flour, cereals) is an easy and safe measure that can potentially improve the niacin reserve of different human groups and function as a means of primary prevention of niacin-deficiency disorders, including alcoholic pellagra.
• Total abstinence from alcohol during pregnancy is recommended because of the potential of alcohol-related teratogenic effects (fetal alcohol spectrum disorder and fetal alcohol syndrome).
Abstinence from alcohol or treatment of alcoholism is the only effective preventive measure for the neurologic complications of alcohol abuse. The means by which abstinence is achieved in the alcoholic population includes medications (eg, disulfiram, calcium carbimide, naltrexone), support groups (eg, "Alcoholics Anonymous"), specialized addiction treatment programs, and more controversial programs stressing moderation versus total abstinence (205).
Wernicke-Korsakoff syndrome. Thiamine supplementation of some staple food products (eg, flour) is an easy and safe measure that can potentially improve the thiamine reserve of different human groups and function as a means of primary prevention of thiamine-deficiency disorders (110).
Because alcohol abuse is the primary cause of Korsakoff disease, moderation of or abstinence from alcohol is an important preventative measure. However, because alcoholics often have multiple presentations with thiamine-deficient states and because they often present after significant neurologic damage has occurred, prevention opportunities are constrained even with optimal recognition and medical management. The possibility of thiamine deficiency should be considered carefully in all patients with a history of alcoholism, malnutrition, or protracted vomiting, with an emphasis on low-threshold diagnosis and prompt treatment (318).
In patients with Wernicke encephalopathy, rapid and aggressive treatment with parenteral thiamine is critical to prevent progression to Korsakoff disease and also to prevent fatal outcomes. This should be done prior to administration of glucose-enriched fluids. Given proper vitamin supplementation, the confusional state seen in Wernicke encephalopathy typically clears, with marked improvement or resolution of the oculomotor manifestations, ataxia, and peripheral neuropathy (beriberi) (258). Effective treatment and prophylaxis may only be achieved by use of parenteral vitamin supplements because oral supplements may not be adequately absorbed (59).
Alcoholic pellagra. Niacin supplementation of some staple food products (eg, flour, cereals) is an easy and safe measure that can potentially improve the niacin reserve of different human groups and function as a means of primary prevention of niacin-deficiency disorders, including alcoholic pellagra.
Alcoholic dementia. Nontraumatic alcohol-related dementia syndromes can be prevented with adequate nutrition, including vitamin supplementation, and limited alcohol consumption.
Alcohol-induced (dry) beriberi. The preventive measures for Wernicke-Korsakoff encephalopathy apply also to alcohol-induced (dry) beriberi.
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Total abstinence from alcohol during pregnancy is recommended because of the potential of alcohol-related teratogenic effects (fetal alcohol spectrum disorder and fetal alcohol syndrome).
Diagram for educational purposes showing how alcohol is transmitted to the fetus
(1) Alcohol consumed, (2) alcohol crosses into the placenta, (3) alcohol metabolizes, (4) byproducts of alcohol metabolism are detected in meconium. When alcohol crosses through the placenta, it is circulated throughout the fet...
Alcohol abuse and encephalopathy. A careful history of alcohol consumption and nutritional status are of primary importance in the differential diagnosis. The differential diagnosis of alcohol abuse and encephalopathy should include alcohol withdrawal, alcohol withdrawal delirium, delirium tremens, Wernicke-Korsakoff syndrome, head trauma, postictal confusion, hepatic encephalopathy (decompensated alcoholic liver disease), and various causes of ischemic, structural, metabolic, infectious, or toxic encephalopathy. Because patients under the influence of alcohol are prone to head injury from falls and other accidents, it is important to rule out a traumatic etiology.
Alcohol withdrawal seizures. Differential diagnoses include epilepsy, psychogenic nonepileptic seizures, convulsive syncope, and nonconvulsive syncope.
Wernicke-Korsakoff syndrome. Persistent global amnesia can occur as a consequence of a number of neurologic disorders, including cerebrovascular accidents, rupture and surgical repair of anterior communicating artery aneurysms, encephalitis, and anoxia. The presentation of the amnesic syndrome may be strikingly similar regardless of etiology; therefore, these neurologic conditions should all be considered in the differential diagnosis. Traumatic brain injury may occasionally result in a selective memory disorder as well.
A history of Wernicke encephalopathy allows a confident diagnosis of Korsakoff disease as a chronic sequela, but Korsakoff disease can occasionally occur without signs of a preceding Wernicke encephalopathy. Attention to the course of illness is critical because the memory disorder seen in Alzheimer disease is progressive, whereas it is stable in established Korsakoff disease.
MRI can be useful in the diagnosis of the acute stages of Wernicke encephalopathy, demonstrating hyperintense signals in the mammillary bodies, colliculi, periventricular gray matter, fornix, and thalamus via fluid-attenuated inversion recovery (FLAIR) (275). Neuroimaging findings suggestive of lesions around the third and fourth ventricles support a diagnosis of Korsakoff syndrome, although the absence of such findings does not rule out the possibility that the underlying neuropathology is associated with thiamine deficiency.
Neuropsychological testing is often useful for providing evidence in support of Korsakoff disease. Patients with Korsakoff syndrome often have memory impairment that is disproportionately severe and, unlike Alzheimer disease, performance on IQ tests can fall in the average range. Failure to release from proactive interference is a characteristic feature of the Korsakoff memory deficit, although this deficit may also be observed in patients with frontal lobe pathology.
Alcoholic pellagra. Pellagra should be considered in the differential diagnosis of patients with chronic alcoholism, malnutrition, and amino acid imbalance, especially in those with dermatitis on sun-exposed skin surfaces, chronic diarrhea of unknown etiology (43), or encephalopathy. Pellagrous encephalopathy in alcoholics is often overlooked, in part because it is frequently mistaken for alcohol withdrawal delirium or Wernicke encephalopathy (255; Oldham and Novic 2012; 176).
Marchiafava-Bignami syndrome. Marchiafava-Bignami disease may be incorrectly diagnosed as a decompensation of a psychiatric disorder (eg, schizophrenia) (38). MRI is helpful for diagnosing Marchiafava-Bignami syndrome if demyelination or necrosis of the corpus callosum is observed. Gadolinium enhancement is suggested to be useful in the determination of severe disease (307). Additional clinical symptoms can also include bilateral frontal lobe symptoms, language deficits, gait disturbance, incontinence, and hallucinations. Lesions involving the corpus callosum can also be seen in high altitude cerebral edema, antiepileptic drug withdrawal, hypoglycemia, hyperglycemia, and infection (93).
Alcoholic dementia. Severe memory disorders can be seen in the context of selective amnestic disorders like Wernicke-Korsakoff syndrome or as part of more global intellectual deterioration. A diagnosis of alcoholic dementia is warranted if patients demonstrate, in addition to amnesia, severe deficits in conceptual and problem-solving abilities as well as marked impairments on visuospatial and visuo-constructive tasks (249; 234). In contrast to the acute onset of Korsakoff disease, the global cognitive deficits seen in alcoholic dementia usually develop more gradually. Differential diagnosis is more difficult when the memory impairment has progressed gradually without a clear-cut history of encephalopathy.
The co-occurrence of dementia and alcohol abuse requires a comprehensive assessment to establish a proper diagnosis. In cases of dementia, the possibility of a primary dementia like Alzheimer disease must be considered. Like many patients with alcohol-induced dementias, patients with Alzheimer disease present with insidious onset, gradual progression, prominent memory loss, and deficits in naming, word generation, visuospatial ability, abstract reasoning, and mental flexibility. It is difficult to definitively rule out the possibility of Alzheimer disease in patients with the above presentation, regardless of the severity of the alcohol history. With sustained abstinence from alcohol, however, significant improvement in cognition and functional ability and the absence of any further deterioration argues against Alzheimer disease pathology.
Frontotemporal dementia should also be considered, especially if disinhibition, impaired social behavior, poor insight, or impaired executive function are early symptoms. Because many patients with frontotemporal dementia develop a craving for carbohydrates, increased alcohol abuse may be secondary to, rather than a cause of, the dementia. As with Alzheimer disease, the differential diagnosis may depend on the patient’s clinical course once abstinence from alcohol has been achieved.
Because alcoholics place themselves at risk for a host of dementia-causing disorders, these too must be considered in the differential diagnosis. For example, alcoholics are at increased risk for cerebral vascular disease. Although hemorrhagic stroke and large vessel infarcts will have a rapid onset, subcortical ischemic vascular disease may also develop gradually and insidiously without clear clinical signs of stroke. Subdural hematomas can also cause dementia, and in the case of alcoholics, a clear history of head injury may not be obtainable. Subdural hematomas typically progress more rapidly than the primary progressive dementias. Electrolyte abnormalities, most notably hyponatremia, are common in the alcoholic population. Alcoholism sometimes coexists with the substance abuse of other drugs. The alcoholic patient population is also at increased risk of trauma and infection.
As with any dementia workup, it is important to rule out delirium. This is particularly important in patients with a history of alcohol abuse because they are at risk not only for metabolic encephalopathies, but also for alcohol intoxication delirium, alcohol withdrawal delirium, alcoholic hallucinosis, and alcohol-related seizures.
Hepatic encephalopathy. Other encephalopathic conditions related to acute and chronic alcoholism can mimic hepatic encephalopathy, including alcohol intoxication, alcohol withdrawal/delirium tremens, Wernicke-Korsakoff syndrome, and pellagra encephalopathy. Other toxic and metabolic encephalopathies should also be considered because alcoholics are at an increased risk of multiorgan dysfunction, electrolyte disorders, sepsis, and nonalcohol toxin exposures.
Alcoholic cerebellar degeneration. Alcoholic cerebellar degeneration is recognized by its subacute course and its propensity to affect the gait with little or no limb involvement. These clinical features, together with radiological and laboratory studies, help to distinguish it from other causes of cerebellar dysfunction, such as intoxication by various drugs, cerebellar ischemia or hemorrhage, viral cerebellitis, posterior fossa neoplasms or abscesses, hypothyroidism, and paraneoplastic cerebellar degeneration. It should also be noted that Torvik and colleagues found evidence of age-dependent cerebellar atrophy in their study of 67 nonalcoholic male patients. They recommended that the diagnosis of alcoholic cerebellar degeneration in patients older than 70 years be “made with caution” (286).
Osmotic demyelination syndrome. Central pontine myelinolysis and Marchiafava-Bignami are relatively rare disorders but should be considered in the differential diagnosis of dementia. Both have a more rapid onset and course than a primary dementia and cause more physical symptoms. In central pontine myelinolysis, symptoms evolve over days to weeks, and patients may have progressive quadriparesis, pseudobulbar palsy, behavioral changes, conjugate gaze palsies, and impaired tongue movements. Cerebrospinal fluid may show elevated pressure and increased protein (67). Demyelination in the base of the pons should be observable on MRI. However, it is noteworthy that several studies revealed magnetic resonance imaging could be misleading in the case of pontine lesions. Some of these lesions were ultimately found to be due to a deep interpeduncular cistern or ischemic changes. Multiple sclerosis and metastases should also be considered (139).
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). Because tobacco-alcohol optic neuropathy and Leber hereditary optic neuropathy (LHON) have a similar phenotype, known Leber hereditary optic neuropathy-associated mutations should be analyzed before establishing a tobacco-alcohol amblyopia diagnosis (148; 277).
Alcoholic neuropathy. Alcoholic polyneuropathy presents as a distal, symmetrical, sensorimotor polyneuropathy. As such, it is indistinguishable from the neuropathies associated with a wide range of common systemic disorders, such as diabetes mellitus, uremia, drug usage, hypothyroidism, and AIDS. Therefore, diagnosis of alcoholic polyneuropathy depends on the exclusion of other causes and on the documentation of improvement with abstinence. Disulfiram, a drug widely used in rehabilitation of alcoholism, also causes a peripheral neuropathy at a dose greater than 125 mg per day (214).
Alcohol-induced (dry) beriberi. Alcohol-induced (dry) beriberi is often confused with alcoholic neuropathy due to direct toxicity of alcohol, and Guillain-Barre syndrome (193; 186; 248; 66; 276).
Alcoholic myopathy. In patients with symptoms suggesting acute alcoholic myopathy, the possibility of other acquired causes of rhabdomyolysis should be considered, such as drug abuse (eg, heroin, cocaine, amphetamines), trauma or crush injury, and depletion of phosphate or potassium. In patients with recurrent episodes of rhabdomyolysis, the possibility of an underlying metabolic defect in carbohydrate or lipid metabolism should be considered.
In patients with symptoms suggesting chronic alcoholic myopathy, care must be taken to exclude other causes of chronic myopathic weakness, such as inflammatory myopathies, acquired metabolic myopathies, and limb girdle dystrophy. The muscle biopsy finding of type II muscle fiber atrophy is also a feature of steroid myopathy, hypophosphatemia, and muscle disuse.
