The ABCs of A lcohol, the B rain and C ognition

1. The ABCs of Alcohol, the Brain and Cognition Janice Knoefel, MD MPH Geriatrics, Internal Medicine, Neurology University of New Mexico

2. Learning Objectives • 1. Review the effects of alcohol on the nervous system • 2. Understand the mechanisms of cognitive decline with alcohol use • 3. Describe treatment options

3. Conflict of Interest • I do not have any potential conflicts of interest, although I do enjoy of glass of wine from time to time

4. To Drink or Not To Drink? “It has long been recognized that the problems with alcohol relate not to the use of a bad thing, but to the abuse of a good thing.” -Abraham Lincoln

5. Is the use of alcohol a big deal? • 4 to 40 percent of medical and surgical patients experience problems related to alcohol • More than 85,000 deaths a year in the US are directly attributed to alcohol use • Annual economic cost of alcohol use estimated at $185 billion+ = $1.90/drink • 1 in 10 deaths among working age adults result from excessive drinking

6. Definitions • Standard US drink: • 12 grams of ethanol = • 5 ounces of wine • 12 ounces of beer • 1.5 ounces of 80 proof spirits • Number and size of drinks varies: • UK and western Europe = 8-12 grams • Japan = 19.75 grams

7. Definitions • Risky alcohol use = consumption of an amount of alcohol that puts an individual at risk for health consequences: • Men under age 65 • More than 14 standard drinks per week on average • More than 4 drinks on any day • Women and adults 65 years and older • More than 7 standard drinks per week on average • More than 3 drinks on any day • Smaller amounts are risky use in pregnancy

8. Definitions • Binge drinking = “consumption within 2 hours such that BAC levels reach 0.08g/dL“ • In women, typically occurs with four drinks • In men, five drinks • Associated with acute injuries due to intoxication • May be associated with an increased cardiovascular risk in young adults

9. Definitions • Alcohol use disorder= “a problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by multiple psychosocial, behavioral, or physiologic features” (DSM-5) • Replaces the terms “alcohol abuse” and “alcohol dependence” from DSM-4R

10. Scope of the Problem – Risky Use • National Institute (NIAAA) reported rates of alcohol consumption among US adults: • 28 percent exceed thresholds for risky use • 16 percent exceed the daily limit • 10 percent exceed both daily and weekly limits • 2 percent exceed the weekly limit • 72 percent never exceed thresholds for risky use • ~30% of population - unhealthy alcohol use • Keep in mind this data is self report • Actual may be higher

11. Scope of the Problem – Alcohol Use Disorder • Prevalence of DSM-4 alcohol abuse and alcohol dependence in the US between 2001 and 2002: • Alcohol abuse — 17.8% lifetime, 4.7% past 12 months • Alcohol dependence — 12.5% lifetime, 3.8% past 12 months • Extrapolated to DSM-5: 30.3% lifetime, 8.5% past 12 months

12. Alcohol Use Disorder: Symptoms & Behaviors • Alcohol Use Disorder symptoms and behaviors: • Drinking resulting in failure to fulfill role obligations • Drinking in hazardous situations • Drinking despite social or interpersonal problems • Evidence of alcohol withdrawal, use of alcohol for relief • Drinking in amounts or longer times than intended • Persistent desire / unsuccessful attempts to stop or reduce • Great deal of time spent obtaining, using, or recovering • Important activities given up because of drinking • Continued drinking despite knowledge of physical or psychological problems caused by alcohol • Alcohol craving

13. Morbidity • Common medical and psychiatric comorbidities associated with unhealthy alcohol use: • Hypertension • Cardiovascular disease • Liver disease and Pancreatitis • Gastritis and Esophagitis • Bone marrow suppression • Chronic infectious diseases • Pneumonia • Malignancies, including mouth, throat, esophagus, liver, colorectal and breast • Depressive and Anxiety disorders • Posttraumatic stress disorder • Eating disorders • Other substance use disorders • Sleep disturbances

14. Mortality • Third leading preventable cause of death in the US • More than 85,000 deaths a year directly attributed to alcohol • 1 in 10 deaths among working age adults • 17,000 traffic fatalities in the US in 2000 • 40 percent of all traffic fatalities • Drowning 3.5x greater for current drinkers than controls • 70% of attempted suicides by college students involved alcohol use • Lifetime rate of suicide attempts among frequent alcohol users 7 percent, comparison adult population is a rate of 1 • Increased incidence of domestic violence and murder

15. Alcohol Use on the Rise • Increased price of tobacco=lower use • Same principle holds for alcohol • Alcohol prices have declined 60% in past 35 years, 90% in the past 60. • Possible to exceed maximum weekly recommended intake (28 drinks for men) for $15 (home consumption)

16. What’s Alcohol got to do with Neurology?

17. Well, a lot Raymond D. Adams, MD (1911-2008), the 20th century eminent Boston neurologist and textbook author once said: ”If you know the effects of alcohol on the nervous system, you will know 90% of neurology” Alcohol is a leading contender in disorders of all neuro systems in adults and hence figures prominently in the differential diagnosis of most neurologic syndromes