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Because of the potential serious implications for fetal development (fetal alcohol spectrum disorder and fetal alcohol syndrome), pregnant women should abstain entirely from alcohol.
• A complete history should be taken with particular emphasis on alcohol use and nutritional status, protracted vomiting or diarrhea, evidence of an acute episode of Wernicke encephalopathy, and any associated features.
• The prompt diagnosis of Wernicke encephalopathy is critical, as delayed treatment may lead to irreversible neurologic deficits.
• Wernicke encephalopathy is an acute neurologic condition classically characterized by the clinical triad of (1) nystagmus with ophthalmoparesis; (2) ataxia; and (3) confusion. Unfortunately, this classic triad is insensitive for diagnosis of Wernicke encephalopathy.
• Modified diagnostic criteria for Wernicke encephalopathy require at least 2 of the following 4 signs: (1) dietary deficiencies (undernutrition, vitamin deficiency); (2) oculomotor abnormalities (ophthalmoplegia, nystagmus, gaze palsy); (3) cerebellar dysfunction; and (4) either an altered mental state or mild-to-moderate memory impairment or confabulation.
• In Marchiafava-Bignami disease, MRI shows demyelination and possible areas of focal necrosis in the corpus callosum.
• No liver function test abnormalities are diagnostic of or specific for hepatic encephalopathy, although elevated blood ammonia levels are suggestive of diagnosis of hepatic encephalopathy in the proper clinical setting.
• EEG abnormalities in hepatic encephalopathy include bilateral synchronous delta waves and triphasic waves, particularly in the frontal regions, but these findings may also be seen in other toxic-metabolic encephalopathies, and there is only a rough correlation between the degree of EEG abnormality and the severity (or stage) of hepatic encephalopathy.
• In alcoholic cerebellar degeneration, brain imaging shows atrophy of the anterior lobes of the cerebellum and the superior vermis.
• In acute alcoholic myopathy, creatine kinase is moderately or severely increased in serum, whereas in chronic alcoholic myopathy, creatine kinase is normal.
• Diagnosis of fetal alcohol syndrome requires identification of a specific pattern of craniofacial dysmorphology (ie, severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum), but most individuals with behavioral and neurologic sequelae of heavy prenatal ethanol exposure do not exhibit defining facial characteristics.
A complete history should be taken with particular emphasis on alcohol use and nutritional status, protracted vomiting or diarrhea, evidence of an acute episode of Wernicke encephalopathy, and any associated features. Information should also be obtained regarding other medical conditions that may be part of the differential diagnosis (eg, encephalitis, anterior communicating artery aneurysm, head injury, tumor) or that may be precipitating conditions (ie, contributing to the development of thiamine deficiency). A complete physical and neurologic examination is necessary.
Initial laboratory evaluation should also include complete blood count, blood coagulation times, serum electrolytes, liver function tests, blood urea nitrogen, creatinine, bilirubin, serum osmolality, serum alcohol, and urine toxicology screen. Serum osmolality is correlated with alcohol concentration, since 100 mg/dL of blood alcohol raises serum osmolality by 22 mOsm/L. Urine toxicology screening is prudent because alcoholics frequently abuse multiple substances. Other laboratory studies (eg, arterial blood gases, vitamin B12 level, thyroid function tests, creatine kinase, etc.) are necessary only if indicated by the clinical condition.
Not infrequently, serious alcoholics ingest other toxic neuroactive substances. Alcoholics sometimes ingest methanol or ethylene glycol instead of ethanol, or "moonshine" that is tainted with methanol or heavy metals (eg, lead or arsenic) (208). Ethylene glycol and methanol cause a severe metabolic acidosis with increased anion and osmolal gaps. Ketoacidosis is not a feature of ethylene glycol or methanol poisoning (185).
Focal neurologic findings or unexplained encephalopathy should prompt imaging studies of the brain, and where appropriate, examination of cerebrospinal fluid for evidence of infection or subarachnoid blood.
Wernicke-Korsakoff syndrome. The prompt diagnosis of Wernicke encephalopathy is critical, as delayed treatment may lead to irreversible neurologic deficits. Wernicke encephalopathy is an acute neurologic condition classically characterized by the clinical triad of (1) nystagmus with ophthalmoparesis; (2) ataxia; and (3) confusion. Unfortunately, the classic triad is insensitive for diagnosis of Wernicke encephalopathy (111; 194). In particular, the incidence of oculomotor findings is low in patients later shown to have had Wernicke encephalopathy. In pathological series, there is a consistently high proportion of cases of Wernicke encephalopathy that never had a clinical diagnosis of that condition during life (111; 194; 41).
To address the poor sensitivity of the classic triad, modified diagnostic criteria have been developed. Modified diagnostic criteria for Wernicke encephalopathy require at least 2 of the following 4 signs; (1) dietary deficiencies (undernutrition, vitamin deficiency); (2) oculomotor abnormalities (ophthalmoplegia, nystagmus, gaze palsy); (3) cerebellar dysfunction; and (4) either an altered mental state or mild-to-moderate memory impairment/confabulation (41).. In a clinicopathologic study of 28 patients, the modified diagnostic criteria improved diagnostic sensitivity from 31% based on the classic triad to 100% compared with pathological diagnoses (41).
Table 3. Caine Operational Criteria for Wernicke Encephalopathy
Requires 2 of 4 signs in chronic alcoholics
• Dietary deficiencies (eg, malnutrition, vitamin deficiency, low body mass index)
• Oculomotor abnormalities (eg, ophthalmoparesis, nystagmus, gaze palsy)
• Cerebellar dysfunction (eg, ataxia, balance deficits, dysmetria)
• Altered metal status or impaired memory (eg, disorientation, coma, confusion, memory problems, confabulation)
MRI is helpful in diagnosis of Wernicke encephalopathy (124; 116). MRI studies may show symmetric hyperintense signal in paraventricular regions of the thalamus, hypothalamus, mamillary bodies, periaqueductal region, and floor of the fourth ventricle on T2-weighted imaging, FLAIR, and diffusion-weighted imaging (DWI) (124; 116).
Korsakoff disease is a clinical diagnosis that is based on the identification of the characteristic amnesic syndrome, usually following an episode or episodes of Wernicke encephalopathy and occurring in the context of a history of alcohol abuse, malnutrition, or protracted vomiting. A diagnosis of Korsakoff disease can be made only when the confusional state associated with Wernicke encephalopathy has sufficiently cleared. All cognitive functions should be thoroughly evaluated in order to characterize the pattern and severity of the memory disorder and to screen for the possibility of a general intellectual decline. A diagnosis of Korsakoff syndrome (or more specifically of Korsakoff disease) is warranted only when the memory deficits are much more prominent that other cognitive disorders in the domains of language, visuoperceptual functioning, problem solving, and judgment (41).
Laboratory tests showing elevation of blood pyruvate levels and reduced transketolase activity in erythrocytes support a diagnosis of Wernicke-Korsakoff syndrome.
Alcoholic pellagra. Alcoholic pellagra is underrecognized. Because endemic pellagra has been eradicated in Western countries, a diagnosis of pellagra is rarely considered, even with risk factors for malnutrition such as chronic alcohol intake, homelessness, or AIDS (209). In a Japanese study, 20 cases of neuropathologically diagnosed pellagra were identified among 74 necropsy cases of chronic alcoholism (126). A therapeutic response to niacin in a patient with the typical symptoms and signs of pellagra establishes the diagnosis.
Marchiafava-Bignami disease. In Marchiafava-Bignami disease, MRI shows demyelination and possibly areas of focal necrosis in the corpus callosum.
Alcohol-related dementia. Diagnostic evaluation for dementia in an alcoholic should include neuroimaging, laboratory tests, and possibly neuropsychological evaluation and EEG. Brain imaging in alcoholic dementia typically shows diffuse cortical atrophy with enlargement of the lateral ventricles; these findings are not specific for alcoholic dementia, however. Brain imaging also helps to exclude alcohol-related traumatic brain injuries, such as subdural hematomas and cerebral contusions. Neuropsychological evaluation should be conducted to measure the degree of cognitive and intellectual impairment and the extent to which it interferes with daily functioning. EEG shows nonspecific loss of background activity with increased theta and delta activity, particularly in the temporal leads bilaterally.
Hepatic encephalopathy. No liver function test abnormalities are diagnostic of or specific for hepatic encephalopathy, although elevated blood ammonia levels are suggestive of diagnosis of hepatic encephalopathy in the proper clinical setting.
Some patients with cirrhosis of the liver, who appear to be otherwise normal on general clinical examination, show impairment on neuropsychological tests of psychomotor speed and executive function—a condition referred to as “minimal hepatic encephalopathy” (21). Reitan's trail-making test is simple and enables serial assessment of the mental state.
EEG abnormalities in hepatic encephalopathy include bilateral synchronous delta waves and triphasic waves, particularly in the frontal regions, but these findings may also be seen in other toxic-metabolic encephalopathies and there is only a rough correlation between the degree of EEG abnormality and the severity (or stage) of hepatic encephalopathy.
The primary utility of brain imaging in patients with suspected hepatic encephalopathy is excluding other relevant intracranial pathology. Brain imaging may also show cerebral edema in the acute stages of fulminant hepatic encephalopathy and may show cerebral atrophy in chronic cases.
Alcoholic cerebellar degeneration. In alcoholic cerebellar degeneration, brain imaging shows atrophy of the anterior lobes of the cerebellum and the superior vermis. Thyroid function tests should also be considered for individuals with cerebellar ataxia.
Osmotic demyelination syndrome. In central pontine myelinolysis, MRI shows demyelination in the basis pontis.
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). Tobacco-alcohol optic neuropathy is often underdiagnosed or only detected at a stage when the full recovery of vision is not possible (53). Workup of suspected nutritional optic neuropathy in an alcoholic should include MRI of the visual pathways, vitamin levels (B12, folate and thiamine), and cyanide levels (277). In addition, because tobacco-alcohol optic neuropathy and Leber hereditary optic neuropathy (LHON) have a similar phenotype, known LHON-associated mutations should be analyzed before establishing a tobacco-alcohol amblyopia diagnosis (148; 277). Visual loss may precede optic disc changes detected by optical coherence tomography (134).
Alcoholic neuromuscular disease. Electromyography and nerve conduction studies help to characterize neuropathy or myopathy. Serum vitamin B12 and thyroid function tests are useful for evaluation of neuropathy, and serum creatine kinase tests are useful for assessing myopathy. Thyroid function tests should also be considered for individuals with chronic myopathy.
In acute alcoholic myopathy, creatine kinase is moderately or severely increased in serum. The workup should include a careful history and a toxicology screen to identify the possible contribution of other drugs or toxins known to produce myoglobinuria. Screening for metabolic derangements that can cause myoglobinuria, particularly hypokalemia and hypophosphatemia, should be performed. Other causes of pigmenturia (eg, hematuria, hemoglobinuria, and porphyria) should be excluded. In an individual with recurrent rhabdomyolysis or evidence of muscle injury that has occurred apart from alcohol abuse, perform an evaluation for a possible inborn error of muscle metabolism. EMG shows myopathic potentials (short duration, small-amplitude units with normal recruitment) and a high frequency of spontaneous discharges (fibrillations and positive sharp waves) attributed to hyperirritability of muscle fibers associated with active muscle fiber necrosis (206). Muscle biopsy, if performed, shows muscle fiber necrosis (221).
In chronic alcoholic myopathy, creatine kinase is normal. In patients with symptoms suggesting chronic alcoholic myopathy, a family history of muscle disease should be excluded and laboratory screening should determine whether an underlying endocrine or electrolyte disorder exists. Electromyography and muscle biopsy are necessary to exclude other causes of chronic proximal weakness and atrophy. EMG often shows mixed myopathic and neuropathic features with variable spontaneous discharges (206). The most frequent histological findings are myocytolysis, fiber-size variability, and type IIB-fiber atrophy (221). Cardiomyopathy and hepatic cirrhosis are more frequent in patients with chronic alcoholic myopathy and should be checked for in chronic alcoholics with skeletal myopathy (246).
In alcohol-induced dry beriberi, nerve conduction studies may show an acute motor axonopathy superimposed on a background polyneuropathy and/or myopathy (193; 120). Clinical features favoring dry beriberi over Guillain-Barre syndrome include the following: (1) 3 or more weeks of symptoms; (2) associated confusion, nystagmus, or vocal cord dysfunction; (3) volume overload; (4) low serum thiamine level; (5) elevated lactate; (6) normal spinal fluid (including normal CSF protein); and (7) absence of a sural-sparing pattern in nerve conduction studies (193; 120; 248). Sural sparing—defined as absent/abnormal median sensory nerve action potential (SNAP) amplitude or absent/abnormal ulnar SNAP amplitude with a normal sural SNAP amplitude—is thought to be a marker for inflammatory demyelinating polyneuropathy.
Nerve conduction studies in patients with alcoholic myopathies often show coincident neuropathic abnormalities (ie, borderline or slowed conduction velocities and absent sensory potentials) because distal neuropathies often coexist with myopathy.
Fetal alcohol spectrum disorder and fetal alcohol syndrome. Fetal alcohol spectrum disorder and fetal alcohol syndrome are frequently underdiagnosed, due to an absence or subtlety of classical facial features, mild neurodevelopmental sequelae, societal attitudes, and suboptimal performance characteristics of current diagnostic criteria. Diagnosis of fetal alcohol syndrome requires identification of a specific pattern of craniofacial dysmorphology (ie, severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum), but most individuals with behavioral and neurologic sequelae of heavy prenatal ethanol exposure do not exhibit defining facial characteristics (172; 267). Variations of diagnostic criteria exist, contributing to the diagnostic confusion (314). Consequently, efforts are ongoing to develop better diagnostic criteria to capture the full spectrum of dysmorphology associated with fetal alcohol spectrum disorders.
Four diagnostic systems for fetal alcohol syndrome and other fetal alcohol spectrum disorders have been developed in North America: (1) The Institute of Medicine (IOM) guidelines (274); (2) The University of Washington diagnostic scheme, "The 4-Digit Diagnostic Code", which ranks the 4 key features of fetal alcohol spectrum disorders on a 4-level Likert scale and yields 256 descriptive codes that can be categorized into 22 distinct clinical categories, ranging from fetal alcohol syndrome to no findings (17; 18; 16); (3) The Centers for Disease Control guidelines, "Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis" (29); and (4) the Canadian guidelines for fetal alcohol spectrum diagnoses, which harmonized most differences between The Institute of Medicine and University of Washington's systems (54).
• Three drugs are approved by the U.S. Food and Drug Administration for the treatment of alcohol abuse and alcohol dependence: disulfiram, acamprosate, and naltrexone.
• Benzodiazepines are recommended as a first-line medication for the management of alcohol withdrawal to alleviate discomfort and agitation, and to prevent seizures and delirium.
• All alcoholic patients should be supplemented with parenteral thiamine and other vitamins.
• Withdrawal seizures are typically self-limited.
• Benzodiazepines, and not nonbenzodiazepine anticonvulsants, should be used following an alcohol withdrawal seizure to prevent further alcohol withdrawal seizures.
• Withdrawal seizures do not represent "latent" epilepsy; therefore, treatment with nonbenzodiazepine anticonvulsants is not recommended. If all convulsions are clearly linked to withdrawal, chronic anticonvulsant therapy is not indicated.
• Chronic management of alcoholic patients prone to recurrent seizures is complicated by the difficulty in separating alcohol-related convulsions and preexisting epileptic conditions.
• Patients at high risk of Wernicke encephalopathy (eg, malnourished, severe withdrawal) should be given 3 to 5 days of parental thiamine.
• In patients with suspected Wernicke encephalopathy, parenteral thiamine should be administered twice daily for 5 days.
• When pellagra is suspected, treatment with oral nicotinamide is an inexpensive, safe, and potentially lifesaving intervention.
• Management of acute exacerbations of chronic hepatic encephalopathy includes identification and correction of precipitating factors, such as correction of diuretic-induced hypokalemia and reduction of the nitrogenous load in the intestine (eg, reducing protein content in the diet, halting gastrointestinal bleeding from esophageal varices, clearing blood and other nitrogenous substances from the colon, etc.).
• Acute rhabdomyolysis with myoglobinuria requires urgent inpatient interventions to monitor and maintain renal function (with hemodialysis if necessary) and to avoid or correct hyperkalemia.
Chronic alcoholism. Three drugs are approved by the U.S. Food and Drug Administration for the treatment of alcohol abuse and alcohol dependence: disulfiram, acamprosate, and naltrexone (47; 137; 243). Disulfiram (Antabuse), the first medicine approved for the treatment of alcohol abuse and alcohol dependence, works by causing a severe adverse reaction: when someone taking the medication consumes alcohol, they get nauseated and vomit, creating a deterrent to drinking (47). A meta-analysis of acamprosate and naltrexone supports their efficacy in relapse reduction (130). Nalmefene, an opioid receptor antagonist similar in chemical composition to naltrexone, has been approved by the European Medicine Agency; it is not currently available in the United States for the treatment of alcohol dependence (238). Gabapentin, a GABA analogue used for treatment of epilepsy and nerve pain, is currently being considered as another possible candidate (183). Other nonbenzodiazepine anticonvulsants such as carbamazepine, valproic acid, and topiramate may also eventually prove helpful both in the treatment of alcohol withdrawal and the prevention of alcohol relapse (33).
Promising developments in the treatment of chronic alcoholism include preliminary studies demonstrating the relationship between the administration of exogenous ghrelin and a decrease in serum leptin levels, which may play a role in decreasing alcohol cravings in humans (103). Another double-blind, placebo-controlled human study comprised of 46 patients found evidence suggesting a role of the ghrelin system in connection to alcohol craving and seeking in alcohol use disorder (104).
The single most important therapeutic factor in treating neurologic complications of alcohol abuse in the long term is abstinence from alcohol. Therefore, an alcohol treatment program is a critical component of treatment. Besides alcoholism rehabilitation and nutritional supplementation, treatment of persistent neurologic abnormalities due to chronic ethanol abuse is largely symptomatic.
Alcohol intoxication and withdrawal. Acute management of alcohol intoxication and delirium tremens is primarily supportive. Cardiovascular collapse and respiratory failure occur with a sufficiently high level of intoxication. In delirium tremens, prolonged fever and sweating may also result in fluid loss and secondary hypotension.
Agitation and autonomic disturbances may be treated with benzodiazepines (eg, oral or intravenous chlordiazepoxide, 25 to 100 mg, with a maximum of 300 mg in the first 24 hours). Recommendations from the World Health Organization advocate supported withdrawal from alcohol in patients with alcohol dependence (312). Mild symptoms of withdrawal can be treated with carbamazepine or gabapentin on an outpatient basis (281). Benzodiazepines are recommended as a first-line medication in a hospital setting for the management of alcohol withdrawal with moderate-to-severe symptoms to alleviate discomfort and agitation, and to prevent seizures and delirium. Long-acting benzodiazepines (eg, chlordiazepoxide or diazepam) are preferred over shorter-acting ones, except in cases of impaired hepatic metabolism (eg, liver failure, elderly). The dose and duration should be individually determined, according to the severity of withdrawal and the presence of other medical disorders. In general, the duration of benzodiazepine treatment should be limited to the first 3 to 7 days after the cessation of alcohol.
All alcoholic patients should be supplemented with parenteral thiamine and other vitamins.
Alcohol withdrawal seizures. Withdrawal seizures are typically self-limited. Benzodiazepines, and not nonbenzodiazepine anticonvulsants, should be used following an alcohol withdrawal seizure to prevent further alcohol withdrawal seizures (312). There is no clear difference in hospital admission, seizures occurring in the emergency department after benzodiazepine administration, or 1-week return visits for discharged patients for patients treated with either diazepam or lorazepam (253). Withdrawal seizures do not represent "latent" epilepsy; therefore, treatment with nonbenzodiazepine anticonvulsants is not recommended (10). If all convulsions are clearly linked to withdrawal, chronic anticonvulsant therapy is not indicated.
Status epilepticus, though rare, needs aggressive intervention with benzodiazepines, anticonvulsants, and treatment of systemic complications.
Chronic management of alcoholic patients prone to recurrent seizures is complicated by the difficulty in separating alcohol-related convulsions and preexisting epileptic conditions.
In patients with epilepsy unrelated to alcohol, drinking in moderation probably has little effect on seizure control or anticonvulsant level (113), whereas heavy or frequent drinking is linked to an increase in seizure frequency (113; 105). Treatment of alcoholism in such individuals is the most effective means of seizure control.
Wernicke-Korsakoff syndrome. As part of withdrawal management, all hospitalized alcoholic patients should be given oral or parenteral thiamine. Patients at high risk of Wernicke encephalopathy (eg, malnourished, severe withdrawal) should be given 3 to 5 days of parental thiamine (312).
In patients with suspected Wernicke encephalopathy, parenteral thiamine should be administered twice daily for 5 days.
Effective treatment and prophylaxis may only be achieved by use of parenteral vitamin supplements because oral supplements may not be adequately absorbed (59). Unfortunately, current evidence is still insufficient to decide the exact dose, frequency, or duration of thiamine treatment for prevention or treatment of Wernicke-Korsakoff syndrome associated with alcohol abuse (65; 123). Thiamine repletion with at least 100 to 200 mg/day intravenously or intramuscularly is recommended (117), and some advocate for much more aggressive initial treatment regimens of 1000 mg or more daily, particularly for the first 3 to 5 days and as long as 2 months (30; 123).
A double-blind, randomized controlled trial of 127 symptomatic subjects found no significant differences in outcomes for any of the dosage conditions: 100 mg three times daily, 300 mg three times daily, or 500 mg three times daily, for 5 days (70). This study found no clear short-term benefit of high-dose thiamine over intermediate or lower doses of thiamine, for the treatment of cognitive and neurologic abnormalities related to Wernicke-Korsakoff syndrome. The authors concluded that "the absence of conclusive evidence for the superiority of high-dose thiamine supports a recommendation for patient-specific treatment, while ensuring that the potential impact of other biochemical factors (eg, magnesium and other B vitamin deficiencies) are considered and corrected if necessary" (70).
Alcoholic pellagra. When pellagra is suspected, treatment with oral nicotinamide (100 mg 3 times daily for 3-4 weeks) is an inexpensive, safe, and potentially lifesaving intervention (209; 19). Affected patients should also be treated with other B vitamins and adequate protein nutrition (19).
Marchiafava-Bignami syndrome. Management of this condition is primarily supportive.
Alcoholic dementia. Treatment for alcohol-induced dementias should include abstinence from alcohol and an adequate diet with vitamin supplements. Patients should be given thiamine hydrochloride 100 to 200 mg intravenously, followed by 100 mg intramuscularly every 12 hours. Electrolyte imbalance should also be corrected (94). Withdrawal from alcohol may require inpatient treatment to be followed by outpatient therapy or support groups such as Alcoholics Anonymous. To the degree that the patients’ cognitive deficits interfere with daily functioning, they may require caregiver support in daily living tasks and may be prohibited from driving. Mental status may improve after patients abstain from alcohol for a sustained period of time.
Social support is necessary for patients with significant cognitive deficits, as many of them have little insight into their impairment. Gait ataxia requires physical therapy and assistive devices. The dysesthesia of peripheral neuropathy responds partially to tricyclic antidepressants, such as desipramine or amitriptyline at 50 to 150 mg at bedtime. Carbamazepine at 400 to 1200 mg per day or gabapentin at 900 to 1800 mg per day have a similar palliative effect.
Hepatic encephalopathy. Management of acute exacerbations of chronic hepatic encephalopathy includes identification and correction of precipitating factors, such as correction of diuretic-induced hypokalemia and reduction of the nitrogenous load in the intestine (eg, reducing protein content in the diet, halting gastrointestinal bleeding from esophageal varices, clearing blood and other nitrogenous substances from the colon, etc.).
Lactulose (1,4 beta galactoside-fructose) is a nonabsorbable synthetic disaccharide composed of galactose and fructose. Because the small intestine does not have enzymes that can split this synthetic disaccharide, it reaches the large intestine unchanged. In the colon, anaerobic bacteria metabolize lactulose, initially to monosaccharides, and then to volatile fatty acids, hydrogen, and methane. Effects of this include increased gas formation and osmolality, as well as acidification (lower pH), within the colon. The increased intraluminal gas and higher osmolality produce a combined volume and osmotic laxative effect, which helps to clear nitrogenous substances from the colon. The reduced intestinal pH shifts ammonia (NH3) produced by gut bacteria to the ammonium ion (NH4+), a charged form that cannot cross biological membranes, including the gut lining. Some colonic bacteria utilize the trapped ammonia as a nitrogen source for protein synthesis, which helps to further sequester ammonia and prevent its absorption. Finally, the acidic pH destroys urease-producing bacteria in the colon, which serves to decrease the colonic ammonia derived from bacteria.
In patients with hepatic encephalopathy, lactulose is typically given enterally as a syrup. For acute hepatic encephalopathy, a bolus of 45 ml (30 gm) can be administered and repeated hourly until the first bowel movement. Once the episode of encephalopathy has subsided, the dose can be titrated to achieve 2 to 3 soft bowel movements a day (typically 15 to 30 ml, 2-4 times daily). Lactulose can also be given as a rectal enema with the patient in a left lateral decubitus position.
A meta-analysis of randomized controlled clinical trials showed that lactulose has significant beneficial effects for patients with minimal hepatic encephalopathy compared with placebo or no intervention (175). In particular, lactulose reduced blood ammonia levels, prevented the progression to overt hepatic, and improved health-related quality of life. However, lactulose significantly increased the incidence of diarrhea and did not significantly lower mortality. Other systematic reviews of randomized controlled trials have also suggested that nonabsorbable disaccharides are associated with a beneficial effect on clinically relevant outcomes compared with placebo or no intervention (96).