18. Neurologic Complications of Alcohol Use • INTOXICATION / BLACKOUTS / COMA / DEATH • ALCOHOL WITHDRAWAL / SEIZURES • NEUROMUSCULAR IMPAIRMENTS • Neuropathies • Myopathies • MARCHIAFAVA-BIGNAMI DISEASE • ALCOHOLIC CEREBELLAR DEGENERATION • FETAL-ALCOHOL SYNDROME • OPTIC NEUROPATHY (tobacco-alcohol amblyopia) • CENTRAL PONTINE MYELINOLYSIS

19. Neurologic Complications of Alcohol Use • VENTRICULAR ENLARGEMENT / CEREBRAL ATROPHY • COGNITIVE DYSFUNCTION • ALCOHOLIC DEMENTIA • WERNICKE ENCEPHALOPATHY • KORSAKOFF SYNDROME • ALCOHOLIC HALLUCINOSIS

20. Neurologic Complications of Alcohol Use CONTRIBUTES TO: • Stroke • Cerebral hemorrhage • Head trauma / brain injury / epilepsy • Spinal cord injury • Sleep disorders • Delirium • Pellegra, scurvy, other nutritional deficiencies • Hepatic encephalopathy • Acquired hepatocerebral degeneration

21. But, this is Grand Rounds on Cognition • Topics to follow: • VENTRICULAR ENLARGEMENT / CEREBRAL ATROPHY • COGNITIVE DYSFUNCTION • ALCOHOLIC DEMENTIA • WERNICKE ENCEPHALOPATHY • KORSAKOFF SYNDROME • ALCOHOLIC HALLUCINOSIS

22. Alcoholic Hallucinosis Seen in alcohol withdrawal, chronic use or acute intoxication Withdrawal may be mild, unrecognized Generally complex hallucinations with vivid imagery May lack insight and interact with the hallucinations

23. VENTRICULAR ENLARGEMENT/CEREBRAL ATROPHY

24. First, Let’s Talk about Risk • Complex relationship of alcohol to risk of dementia and all cause mortality in humans • J-shaped curve(more like the Nike swoosh): • Light - moderate daily alcohol consumption of 1 drink (women) or 2 drinks (men) is protective • Increasingly excessive consumption results in proportional worsening of outcomes • Daily “dose” appears to be more protective • Alcohol effect • decreased risk of dementia for AD, dementia

25. What is good for the heart is good for the brain

26. Proposed protective mechanism? • Alcohol “preconditioning” may protect from inflammation of beta-amyloid and other neuroinflammatory proteins • Analogous mechanisms may occur in heart and vasculature • Complex interactions of insulin sensitivity, HDL cholesterol • Low, daily dose most effective • Binge drinking is harmful

27. Etiology of Harm • Of all the substances of abuse, alcohol is the only one to have direct toxicity on neurons • There is regional vulnerability: • Density in the superior frontal cortex reduced by 22 percent compared with controls (structural) • Selective loss of neurons is mirrored by regional hypometabolism on PET (metabolic) • Correlates with deficits in executive and memory functions

28. Ventricular Enlargement & Cerebral Atrophy • 50-70% of persons with alcohol use disorder have measurable cognitive deficits, primarily memory and executive function • Brain imaging shows enlargement of ventricles and sulci in most • Improves within a month of abstinence, but generally does not resolve

29. Cognitive Dysfunction • Likely to be a continuum: • normal cognitive function --> • alcohol related dementia (ARD) --> • Wernicke’s Encephalopathy (WE) --> • Korsakoff’s Psychosis (KS) • Not necessarily a linear progression • May be early stage mixed nutritional deficiency and direct toxic effects of alcohol • May be (partially) reversible if abstinence and improved nutrition possible long term

30. Alcohol-Related Dementias • Alcohol-related dementias (ARDs) estimated at 10% of all dementias • Diagnosis imprecise, based only on clinical criteria, so prevalence estimates vary • May be combined with other dementias: • Alzheimer • Vascular • Trauma • Residual of delirium, withdrawal, seizures

31. Alcohol-Related Dementia Memory impairment in ARD correlates best with lesions of the thalamus Atrophy of the mamillary bodies is specific for Wernicke’s Encephalopathy (WE) Diagnosis is clinical, not radiological

32. Is there a Separate Entity Of “Alcoholic Dementia”? • Experts feel there is a continuum: ARD -> Wernicke -> Korsakoff ARD -> Korsakoff • Most abusers are malnourished • Difficult to separate effects of poor nutrition from direct toxic effect of alcohol • However, if executive deficits >> memory deficits, may be direct alcohol toxicity, BUT on the way to WE or KS

33. Graded brain-volume deficits in alcoholism and its sequelae • 63 yo healthy man, no EtOH • 59 yo man with alcohol use disorder • 63 yo man with WE

34. Wernicke’s Encephalopathy Described in 1881 by German physician, anatomist, psychiatrist and neuropathologist Carl Wernicke