In the HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study, a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis admitted for hepatic encephalopathy, polyethylene glycol 3350-electrolyte solution led to more rapid resolution of hepatic encephalopathy than standard therapy with lactulose (231). This suggests that polyethylene glycol 3350-electrolyte solution may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute hepatic encephalopathy.
Broad-spectrum nonabsorbable antibiotics, such as rifaximin, are quite effective and safe for the treatment of hepatic encephalopathy. In one systematic review of randomized clinical trials, antibiotics were superior to nonabsorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this apparent difference is clinically important (08; 09). A later meta-analysis of clinical trials found that rifaximin is at least as effective as other conventional oral agents for the treatment of hepatic encephalopathy and has a better safety profile (74).
In any case, addition of rifaximin to lactulose significantly reduces the risk of recurrence and related hospitalization, compared with lactulose therapy alone (121). Rifaximin's clinical effect is likely due to effects on metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance (22).
Surgical treatments for hepatic encephalopathy include procedures to prevent variceal (re)bleeding, procedures to occlude portacaval shunts (using a balloon or open surgical technique), and liver transplantation (potentially definitive in suitable candidates).
Because Wernicke encephalopathy neuropathology is identified in a substantial portion of patients with hepatic encephalopathy, patients who develop hepatic encephalopathy should also be treated presumptively with thiamine (41).
Alcoholic cerebellar degeneration. Management of this condition is primarily supportive.
Osmotic demyelination syndrome. Management of this condition is primarily supportive.
Tobacco-alcohol amblyopia (tobacco-alcohol optic neuropathy). The visual abnormalities improve in approximately half of the patients with alcohol and tobacco cessation combined with vitamin replacement and then supplementation, but complete recovery was never reached (155). Most cases improve when smoking is stopped and even when it is reduced (88).
Alcoholic neuropathy. A trial of oral thiamine and multivitamins is recommended. Gabapentin and other medications may be needed for symptomatic relief of dysesthesias. Management of this condition is otherwise primarily supportive.
Alcohol-induced (dry) beriberi. The appropriate therapy is thiamine repletion and then supplementation. Depending on severity, thiamine may initially be administered orally if mild, or parenterally if moderate or severe.
Alcoholic myopathy. Acute rhabdomyolysis with myoglobinuria requires urgent inpatient interventions to monitor and maintain renal function and to avoid or correct hyperkalemia. Hemodialysis may be needed (15; 216). Blood levels of potassium, phosphate, and magnesium should be determined, and any identified deficiencies should be corrected. In chronic alcoholic myopathy, associated nutritional deficiencies need to be corrected and a diet with adequate protein and carbohydrates ensured.
Fetal alcohol spectrum disorder (and fetal alcohol syndrome). Management of this condition is primarily supportive.
Reduction in tobacco consumption may be associated with better outcomes in the treatment of alcoholism, although alcoholics who abstain from drinking often replace their addiction to alcohol with an inordinate amount of smoking and caffeine use (89).
Prenatal exposure to excessive alcohol can cause fetal alcohol syndrome; hence, the use of any alcohol during pregnancy is contraindicated.
Patients at risk of developing peri-operative alcohol withdrawal symptoms can be identified by laboratory evaluation as well as patient interviews and questionnaires. Rapid-sequence intubation is recommended (291).
- Adams RD, Foley JM. Neurological changes in more common types of severe liver disease. Trans Am Neurol Assn 1949a;74:217-9.
- Adams RD, Foley JM. IVe Congrès Internationale. Vol. II. Communications. Paris: Masson et Cie, 1949b:62.
- Adams RD, Foley JM. The neurological disorder associated with liver disease. In: Metabolic and toxic diseases of the nervous system. Proceedings of the Association for Research in Nervous and Mental Diseases. Baltimore: Williams and Wilkins, 1953a:198-237.
- Adams RD, Foley JM. The disorder of movement in the more common varieties of liver disease. Electroencephalography and Clinical Neurophysiology 1953b;5(Suppl 3):51.
- Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry 1959;81:154-72. PMID 13616772
- Akano EO, Otite FO, Chaturvedi S. Alcohol withdrawal is associated with poorer outcome in acute ischemic stroke. Neurology 2019;93(21):e1944-54. PMID 31653706
- Alfonso-Loeches S, Guerri C. Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Crit Rev Clin Lab Sci 2011:48(1):19-47.** PMID 21657944
- Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004a;328(7447):1046. PMID 15054305
- Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database Syst Rev 2004b;(2):CD003044. PMID 15106187
- Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev 2011;15(6):CD008537.** PMID 21678378
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 2nd edition. Washington DC, 1968.
- American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 4th edition, text revision. Washington, DC: APA, 2000.
- Arabadjief MA, Elsayed OH, Bashir S, et al. Chlordiazepoxide-induced delirium in a patient undergoing alcohol withdrawal: a case report. J Med Case Rep 2022;16(1):269. PMID 35799217
- Arts NJ, Walvoort SJ, Kessels RP. Korsakoff’s syndrome: a critical review. Neuropsychiatr Dis Treat 2017;13:2875-90. PMID 29225466
- Asokan N, Binesh VG, Andrews AM, Jayalakshmi PS. Bullous lesions, sweat gland necrosis and rhabdomyolysis in alcoholic coma. Indian J Dermatol 2014;59(6):632. PMID 25484420
- Astley SJ. Fetal alcohol syndrome prevention in Washington State: evidence of success. Paediatr Perinat Epidemiol 2004;18(5):344-51. PMID 15367321
- Astley SJ, Clarren SK. A case definition and photographic screening tool for the facial phenotype of fetal alcohol syndrome. J Pediatr 1996;129(1):33-41. PMID 8757560
- Astley SJ, Stachowiak J, Clarren SK, Clausen C. Application of the fetal alcohol syndrome facial photographic screening tool in a foster care population. J Pediatr 2002;141(5):712-7. PMID 12410204
- Badawy AA. Pellagra and alcoholism: a biochemical perspective. Alcohol Alcohol 2014;49(3):238-50. PMID 24627570
- Baj J, Forma A, Kobak J, et al. Toxic and nutritional optic neuropathies-an updated mini-review. Int J Environ Res Public Health 2022;19(5):3092. PMID 35270784
- Bajaj JS. Management options for minimal hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 2008;2(6):785-90. PMID 19090738
- Bajaj JS. Potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther 2016;43 Suppl 1:11-26. PMID 26618922
- Baruah JK, Washington M, Kinder D. Ethanol induced skeletal muscle degeneration--role of calcium. Exp Pathol 1988;33(4):207-12. PMID 3229456
- Bearer CF, Mechanisms of brain injury: L1 cell adhesion molecule as a target for ethanol-induced prenatal brain injury. Semin Pediatr Neurol 2001;8(2):100-7. PMID 11464956
- Behbehani R, Sergott RC, Savino PJ. Tobacco-alcohol amblyopia: a maculopathy? Br J Ophthalmol 2005;89(11):1543-4. PMID 16234480
- Behse F, Buchthal F. Alcoholic neuropathy: clinical, electrophysiological and biopsy findings. Ann Neurol 1977;2:95-110.
- Benson DF, Djenderedjian A, Miller BL, et al. The neural basis of confabulation. Neurology 1996;46:1239-43. PMID 8628459
- Berger K, Ajani UA, Kase CS, et al. Light-to-moderate alcohol consumption and risk of stroke among US male physicians. N Engl J Med 1999;341:1557-64. PMID 10564684
- Bertrand J, Floyd LL, Weber MK, et al. Guidelines for identifying and referring persons with fetal alcohol syndrome. MMWR Recomm Rep 2005;54(RR-11):1-14. PMID 16251866
- Bilici R, Saridogan GE, Turan C, et al. A case of Wernicke-Korsakoff syndrome treated 1 year after the onset of symptoms. Prim Care Companion CNS Disord 2015;17(6). PMID 27057403
- Bleuler E. Lehrbuch der Psychiatrie. Berlin: Julius Springer, 1916.
- Bönnemann C, Meinecke P. Holoprosencephaly as a possible embryonic alcohol effect: another observation. Am J Med Genet 1990;37(3):431-2. PMID 2260579
- Book SW, Myrick H. Novel anticonvulsants in the treatment of alcoholism. Expert Opin Investig Drugs 2005;14(4):371-6. PMID 15882114
- Bookstein FL, Sampson PD, Connor PD, Streissguth AP. Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage. Anat Rec 2002;269(3):162-74. PMID 12124903
- Bruce BB, Biousse V, Dean AL, Newman NJ. Neurologic and ophthalmic manifestations of fetal alcohol syndrome. Rev Neurol Dis 2009;6(1):13-20. PMID 19367219
- Brun A, Andersson J. Frontal dysfunction and frontal cortical synapse loss in alcoholism--the main cause of alcohol dementia. Dement Geriatr Cogn Disord 2001;12:289-94. PMID 11351140
- Bruno MC, Vilela MA, Oliveira CA. Study on dermatoses and their prevalence in groups of confirmed alcoholic individuals in comparison to a non-alcoholic group of individuals. An Bras Dermatol 2013;88(3):368-75. PMID 23793198
- Buesa-Lorenzo JB, Rojo-Bofill LMR, Plumed-Domingo JP, Rubio-Granero T, Rojo-Moreno L. Marchiafava-Bignami disease in a patient with schizophrenia and alcohol use disorder. Actas Esp Psiquiatr 2021;49(5):228-31. PMID 34533206
- Butters N. Alcoholic Korsakoff's syndrome: some unresolved issues concerning etiology, neuropathology, and cognitive deficits. J Clin Exp Neuropsychol 1985;7(2):181-210. PMID 3157699
- Caballero-Mateos AM, García Márquez J, Ortiz Sánchez A, Roa Colomo A, Rodríguez Acosta C. Is gastroparesis that is often detected in patients with alcoholic chronic liver disease a manifestation of an autonomic dysfunction syndrome? A preliminary study. Rev Esp Enferm Dig 2021;113(4):269-71. PMID 33233909
- Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy. J Neurol Neurosurg Psychiatry 1997;62:51-60. PMID 9010400
- Campbell ACP, Biggart JH. Wernicke's encephalopathy (polioencephalitis haemorrhagica superior): its alcoholic and non-alcoholic incidence. J Pathol Bacteriol 1939;48:245-62.
- Cao S, Wang X, Cestodio K. Pellagra, an almost-forgotten differential diagnosis of chronic diarrhea: more prevalent than we think. Nutr Clin Pract 2020;35(5):860-3. PMID 31599018
- Carboni S, Isola R, Gessa GL, Rossetti ZL. Ethanol prevents the glutamate release induced by N-methyl-D-aspartate in the rat striatum. Neurosci Lett 1993;152(1-2):133-6. PMID 8100051
- Carroll FD. Nutritional amblyopia. Arch Ophthalmol 1966;76(3):406-11. PMID 5946114
- Catlin MC, Guizzetti M, Costa LG. Effects of ethanol on calcium homeostasis in the nervous system: implications for astrocytes. Mol Neurobiol 1999;19:1-24. PMID 10321969
- Center for Substance Abuse Treatment. Incorporating alcohol pharmacotherapies into medical practice. Rockville (MD): U.S. Substance Abuse and Mental Health Services Administration, 2009.
- Centerwall BS, Criqui MH. Prevention of the Wernicke-Korsakoff syndrome: a cost-benefit analysis. N Engl J Med 1978;299(6):285-9. PMID 96343
- Cerroni MP, Barrado JC, Nobrega AA, et al. Outbreak of beriberi in an Indian population of the upper Amazon region, Roraima State, Brazil, 2008. Am J Trop Med Hyg 2010;83(5):1093-7. PMID 21036843
- Charness ME. Brain lesions in alcoholics. Alcohol Clin Exp Res 1993;17:2-11. PMID 8452204
- Charness ME, Simon RP, Greenberg DA. Ethanol and the nervous system. N Engl J Med 1989;321:442-54.** PMID 2668759
- Chindarkar NS, Rentmeester LL, Ly BT, Fitzgerald RL. Black urine due to urobilinogen in a patient with alcoholic pellagra. Clin Biochem 2014;47(12):1132-5. PMID 24709296
- Chiotoroiu SM, Noaghi M, Stefaniu GI, Secureanu FA, Purcarea VL, Zemba M. Tobacco-alcohol optic neuropathy--clinical challenges in diagnosis. J Med Life 2014;7(4):472-6. PMID 25713605
- Chudley AE, Conry J, Cook JL, et al. Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis. CMAJ 2005;172(5 Suppl):S1-S21. PMID 15738468
- Claus D, Eggers R, Engelhardt A, Neundorfer B, Warecka K. Ethanol and polyneuropathy. Acta Neurol Scand 1985;72:312-6. PMID 2998144
- Coelho MPP, Diniz KGD, Bering T, et al. Skeletal muscle mass index and phase angle are decreased in individuals with dependence on alcohol and other substances. Nutrition 2020;71:110614. PMID 31869659
- Cohen MM, Shiota K. Teratogenesis of holoprosencephaly. Am J Med Genet 2002;109(1):1-15. PMID 11932986
- Contet C. Gene expression under the influence: transcriptional profiling of ethanol and the brain. Curr Psychopharmacol 2012;1(4):301-14. PMID 24078902
- Cook CC. Prevention and treatment of Wernicke-Korsakoff syndrome. Alcohol Alcohol Suppl 2000;35(1):19-20. PMID 11304070
- Crews FT, Robinson DL, Chandler LJ, et al. Mechanisms of persistent neurobiological changes following adolescent alcohol exposure: NADIA consortium findings. Alcohol Clin Exp Res 2019;43(9):1806-22. PMID 31335972
- Cunha DF, Monteiro JP, Ortega LS, Alves LG, Cunha SF. Serum electrolytes in hospitalized pellagra alcoholics. Eur J Clin Nutr 2000;54(5):440-2. PMID 10822294
- D'Amour ML, Butterworth RF. Pathogenesis of alcoholic peripheral neuropathy: direct effect of ethanol or nutritional deficit. Metab Brain Dis 1994;9:133-41. PMID 25584583
- Dang CV. Tobacco-alcohol amblyopia: a proposed biochemical basis for pathogenesis. Med Hypotheses 1981;7(11):1317-28. PMID 7033739
- Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28(4):263-74. PMID 12921221
- Day E, Bentham PW, Callaghan R, Kuruvilla T, George S. Thiamine for prevention and treatment of Wernicke-Korsakoff syndrome in people who abuse alcohol. Cochrane Database Syst Rev 2013;7:CD004033. PMID 23818100
- Dhaliwal A, Larson JL, Dhindsa BS, Bhogal N, Rochling FA. Dry beriberi manifesting as acute inflammatory demyelinating polyneuropathy in a patient with decompensated alcohol-induced cirrhosis. Cureus 2020;12(10):e11281. PMID 33274156
- Diamond I, Messing RO. Neurologic effects of alcoholism. West J Med 1994;161:279-87. PMID 7975567
- Dietrich O, Heun M, Notroff J, Schmidt K, Zarnkow M. The role of cult and feasting in the emergence of Neolithic communities. New evidence from Göbekli Tepe, south-eastern Turkey. Antiquity 2012;86(333):674-95.
- Di Marco S, Pilati L, Brighina F, Fierro B, Cosentino G. Wernicke-Korsakoff syndrome complicated by subacute beriberi neuropathy in an alcoholic patient. Clin Neurol Neurosurg 2018;164:1-4. PMID 29128624
- Dingwall KM, Delima JF, Binks P, Batey R, Bowden SC. What is the optimum thiamine dose to treat or prevent Wernicke's encephalopathy or Wernicke-Korsakoff syndrome? Results of a randomized controlled trial. Alcohol Clin Exp Res 2022;46(6):1133-47. PMID 35428992
- Edenberg HJ, Foroud T. Genetics of alcoholism. Handb Clin Neurol 2014;125:561-71.** PMID 25307596
- Elliott M, Terrett G, Curran HV, De Bono N, Rendell PG, Henry JD. Prospective memory deficits following acute alcohol consumption. J Psychopharmacol 2021;35(11):1386-97. PMID 34747256
- Ellison RC. Balancing the risks and benefits of moderate drinking. Ann NY Acad 2002;957:1-6. PMID 12074956
- Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol 2012;18(8):767-77. PMID 22371636
- Emsley R, Smith R, Roberts M, Kapnias S, Pieters H, Maritz S. Magnetic resonance imaging in alcoholic Korsakoff's syndrome: evidence for an association with alcoholic dementia. Alcohol Alcohol 1996;31(5):479-86. PMID 8949964
- Engberg G, Hajos M. Ethanol attenuates the response of locus coeruleus neurons to excitatory amino acid agonists in vivo. Naunyn Schmiedebergs Arch Pharmacol 1992;345(2):222-6. PMID 1314963
- Engelmann C, Schob S, Nonnenmacher I, et al. Loss of paraspinal muscle mass is a gender-specific consequence of cirrhosis that predicts complications and death. Aliment Pharmacol Ther 2018;48(11-12):1271-81. PMID 30417398
- Estruch R, Sacanella E, Fernandez-Sola J, Nicolas JM, Rubin E, Urbano-Marquez A. Natural history of alcoholic myopathy: a 5-year study. Alcohol Clin Exp Res 1998;22(9):2023-8. PMID 9884146
- Fama R, Le Berre AP, Sassoon SA, Zahr NM, Pohl KM, Pfefferbaum A, Sullivan EV. Memory impairment in alcohol use disorder is associated with regional frontal brain volumes. Drug Alcohol Depend 2021;228:109058. PMID 34610518
- Fellgiebel A, Scheurich A, Siessmeier T, Schmidt LG, Bartenstein P. Persistence of disturbed thalamic glucose metabolism in a case of Wernicke-Korsakoff syndrome. Psychiatry Res 2003;124(2):105-12. PMID 14561428
- Fernandez-Sola J, Estruch R, Grau JM, Pare JC, Rubin E, Urbano-Marquez A. The relation of alcoholic myopathy to cardiomyopathy. Ann Intern Med 1994;120(7):529-36. PMID 8116990
- Fernandez-Sola J, Preedy VR, Lang CH, et al. Molecular and cellular events in alcohol-induced muscle disease. Alcohol Clin Exp Res 2007;31(12):1953-62. PMID 18034690
- Filgueiras F, Stolarczuk D, Gripp AC, Succi IC. Benign symmetrical lipomatosis and pellagra associated with alcoholism. An Bras Dermatol 2011;86(6):1189-92. PMID 22281911
- Fink A, Hays RD, Moore AA, Beck JC. Alcohol-related problems in older persons. Arch Intern Med 1996;156:1150-6. PMID 8639009
- Foley JM, Watson CW, Adams RD. Significance of the electroencephalographic changes in hepatic coma. Trans Am Neurol Assoc 1950;51:161-5. PMID 14788100
- Foulds WS, Bronte-Stewart JM, Chisholm IA. Serum thiocyanate concentrations in tobacco amblyopia. Nature 1968;218(5141):586. PMID 5655189
- Foulds WS, Chisholm IA, Brontë-Stewart J, Wilson TM. Vitamin B 12 absorption in tobacco amblyopia. Br J Ophthalmol 1969;53(6):393-7. PMID 5794955
- Freeman AG. Optic neuropathy and chronic cyanide intoxication: a review. J R Soc Med 1988;81(2):103-6. PMID 3279198
- Friend KB, Pagano ME. Changes in cigarette consumption and drinking outcomes: findings from Project MATCH. J Subst Abuse Treat 2005;29(3):221-9. PMID 16183471
- Fujiwara E, Brand M, Borsutzky S, Steingass HP, Markowitsch HJ. Cognitive performance of detoxified alcoholic Korsakoff syndrome patients remains stable over two years. J Clin Exp Neuropsychol 2008;30(5):576-87. PMID 17852615
- Gamper E. Zur frage der polioencephalitis haemorrhagica der chronischen alkoholiker. Anatomische befunde beim alkolischen Korsakoff and ihre beziehungen zum klinischen bild. Deutsch Z Nervenheilk 1928;102(1):122-9.
- Ganguli M, Vander Bilt J, Saxton JA, Shen C, Dodge HH. Alcohol consumption and cognitive function in late life: a longitudinal community study. Neurology 2005;65(8):1210-7. PMID 16247047
- Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name. J Neuroimaging 2011;21(2):e1-14. PMID 18681931
- Gilroy J. Basic neurology. New York: Pergamon Press, 1990.
- Glass IB. Alcoholic hallucinosis: a psychiatric enigma--1. The development of an idea. Br J Addict 1989;84(1):29-41. PMID 2644996
- Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2016;(5):CD003044. PMID 27153247
- Grzybowski A, Holder GE. Tobacco optic neuropathy (TON) - the historical and present concept of the disease. Acta Ophthalmol 2011;89(5):495-9. PMID 20337605
- Grzybowski A, Pieniążek M. Tobacco-alcohol amblyopia does not exist. Acta Ophthalmol 2014;92(1):e77-8. PMID 23506382
- Grzybowski A, Zülsdorff M, Wilhelm H, Tonagel F. Toxic optic neuropathies: an updated review. Acta Ophthalmol 2015;93(5):402-10. PMID 25159832
- Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH. Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. Am J Physiol Regul Integr Comp Physiol 2001;281:R365-72. PMID 11404314
- Gül G, Özerden M, Özdemir Z, et al. Marchiafava-Bignami disease: report of three cases. Ideggyogy Sz 2020;73(1-2):65-9. PMID 32057207
- Gummel K, Ygge J. Ophthalmologic findings in Russian children with fetal alcohol syndrome. Eur J Ophthalmol 2013;23(6):823-30. PMID 23661538
- Haass-Koffler CL, Aoun EG, Swift RM, de la Monte SM, Kenna GA, Leggio L. Leptin levels are reduced by intravenous ghrelin administration and correlated with cue-induced alcohol craving. Transl Psychiatry 2015;5:e646. PMID 26418274
- Haass-Koffler CL, Long VM, Farokhnia M, et al. Intravenous administration of ghrelin increases serum cortisol and aldosterone concentrations in heavy-drinking alcohol-dependent individuals: results from a double-blind, placebo-controlled human laboratory study. Neuropharmacology 2019;158:107711. PMID 31310775
- Hamerle M, Ghaeni L, Kowski A, Weissinger F, Holtkamp M. Alcohol use and alcohol-related seizures in patients with epilepsy. Front Neurol 2018;9:401. PMID 29922217
- Han L, Han H, Liu H, et al. Alcohol abuse and alcohol withdrawal are associated with adverse perioperative outcomes following elective spine fusion surgery. Spine (Phila Pa 1976) 2021;46(9):588-95. PMID 33315773
- Harding A, Halliday G, Caine D, Kril J. Degeneration of thalamic nuclei differentiates alcoholics with amnesia. Brain 2000;(Pt 1):141-54. PMID 10611128
- Hariharasubramony A, Chankramath S, Prathyusha D. A case of alcohol-dependent syndrome and pellagra. Int J Nutr Pharmacol Neurol Dis 2013;3:61-3.
- Harper C. The neuropathology of alcohol-related brain damage. Alcohol Alcohol 2009;44(2):136-140.** PMID 19147798
- Harper C. Thiamine (vitamin B1) deficiency and associated brain damage is still common throughout the world and prevention is simple and safe! Eur J Neurol 2006;13(10):1078-82. PMID 16987159
- Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Psychiatry 1986;49(4):341-5. PMID 3701343
- Harris RA, Trudell JR, Mihic SJ. Ethanol’s molecular targets. Sci Signal 2008;1(28):re7. PMID 18632551
- Hauser WA, Ng SK, Brust JC. Alcohol, seizures, and epilepsy. Epilepsia 1988;29(Suppl 2):S66-78. PMID 3168960
- Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol 2004;43(1):1-5. PMID 14693013
- Henriques JF, Portugal CC, Canedo T, Relvas J, Summavielle T, Socodato R. Microglia and alcohol meet at the crossroads: microglia as critical modulators of alcohol neurotoxicity. Toxicol Lett 2018;283:21-31. PMID 29129797
- Hernandez L, Brockman T, Mehta T. Identification of Wernicke encephalopathy in a patient presenting with altered mental status and dehydration. WMJ 2022;121(1):E10-4. PMID 35442587
- Heye N, Terstegge K, Sirtl C, McMonagle U, Schreiber K, Meyer-Gessner M. Wernicke's encephalopathy--causes to consider. Intensive Care Med 1994;20(4):282-6. PMID 8046122
- Hillbom M, Saloheimo P, Fujioka S, Wszolek ZK, Juvela S, Leone MA. Diagnosis and management of Marchiafava-Bignami disease: a review of CT/MRI confirmed cases. J Neurol Neurosurg Psychiatry 2014;85(2):168-73. PMID 23978380
- Hong M, Krauss RS. Ethanol itself is a holoprosencephaly-inducing teratogen. PLoS One 2017;12(4):e0176440. PMID 28441416
- Howard AJ, Kulkarni O, Lekwuwa G, Emsley HC. Rapidly progressive polyneuropathy due to dry beriberi in a man: a case report. J Med Case Rep 2010;4:409. PMID 21176139
- Hudson M, Schuchmann M. Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence. Eur J Gastroenterol Hepatol 2019;31(4):434-50. PMID 30444745
- Huq S, Wong M, Chan H, Crimmins D. Osmotic demyelination syndromes: central and extrapontine myelinolysis. J Clin Neurosci 2007;14(7):684-688. PMID 17462902
- Infante MT, Fancellu R, Murialdo A, Barletta L, Castellan L, Serrati C. Challenges in diagnosis and treatment of Wernicke encephalopathy: report of 2 cases. Nutr Clin Pract 2016;31(2):186-90. PMID 26869612
- Inoue A, Itabashi K, Iwai T, Kitahara H, Watanabe Y. Imaging findings of vitamin deficiencies: are they forgotten diseases? BJR Open 2021;3(1):20210011. PMID 34877451
- Iorio KR, Reinlib L, Tabakoff B, Hoffman PL. Chronic exposure of cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol 1992;41(6):1142-8. PMID 1535416
- Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 1981;44(3):209-15. PMID 7229643
- Jacobson RR, Lishman WA. Cortical and diencephalic lesions in Korsakoff's syndrome: a clinical and CT scan study. Psychol Med 1990;20(1):63-75. PMID 2320699
- Jarmasz JS, Basalah DA, Chudley AE, Del Bigio MR. Human brain abnormalities associated with prenatal alcohol exposure and fetal alcohol spectrum disorder. J Neuropathol Exp Neurol 2017;76(9):813-33. PMID 28859338
- Johkura K, Naito M, Naka T. Cortical involvement in Marchiafava-Bignami disease. AJNR Am J Neuroradiol 2005;26(3):670-3. PMID 15760886
- Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014;311(18);1899-900.** PMID 24825644
- Jouanna J. Wine and medicine in Ancient Greece. In: van der Eijk P, editor. Greek medicine from Hippocrates to Galen: selected papers. Leiden and Boston: Brill, 2012:173-93.