35. Wernicke’s Encephalopathy • Common at autopsy: • 2.8% of the general population • 12.5% in alcohol abusers • 59% in alcohol-related deaths • Acute onset neurologic disorder • Clinical triad = easy diagnosis: • Encephalopathy • Oculomotor dysfunction • Gait ataxia • Only 10-20% present this way

36. Wernicke’s Encephalopathy • Caused by thiamine (B1) deficiency • Critical for glucose and lipid metabolism • Seen most often with chronic alcoholism • May occur with: • With malabsorption and poor dietary intake • Increased metabolic requirement • Increased loss of this water-soluble vitamin, as seen with renal dialysis • Non-drinkers accounted for 23% in series

37. Wernicke’s Encephalopathy • Chronic alcoholism • Anorexia nervosa or dieting • Hyperemesis of pregnancy • Prolonged intravenous feeding, no supplement • Prolonged fasting or starvation • Gastrointestinal surgery / bariatric surgery • Systemic malignancy • Transplantation • Hemodialysis or peritoneal dialysis • Acquired immunodeficiency syndrome

38. Why Thiamine? • Cofactor for several key enzymes important in energy metabolism (Krebs cycle) • Thiamine requirements depend on metabolic rate, with greatest need during high metabolic demand and glucose intake • Often have sx onset during acute illnesses • WE can be precipitated in susceptible patients by administration of intravenous glucose before thiamine supplementation

39. Why Alcoholics? • Thiamine deficiency in alcohol abusers results from: • Inadequate dietary intake • Reduced gastrointestinal absorption on co-consumption with alcohol (70%) • Decreased hepatic storage • Impaired utilization • Other medical conditions not as common: • Likely only one mechanism at work

40. Why Not All Alcoholics? • Only a subset of alcohol abusers with WE • Greater susceptibility among identical rather than fraternal twins = genetic predisposition • Thiamine-dependent enzyme transketolasehas altered/reduced affinity for thiamine in alcoholics and persons with other conditions who develop WE = genetic variant

41. Neuropathology • Acute WE lesions: • Vascular congestion • Microglial proliferation • Petechial hemorrhages • Which is why we can see it on imaging • Chronic WE lesions: • Demyelination • Gliosis • Loss of neuropil with preservation of neurons • Which is why we see atrophy in chronic cases

42. Neuropathology • Mamillary bodies involved in cases acutely • Atrophy of the mamillary bodies specific for chronic WE and Korsakoff syndromes • Symmetrical in structures: • surrounding the 3rd and 4th ventricles, aqueduct • dorsomedial thalamus, locus ceruleus, periaqueductal gray, ocular motor nuclei, and vestibular nuclei • Less frequently in colliculi, fornices, septal region, hippocampus and cerebral cortex

43. Clinical Clues • Clinical triad = easy diagnosis: • Encephalopathy • Oculomotor dysfunction • Nystagmus, lateral rectus &conjugate gaze palsies • Gait ataxia • One symptom of triad = difficult diagnosis • Exception more common than the rule • Triad present in only 10-20% of patients • Confusion most common presentation • Ataxic gait, ocular problems less common

44. So What Happens Next? • Significantly disabling -> 80% permanent • Potentially lethal -> 17% mortality • Ataxia, ophthalmoplegia may resolve briskly • Confusional state appears to improve rapidly within hours of treatment • However, impairment of memory and learning responds more slowly, if at all • Only 20% recover completely

45. Korsakoff’s Psychosis(Syndrome) Described in 1884 by Russian neuropsychiatrist, physician and neuropathologist Sergei Korsakoff

46. Korsakoff’s Psychosis • A striking disorder of selective anterograde and retrograde amnesia • Seen most frequently in alcohol abusers • Often follows episode of WE (80%) • Can occur in a variety of conditions that damage bilateral medial temporal lobes: • Herpes encephalitis • Bitemporal lobectomy • KS show typical WE lesions on autopsy

47. Korsakoff’s Psychosis • Clinical: • Anterograde and retrograde amnesia • Behavioral apathy • Intact sensorium • Relative preservation of long-term memory • Confabulation is a feature in some cases • Attention and social behavior are preserved • Generally unaware of their illness • Anxiety prevalent if aware of impaired memory

48. Korsakoff’s Psychosis • Patients with full blown KP rarely recover • Most require supervision and social support • Always treat with thiamine • Anecdotal reports of improvement with acetylcholinesterase inhibitors, memantine • no controlled studies • minimal risk profile makes therapeutic trials acceptable

49. Relationship between WE and KS • 80% of alcohol abusers recovering from WE exhibit the memory disturbance of KS • However, only 20% diagnosed pre-mortem • 80% WE->KS undiagnosed during life! • Support of this finding from: • Australia, Cleveland, NY Bellevue, Norway autopsy series and others C. Harper, JNNP 46:593-598, 1983

50. Why Am I Interested? • Staffing the Memory Clinic • Seeing undiagnosed WE/KS cases • Alcohol rarely considered as etiology • Alcohol use rarely queried • Thiamine never administered IM in outpatient settings at UNM outside ER • IM Thiamine unable to order in clinics