- Jung YC, Chanraud S, Sullivan EV. Neuroimaging of Wernicke's encephalopathy and Korsakoff's syndrome. Neuropsychol Rev 2012;22(2):170-80. PMID 22577003
- Kant F. Die pseudoencephalitis Wernicke der alkholiker (polioencephalitis haemorrhagica superior acuta). Arch Psychiat Nervenk 1932;98:702-68.
- Kee C, Hwang JM. Optical coherence tomography in a patient with tobacco-alcohol amblyopia. Eye (Lond) 2008;22(3):469-70. PMID 17435689
- Kermode AG, Plant GT, Miller DH, Kendall BE, McDonald WI. Tobacco-alcohol amblyopia: magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 1989;52(12):1447. PMID 2614454
- Kertesz SG. Pellagra in 2 homeless men. Mayo Clin Proc 2001;76(3):315-8. PMID 11243279
- Kiefer F, Helwig H, Tarnaske T, Otte C, Jahn H, Wiedemann K. Pharmacological relapse prevention of alcoholism: clinical predictors of outcome. Eur Addict Res 2005;11(2):83-91. PMID 15785069
- Klauder JV, Winkelman NW. Pellagra among chronic alcoholics: a clinical and laboratory study. JAMA 1928;90(5):364-71.
- Kleinschmidt-DeMasters BK, Anderson CA, Rubinstein D. Asymptomatic pontine lesions found by magnetic resonance imaging: are they central pontine myelinolysis. J Neurol Sci 1997;149(1):27-35. PMID 9168162
- Kleinschmidt-DeMasters BK, Rojiani A, Filley C. Central and extrapontine myelinolysis: then…and now. J Neuropathol Exp Neurol 2006;65(1):1-11. PMID 16410743
- Klockgether T. Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol 2010;9(1):94-104. PMID 20083040
- Klopstock T, Haller R, DiMauro S. Alcoholic myopathy. In: Gilman S, editor. MedLink Neurology. San Diego: MedLink Corporation. Available at www.medlink.com. Accessed 2010.
- Kobayashi S, Hirose M, Akutsu Y, Hirayama K, Ishida Y, Ugawa Y. Disconnected motor intention and spatial attention in a case of probable Marchiafava-Bignami disease. Cogn Behav Neurol 2021;34(3):226-32. PMID 34473675
- Koehler PJ, Lanska DJ. Carl Wernicke. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of the neurological sciences, 2nd ed. Oxford: Academic Press/Elsevier, 2014;4:748-50.**
- Koehler PJ, Lanska DJ. Carl Wernicke. Reference module on neuroscience and biobehavioral psychology. Oxford: Elsevier Ltd, 2016.
- Kopelman M, Thomson AD, Guerrini I, Marshall EJ. The Korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol Alcohol 2009;44(2):148-54. PMID 19151162
- Kopelman MD. What is the Korsakoff syndrome? - a paper in tribute to Prof Alwyn Lishman. Cogn Neuropsychiatry 2022;27(4):296-313. PMID 35477346
- Korkiamaki P, Kervinen M, Karjalainen K, Majamaa K, Uusimaa J, Remes AM. Prevalence of the primary LHON mutations in Northern Finland associated with bilateral optic atrophy and tobacco-alcohol amblyopia. Acta Ophthalmol 2013;91(7):630-4. PMID 22970697
- Korsakoff SS. Disturbance of psychic function in alcoholic paralysis and its relation to the disturbance of the psychic sphere in multiple neuritis of non-alcoholic origin. 1887. Quoted by Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome. Oxford: Blackwell, 1971.
- Korsakoff SS. Étude médico-psychologique sur une forme des maladies de la mémoire. Revue philosophique de la France et de l'étranger 1889b;28:501-30.
- Korsakoff SS. Sur une forme de maladie mentale combinée avec la névrite multiple dégénérative. In: Congrès international de médecine mentale. Paris: Masson, 1889a:75-94.
- Kramer JH, Blusewicz MB, Preston K. The premature aging hypothesis: Old before its time. J Consult Clin Psychol 1989;57:257-62. PMID 2708614
- Kril JJ. Neuropathology of thiamine deficiency disorders. Metab Brain Dis 1996;11(1):9-17. PMID 8815394
- Kril JJ, Harper CG. Neuroanatomy and neuropathology associated with Korsakoff's syndrome. Neuropsychol Rev 2012;22(2):72-80. PMID 22528862
- Krumsiek J, Krüger C, Patzold U. Tobacco-alcohol amblyopia neuro-ophthalmological findings and clinical course. Acta Neurol Scand 1985;72(2):180-7. PMID 4050326
- Kuehn D, Aros S, Cassorla F, et al. A prospective cohort study of the prevalence of growth, facial, and central nervous system abnormalities in children with heavy prenatal alcohol exposure. Alcohol Clin Exp Res 2012;36(10):1811-9. PMID 22823161
- Kuncl RW, Wiggins WW. Toxic myopathies. Neurol Clin 1988;6(3):593-619. PMID 3065603
- Lanska DJ. Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. In: Boller F, Finger S, Tyler KL, editors. History of Neurology (Handbook of Clinical Neurology. Third series.) Amsterdam: Elsevier Science Publishing Company, 2010;95:445-76.**
- Lanska DJ. In memoriam: Joseph Michael Foley, MD (1916-2012). Arch Neurol 2012a;69(12):1656-9.**
- Lanska DJ. The discovery of niacin, biotin, and pantothenic acid. Discovery of the vitamins - 100th anniversary special issue. Ann Nutr Metab 2012b;61(3):246-53.** PMID 23183297
- Lanska DJ. Sergei Korsakoff. In: Aminoff MJ, Daroff RB, editors. Encyclopedia of the neurological sciences, 2nd ed. Oxford: Academic Press/Elsevier, 2014;2:807-8.**
- Lanska DJ. Sergei Korsakoff. Reference module on neuroscience and biobehavioral psychology. Oxford, UK: Elsevier Ltd, 2016.
- Lanska DJ, Ruff RL. Myopathies and myalgias in the aged. In: Barclay L, editor. Clinical geriatric neurology. Philadelphia: Lea & Febinger Publishing Co, 1993:294-309.**
- Lanska DJ, Sommers BW. Interview with Joseph M. Foley, MD. American Academy of Neurology oral history project. December 8, 2011. Minneapolis: American Academy of Neurology, 2011.
- Larner AJ, Gardner-Thorpe C. Robert Lawson (1846-1896). J Neurol 2012;259(4):792-3. PMID 22008869
- Lawson R. On the symptomatology of alcoholic brain disorders. Brain 1878;1:182-94.
- Lebel C, Mattson SN, Riley EP, et al. A longitudinal study of the long-term consequences of drinking during pregnancy: heavy in utero alcohol exposure disrupts the normal processes of brain development. J Neurosci 2012;32(44):15243-51. PMID 23115162
- Leigland LA, Ford MM, Lerch JP, Kroenke CD. The influence of fetal ethanol exposure on subsequent development of the cerebral cortex as revealed by magnetic resonance imaging. Alcohol Clin Exp Res 2013;37(6):924-32. PMID 23442156
- Leone M, Bottacchi E, Beghi E, et al. Alcohol use is a risk factor for a first generalized tonic-clonic seizure. The ALC.E. (Alcohol and Epilepsy) Study Group. Neurology 1997;48(3):614-20. PMID 9065535
- Lettsom JC. Some remarks on the effects of lignum quassiae amarae. Memoirs of the Medical Society of London 1792;1:128-65.
- Li R, Yu K, Wang Q, Wang L, Mao J, Qian J. Pellagra secondary to medication and alcoholism: a case report and review of the literature. Nutr Clin Pract 2016;31(6):785-9. PMID 27491713
- Lipinski RJ, Hammond P, O'Leary-Moore SK, et al. Ethanol-induced face-brain dysmorphology patterns are correlative and exposure-stage dependent. PLoS One 2012;7(8):e43067. PMID 22937012
- Lishman WA. Alcoholic dementia: A hypothesis. Lancet 1986;155:1184-6. PMID 2871423
- Lobo IA, Harris RA. GABA(A) receptors and alcohol. Pharmacol Biochem Behav 2008;90(1):90-4. PMID 18423561
- Luo M, Li L, Lu CZ, Cao WK. Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol 2011;23(12):1250-7. PMID 21971378
- Luthe SK, Sato R. Alcoholic pellagra as a cause of altered mental status in the emergency department. J Emerg Med 2017;53(4):554-7. PMID 28736097
- Maillard A, Laniepce A, Cabé N, et al. Temporal cognitive and brain changes in Korsakoff syndrome. Neurology 2021;96(15):e1987-98. PMID 33637634
- Mair WG, Warrington EK, Weiskrantz L. Memory disorder in Korsakoff's psychosis: a neuropathological and neuropsychological investigation of two cases. Brain 1979;102(4):749-83. PMID 116710
- Manto M, Perrotta G. Toxic-induced cerebellar syndrome: from the fetal period to the elderly. Handb Clin Neurol 2018;155:333-52. PMID 29891070
- Marcel CNS. De la folie causée par l’abus des boissons alcoolliques. Thèse pour le doctorate n médicine. Paris: Faculté de Médecine, 1847.
- Marchiafava E, Bignami A. Sopra un'alterazione del corpo calloso osservata da sogetti alcoolisti. Rivista di patologia nervosa e mentale 1903;8(12):544-9.
- Martin F, Ward K, Slavin G, Levi J, Peters TJ. Alcoholic skeletal myopathy, a clinical and pathological study. Q J Med 1985;55(218):233-51. PMID 2991970
- Mason BJ, Quello S, Shadan F. Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs 2018;27(1):113-24. PMID 29241365
- McGee CL, Riley EP. Brain imaging and fetal alcohol spectrum disorders. Ann Ist Super Sanita 2006;42(1):46-52. PMID 16801725
- McGuire LC, Cruickshank AM, Munro PT. Alcoholic ketoacidosis. Emerg Med J 2006;23(6):417-20. PMID 16714496
- Mellion M, Gilchrist JM, de la Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic, or both? Muscle Nerve 2011;43(3):309-16. PMID 21321947
- Mifsud F, Messager D, Jannot AS, et al. Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital. Clin Nutr 2022;41(1):33-9. PMID 34864453
- Miller M, Israel J, Cuttone J. Fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 1981;18(4):6-15. PMID 7264859
- Monforte R, Estruch R, Valls-Sole J, Nicolas J, Villalta J, Urbano-Marquez A. Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Arch Neurol 1995;52:45-51. PMID 7826275
- Moore EM, Riley EP. What happens when children with fetal alcohol spectrum disorders become adults? Curr Dev Disord Rep 2015;2(3):219-27. PMID 26543794
- Morgagni GB. Letter the thirty-eighth: treats of the hydrops ascites, tympanities, of the dropsy of the peritonaeum, and of others that are call’d encysted dropsies. In: The seats and causes of diseases. Vol 2. Translated by Benjamin Alexander. London: Miller and Cadell, 1769:280-361.
- Morse RM, Flavin DK. The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism. JAMA 1992;268(8):1012-4. PMID 1501306
- Murphy C, Bangash IH, Varma A. Dry beriberi mimicking the Guillain-Barre syndrome. Pract Neurol 2009;9(4):221-4. PMID 19608771
- Naidoo DP, Bramdev A, Cooper K. Wernicke's encephalopathy and alcohol-related disease. Postgrad Med J 1991;67(793):978-81. PMID 1775421
- Nakada T, Knight RT. Alcohol and the central nervous system. Med Clin N Am 1984;68:121-31. PMID 6318000
- Needham LK, Thelen K, Maness PF. Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions. J Neurosci 2001;21(5):1490-500. PMID 11222639
- Neiman J, Lang AE, Fornazzari L, Carlen PL. Movement disorders in alcoholism: a review. Neurology 1990;40:741-6.** PMID 2098000
- Nemirovskaya TL, Shenkman BS, Zinovyeva oE, Kazantseva Iu V, Samkhaeva ND. The development of clinical and morphological manifestations of chronic alcoholic myopathy in men with prolonged alcohol intoxication. [Article in Russian] Fiziol Cheloveka 2015;41(6):65-9. PMID 26859989
- Neri G, Sammito V, Romano C, Sanfilippo S, Opitz JM. Facial midline defect in the fetal alcohol syndrome: embryogenetic considerations in two clinical cases. Am J Med Genet 1988;29(3):477-82. PMID 3376992
- Ng SK, Hauser WA, Brust JC, Susser M. Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med 1988;319(11):666-73. PMID 3412384
- Niclot P, Guichard JP, Djomby R, Sellier P, Bousser MG, Chabriat H. Transient decrease of water diffusion in Wernicke encephalopathy. Neuroradiology 2002;44(4):305-7. PMID 11914805
- Nicolas JM, Garcia G, Fatjo F, et al. Influence of nutritional status on alcoholic myopathy. Am J Clin Nutr 2003;78(2):326-33. PMID 12885717
- Nilles EJ, Manaia A, Ruaia B, et al. Re-emergence of thiamine deficiency disease in the Pacific islands (2014-15): A case-control study. PLoS One 2018;13(6):e0198590. PMID 29879174
- Nishida A, Zensho H, Hisaoka K, Miyata M, Yamawaki S. Differential display of ethanol-induced gene in N18TG2 cells. Alcohol Clin Exp Res 2000;24:348-51. PMID 10776674
- Ogborne AC. Identifying and treating patients with alcohol-related problems. CMAJ 2000;162:1705-8. PMID 10870503
- Oh SJ. Alcoholic myopathy, electrophysiological study. Electromyogr Clin Neurophysiol 1976;16(2-3):205-18. PMID 964199
- Ohnishi A, Tsuji S, Igisu H, et al. Beriberi neuropathy. Morphometric study of sural nerve. J Neurol Sci 1980;45:177-90. PMID 7365498
- Oldach DW, Richard RE, Borza EN, Benitez RM. A mysterious death. N Engl J Med 1998;338:1764. PMID 9625631
- Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract 2012;7(1):12. PMID 23186222
- Olpp G. Hervorragende Tropenärzte in Wort und Bild. München: Ärztlichen Rundschau, O Gmelin, 1932.
- Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol 1997;153:185-92. PMID 9296132
- Oslin D, Atkinson RM, Smith DM, Hendrie H. Alcohol related dementia: proposed clinical criteria. Int J Ger Psychiatry 1998;13:203-12. PMID 9646147
- Ota Y, Capizzano AA, Moritani T, Naganawa S, Kurokawa R, Srinivasan A. Comprehensive review of Wernicke encephalopathy: pathophysiology, clinical symptoms and imaging findings. Jpn J Radiol 2020;38(9):809-20. PMID 32390125
- Palliyath SK, Schwartz BD, Gant L. Peripheral nerve functions in chronic alcoholic patients on disulfiram: a six month follow up. J Neurol Neurosurg Psychiatry 1990;53:227-30. PMID 2157819
- Panayi M, Gokhale D, Mansour S, Elles R. Prenatal diagnosis in a family with X-linked hydrocephalus. Prenat Diagn 2005;25(10):930-5. PMID 16088863
- Papadatos SS, Deligiannis G, Bazoukis G, et al. Nontraumatic rhabdomyolysis with short-term alcohol intoxication - a case report. Clin Case Rep 2015;3(10):769-72. PMID 26509002
- Park K, Oeda T, Sawada H. A case of alcoholic pellagra encephalopathy presenting with spinal myoclonus. Neurol Clin Pract 2015;5(6):472-4. PMID 29595842
- Park SH, Na DL, Lee JH, et al. Alcoholic pellagra encephalopathy combined with Wernicke disease. J Korean Med Sci 1991;6(1):87-93. PMID 1888455
- Perkoff GT. Alcoholic myopathy. Annu Rev Med 1971;22:125-32. PMID 4944411
- Perkoff GT, Hardy P, Velez-Garcia E. Reversible acute muscular syndrome in chronic alcoholism. N Engl J Med 1966;274(23):1277-85. PMID 5936410
- Peters TJ, Martin F, Ward K. Chronic alcoholic skeletal myopathy--common and reversible. Alcohol 1985;2(3):485-9. PMID 3161521
- Peters R, Peters J, Warner J, Beckett N, Bulpitt C. Alcohol, dementia and cognitive decline in the elderly: a systematic review. Age Ageing 2008;37(5):505-12. PMID 18487267
- Piqué-Duran E, Pérez-Cejudo JA, Cameselle D, Palacios-Llopis S, García-Vázquez O. Pellagra: a clinical, histopathological, and epidemiological study of 7 cases. Actas Dermosifiliogr 2012;103(1):51-8. PMID 22456595
- Pitel AL, Segobin SH, Ritz L, Eustache F, Beaunieux H. Thalamic abnormalities are a cardinal feature of alcohol-related brain dysfunction. Neurosci Biobehav Rev 2015;54:38-45. PMID 25108034
- Pitkin SR, Savage LM. Age-related vulnerability to diencephalic amnesia produced by thiamine deficiency: the role of time of insult. Behav Brain Res 2004;148(1-2):93-105. PMID 14684251
- Popescu BF, Bunyan RF, Guo Y, Parisi JE, Lennon VA, Lucchinetti CF. Evidence of aquaporin involvement in human central pontine myelinolysis. Acta Neuropathol Commun 2013;1(1):40. PMID 24252214
- Preedy VR, Salisbury JR, Peters TJ. Alcoholic muscle disease: features and mechanisms. J Pathol 1994b;173(4):309-15. PMID 7965390
- Preedy VR, Siddiq T, Why HJ, Richardson PJ. Ethanol toxicity and cardiac protein synthesis in vivo. Am Heart J 1994a;127(5):1432-9. PMID 8172081
- Preedy VR, Patel VB, Reilly ME, Richardson PJ, Falkous G, Mantle D. Oxidants, antioxidants and alcohol: implications for skeletal and cardiac muscle. Front Biosci 1999b;4:e58-66. PMID 10430553
- Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 1999;156:34-40. PMID 9892295
- Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med 2014;174(11):1727-33. PMID 25243839
- Ramanathan R, Wilkemeyer MF, Mittal B, Perides G, Charness ME. Alcohol inhibits cell-cell adhesion mediated by human L1. J Cell Biol 1996;133(2):381-90. PMID 8609170
- Reinecke LC, Doerrfuss JI, Kowski AB, Holtkamp M. Acute symptomatic seizures in the emergency room: predictors and characteristics. J Neurol 2022;269(5):2707-14. PMID 34727204
- Ridley NJ, Draper B, Withall A. Alcohol-related dementia: an update of the evidence. Alzheimers Res Ther 2013;5(1):3.** PMID 23347747
- Riggs JE, Schochet SS Jr. Osmotic stress, osmotic myelinolysis, and oligodendrocyte topography. Arch Pathol Lab Med 1989;113(12):1386-8. PMID 2589951
- Riley EP, Mattson SN, Sowell ER, Jernigan TL, Sobel DF, Jones KL. Abnormalities of the corpus callosum in children prenatally exposed to alcohol. Alcohol Clin Exp Res 1995;19(5):1198-202. PMID 8561290
- Rodger FC. Degenerative changes in the rat visual pathway when thiamin and riboflavin deficiencies are combined. Br J Ophthalmol 1954;38(3):144-55. PMID 13149754
- Roerecke M, Sorensen P, Laramee P, Rahhali N, Rehm J. Clinical relevance of nalmefene versus placebo in alcohol treatment: Reduction in mortality risk. J Psychopharmacol 2015;29(11):1152-8. PMID 26349557
- Rojiani AM, Prineas JW, Cho ES. Protective effect of steroids on electrolyte-induced demyelination. J Neuropathol Exp Neurol 1987;46(4):495-504. PMID 3598606
- Romagna ES, Appel-da-Silva MC, Suwa E, Maeda FK, Mattos AA, Tovo CV. Muscle depletion in cirrhotic patients assessed using computed tomography: a cross-sectional study. Sao Paulo Med J 2020;138(2):152-7. PMID 32321002
- Ronen GM, Andrews WL. Holoprosencephaly as a possible embryonic alcohol effect. Am J Med Genet 1991;40(2):151-4. PMID 1897567
- Roussotte FF, Sulik KK, Mattson SN, et al. Regional brain volume reductions relate to facial dysmorphology and neurocognitive function in fetal alcohol spectrum disorders. Hum Brain Mapp 2012;33(4):920-37. PMID 21416562
- Rubio G, Ponce G, Rodriguez-Jimenez R, Jimenez-Arriero MA, Hoenicka J, Palomo T. Clinical predictors of response to naltrexone in alcoholic patients: who benefits most from treatment with naltrexone. Alcohol Alcohol 2005;40(3):227-33. PMID 15797885
- Ruitenberg A, van Swieten JC, Witteman JC, et al. Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet 2002;359:281-6.** PMID 11830193
- Ryan C, Butters N. Neuropsychology of alcoholism. In: Wedding D, Horton AM, Webster JS, editors. The neuropsychology handbook. New York: Springer, 1986.
- Sacanella E, Fernandez-Sola J, Cofan M, et al. Chronic alcoholic myopathy: diagnostic clues and relationship with other ethanol-related diseases. QJM 1995;88(11):811-7. PMID 8542266
- Sadrian B, Wilson DA, Saito M. Long-lasting neural circuit dysfunction following developmental ethanol exposure. Brain Sci 2013;3(2):704-27. PMID 24027632
- Saini M, Lin W, Kang C, Umapathi T. Acute flaccid paralysis: Do not forget beriberi neuropathy. J Peripher Nerv Syst 2019;24(1):145-9. PMID 30569499
- Salmon DP, Butters N, Heindel WC. Alcoholic dementia and related disorders. In: Parks RW, Zec RC, editors. Neuropsychology of Alzheimer's disease and other dementias. New York: Oxford University Press, 1993:186-209.
- Samples JR, Younge BR. Tobacco-alcohol amblyopia. J Clin Neuroophthalmol 1981;1(3):213-8. PMID 6213664
- Saunders PA, Copeland JR, Dewey ME, et al. Heavy drinking as a risk factor for depression and dementia in elderly men: findings from the Liverpool longitudinal community study. Br J Psychiatry 1991;159:213-6. PMID 1773236
- Schafer MKE, Altevogt P. L1CAM malfunction in the nervous system and human carcinomas. Cell Mol Life Sci 2010;67(14):2425-37. PMID 20237819
- Scheuermeyer FX, Miles I, Lane DJ, et al. Lorazepam versus diazepam in the management of emergency department patients with alcohol withdrawal. Ann Emerg Med 2020;76(6):774-81. PMID 32736932
- Sechi G, Serra A. Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007;6(5):442-55. PMID 17434099
- Serdaru M, Hausser-Hauw C, Laplane D, et al. The clinical spectrum of alcoholic pellagra encephalopathy: a retrospective analysis of 22 cases studied pathologically. Brain 1988;111:829-42. PMID 3401685
- Sharma B, Sannegowda RB, Jain R, Dubey P, Prakash S. A rare case of alcoholic pellagra encephalopathy with startle myoclonus and marked response to niacin therapy: time for a new dictum? BMJ Case Rep 2013;2013. PMID 23608853
- Sherlock S, Summerskill WH, White LP, Phear EA. Porto-systemic encephalopathy: neurological complications of liver disease. Lancet 1954;267(6836):454-7. PMID 13193045
- Shible AA, Ramadurai D, Gergen D, Reynolds PM. Dry beriberi due to thiamine deficiency associated with peripheral neuropathy and Wernicke's encephalopathy mimicking Guillain-Barré syndrome: a case report and review of the literature. Am J Case Rep 2019;20:330-4. PMID 30862772
- Shiota JY, Nakano I, Kawamura M, Hirayama K. An autopsy case of Marchiafava-Bignami disease with peculiar chronological CT changes in the corpus callosum: neuroradiopathological correlations. J Neurol Sci 1996;136:90-3. PMID 8815185
- Signore AP, Yeh HH. Chronic exposure to ethanol alters GABA(A) receptor-mediated responses of layer II pyramidal cells in adult rat piriform cortex. J Neurophysiol 2000;84:247-54. PMID 10899200
- Singh SP, Gao Y, Kunapuli SP, Ravindra R. Ethanol inhibits G-protein-mediated glucose uptake by C6 glioma cells. Neuroreport 1999;10:595-9. PMID 10208596
- Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21(12):1443-50.** PMID 25220878
- Sinha S, Kataria A, Kolla B, Thusius N, Loukianova L. Wernicke encephalopathy-clinical pearls. Mayo Clinic Proc 2019;94(6):1065-72. PMID 31171116
- Slager UT. Central pontine myelinolysis and abnormalities in serum sodium. Clin Neuropathol 1986;5(6):252-6. PMID 3815936
- Smiddy WE, Green WR. Nutritional amblyopia. A histopathologic study with retrospective clinical correlation. Graefes Arch Clin Exp Ophthalmol 1987;225(5):321-4. PMID 3666474
- Smith AD, Duckett S. Cyanide, vitamin B-12, experimental demyelination and tobacco amblyopia. Br J Exp Pathol 1965;46(6):615-22. PMID 5846092
- Smith SM, Garic A, Flentke GR, Berres ME. Neural crest development in fetal alcohol syndrome. Birth Defects Res C Embryo Today 2014;102(3):210-20. PMID 25219761
- Spadoni AD, McGee CL, Fryer SL, Riley EP. Neuroimaging and fetal alcohol spectrum disorders. Neurosci Biobehav Rev 2007;31(2):239-45. PMID 17097730
- Stacey PS, Sullivan KA. Preliminary investigation of thiamine and alcohol intake in clinical and healthy samples. Psychol Rep 2004;94(3 Pt 1):845-8. PMID 15217037
- Stanca S, Ulmeanu CE, Stanca HT, Iovanescu G. Clinical features in toxic coma in children. Exp Ther Med. 2019;18(6):5082-5087. PMID 31819771
- Stephen Rich J, Martin PR. Co-occuring psychiatric disorders and alcoholism. Handb Clin Neurol 2014;125:573-88. PMID 25307597
- Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980;209:353-61. PMID 6992275
- Stewart DO. A parody outline of history: wherein may be found a curiously irreverent treatment of American historical events, imagining them as they would be narrated by America's most characteristic contemporary authors. New York: George H Doran Company, 1921.
- Stratton SJ, Rogers C, Green K. Sudden death in individuals in hobble restraints during paramedic transport. Ann Emerg Med 1995;25(5):710-2. PMID 7741355
- Sullivan EV, Pfefferbaum A. Neuroimaging of the Wernicke-Korsakoff syndrome. Alcohol Alcohol 2009:44(2):155-65. PMID 19066199
- Sycks K, Simerlink S, McKnight L, Trovato V. A case of dry beriberi from alcohol use disorder and disordered eating. Subst Abus 2022;43(1):204-5. PMID 34344284
- Syed S, Lioutas V. Tobacco-alcohol amblyopia: a diagnostic dilemma. J Neurol Sci 2013;327(1-2):41-5. PMID 23477666
- Terada N, Kinoshita K, Taguchi S, Tokuda Y. Wernicke encephalopathy and pellagra in an alcoholic and malnourished patient. BMJ Case Rep 2015;2015. PMID 264909971
- Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis. Alcohol Alcohol 2006;41(2):151-8. PMID 16384871
- Thornton AM, Drummond CJ. An unexpected case of pellagra. Med J Aust 2014;200(9):546-8. PMID 24835720
- Tiglao SM, Meisenheimer ES, Oh RC. Alcohol withdrawal syndrome: outpatient management. Am Fam Physician 2021;104(3):253-62. PMID 34523874
- Tomasi DG, Wiers CE, Shokri-Kojori E, et al. Association between reduced brain glucose metabolism and cortical thickness in alcoholics: evidence of neurotoxicity. Int J Neuropsychopharmacol 2019;22(9):548-59. PMID 31369670
- Torvik A. Wernicke’s encephalopathy--prevalence and clinical spectrum. Alcohol Alcohol Suppl 1991;1:381-4. PMID 1845567
- Torvik A, Lindboe CF, Rogde S. Brain lesions in alcoholics. A neuropathological study with clinical correlations. J Neuro Sci 1982;56(2-3):233-48. PMID 7175549
- Torvik A, Torp S. The prevalence of alcoholic cerebellar atrophy. A morphometric and histological study of an autopsy material. J Neurol Sci 1986;75(1):43-51. PMID 3746340
- Torvik A, Torp S, Lindboe CF. Atrophy of the cerebellar vermis in ageing. A morphometric and histologic study. J Neurol Sci 1986;76(2-3):283-94. PMID 3794753
- Trevisan L, Fitzgerald LW, Brose N, et al. Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus. J Neurochem 1994;62(4):1635-8. PMID 8133290
- Trudell JR, Messing RO, Mayfield J, Harris RA. Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 2014;35(7):317-23. PMID 24865944
- Turnbull J, Lumsden D, Siddiqui A, Lin JP, Lim M. Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of the literature. Acta Paediatr 2013;102(4):e164-8. PMID 23278861
- Urbano-Marquez A, Estruch R, Navarro-Lopez F, Grau JM, Mont L, Rubin E. The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med 1989;320:409-15. PMID 2913506
- Vagts DA, Noldge-Schomburg GF. [Managing anesthesia in the alcoholic patient]. Anaesthesiol Reanim 2002;27(6):160-7. PMID 12596575
- Van Der Werf YD, Jolles J, Witter MP, Uylings BM. Contributions of thalamic nuclei to declarative memory functioning. Cortex 2003;39(4-5):1047-62. PMID 14584566
- Vaz SS, Chodirker B, Prasad C, Seabrook JA, Chudley AE, Prasad AN. Risk factors for nonsyndromic holoprosencephaly: a Manitoba case-control study. Am J Med Genet A 2012;158A(4):751-8. PMID 22419615
- Vedder LC, Hall JM, Jabrouin KR, Savage LM. Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility. Alcohol Clin Exp Res 2015;39(11):2143-53. PMID 26419807
- Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Pshychol Med 2015;45(5):1061-72. PMID 25171596
- Vernescu RM, Adams RJ, Courage ML. Children with fetal alcohol spectrum disorder show an amblyopia-like pattern of vision deficit. Dev Med Child Neurol 2012;54(6):557-62. PMID 22574626
- Victor M. Alcoholic dementia. Can J Neurol Sci 1994;21:88-99. PMID 8087744
- Victor M. Toxic and nutritional myopathies. In: Engel AG, Banker BQ, editors. Myology. New York: McGraw-Hill, 1986:1807-42.
- Victor M, Adams RD. The alcoholic dementias. In: JAM Frederiks, editor. Handbook of clinical neurology, Vol 2 (46): Neurobehavioral disorders. Amsterdam: Elsevier Science, 1995.
- Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome. Oxford: Blackwell, 1971.
- Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome and related neurologic disorders due to alcoholism and malnutrition. Philadelphia: F. A. Davis, 1989.**
- Victor M, Adams RD, Mancall EL. A restricted form of cerebellar cortical degeneration occurring in alcoholic patients. Arch Neurol 1959;71:579-688.
- Victor M, Brausch C. The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 1967;8:1-20. PMID 4961509
- Victor M, Ropper A. Principles of neurology. New York: McGraw-Hill, 2001.
- Victor M, Yakovlev PI. S.S. Korsakoff's psychic disorder in conjunction with peripheral neuritis: a translation of Korsakoff's original article with comments on the author and his contribution to clinical medicine. Neurology 1955;5(6):394-406.** PMID 14383944
- Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014;60(2):715-35. PMID 25042402
- Wang Z, Wang J, Fang Y, Zhou L, Zhou Y. Gadolinium enhancement may indicate a condition at risk of developing necrosis in Marchiafava-Bignami disease: A case report and literature review. Front Hum Neurosci 2019;13:79. PMID 30873016
- Watson-Williams EJ, Bottomley AC, Ainley RG, Phillips CI. Absorption of vitamin B12 in tobacco amblyopia. Br J Ophthalmol 1969;53(8):549-52. PMID 5811224
- Weissenborn K. Hepatic encephalopathy: definition, clinical grading and diagnostic principles. Drugs 2019;79(Suppl 1):5-9.** PMID 30706420
- Wernicke C. Lehrbuch der Gehirnkrankheiten II. Kassel: Fischer, 1881:229-42.
- Wernicke C. Grundriss der Psychiatrie in klinischen Vorlesungen. Second edition. Leipzig: Georg Thieme, 1906.
- WHO. Management of alcohol withdrawal. World Health Organization, 2012.
- Wozniak JR, Mueller BA, Muetzel RL, et al. Inter-hemispheric functional connectivity disruption in children with prenatal alcohol exposure. Alcohol Clin Exp Res 2011;35(5):849-61. PMID 21303384
- Wozniak J, Riley E, Charness M. Clinical presentation, diagnosis, and management of alcohol spectrum disorder. Lancet Neurol 2019;18(8):760-70. PMID 31160204
- Yang X, Criswell HE, Breese GR. Ethanol modulation of gamma-aminobutyric acid (GABA)-mediated inhibition of cerebellar Purkinje neurons: relationship to GABAb receptor input. Alcohol Clin Exp Res 2000;24:682-90. PMID 10832910
- Yokota O, Tsuchiya K, Terada S, et al. Frequency and clinicopathological characteristics of alcoholic cerebellar degeneration in Japan: a cross sectional study of 1,509 postmortems. Acta Neuropathol 2006;112(1):43-51. PMID 16622656
- Yoneoka Y, Takeda N, Inoue A, et al. Acute Korsakoff syndrome following mammillothalamic tract infarction. AJNR Am J Neuroradiol 2004;25(6):964-8. PMID 15205131
- Yoon C, Gedzior J, DePry D. Wernicke-Korsakoff syndrome: focus on low-threshold diagnosis and prompt treatment in the primary care setting. Int J Psychiatry Med 2019;54(3):172-80. PMID 30823858
- Yoshimoto K, Ueda S, Kato B, et al. Alcohol enhances characteristic releases of dopamine and serotonin in the central nucleus of the amygdala. Neurochem Int 2000;37(4):369-76. PMID 10825577
- Zahr NM, Kaufman KL, Harper CG. Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol 2011;7(5):284-94. PMID 21487421
- Zhang P, Cao J, Shen Y, Zhang Y, Ding, Xu J. Transient paraparesis after anterior decompression in a patient with ossification of the cervical posterior longitudinal ligament. Orthop Surg 2010;2(3):234-6. PMID 22009955
- Zhang S, Zhang X, Ling Y, Li A. Predicting recurrent hypertensive intracerebral hemorrhage: derivation and validation of a risk-scoring model based on clinical characteristics. World Neurosurg 2019;127:e162-71. PMID 30876994
- Zimmerman HM, Cohen LH, Gildea EF. Pellagra in association with chronic alcoholism. Arch Neur Psych 1934;31(2):290-309.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.See Profile
- Yuen So MD (original author), Elijah W Stommel MD, Laura S Hair MD, and Kelly G Devers MD
- Age range of presentation
- 19 to 65+ years
- Sex preponderance
- male>female, >1:1
- heredity may be a factor
- Population groups selectively affected
- none selectively affected
- Occupation groups selectively affected
- none selectively affected
ICD & OMIM codes
- Alcoholic cerebellar degeneration: 331.7
- Alcohol-induced persisting dementia: 291.2
- Alcohol intoxication: 305.0
- Alcoholic myopathy: 359.4
- Alcoholic neuropathy: 357.5
- Alcohol withdrawal syndrome: 291.81
- Central pontine myelinolysis: 341.8
- Degeneration of nervous system due to alcohol: 334.4
- Delirium tremens: 291.0
- Fetal alcohol syndrome: 760.71
- Marchiafava-Bignami disease: 341.8
- Pellagra: 265.2
- Wernicke encephalopathy: 265.1
- Wernicke-Korsakoff syndrome or psychosis (alcoholic): 294.0
- Alcoholic cerebellar degeneration: G31.2
- Alcohol-induced persisting dementia: F10.27
- Alcohol intoxication: F10.0
- Alcoholic ketoacidosis: F10.129
- Alcoholic myopathy: G72.1
- Alcoholic neuropathy: G62.1
- Alcohol withdrawal syndrome: F10.5
- Central pontine myelinolysis: G37.2 and G37.8
- Degeneration of nervous system due to alcohol: G31.2
- Delirium tremens: F10.4
- Fetal alcohol syndrome (dysmorphic): Q86.0
- Fetus and newborn affected by maternal use of alcohol: P04.3
- Marchiafava-Bignami disease: G37.1
- Pellagra: E52
- Wernicke encephalopathy: E51.2
- Wernicke-Korsakoff syndrome or psychosis (alcoholic): F10.96
This is an article preview.
Start a Free Account
to access the full version.
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.