Download Why Alcoholics?

The ABCs of Alcohol, the
Brain and Cognition
Janice Knoefel, MD MPH
Geriatrics, Internal Medicine, Neurology
University of New Mexico
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
Conflict of Interest

I do not have any potential conflicts of
interest, although I do enjoy of glass
of wine from time to time
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
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
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
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
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
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
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
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
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
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
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
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)
What’s Alcohol got to do
with Neurology?
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
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
Neurologic Complications
of Alcohol Use






VENTRICULAR ENLARGEMENT / CEREBRAL
ATROPHY
COGNITIVE DYSFUNCTION
ALCOHOLIC DEMENTIA
WERNICKE ENCEPHALOPATHY
KORSAKOFF SYNDROME
ALCOHOLIC HALLUCINOSIS
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
But, this is Grand Rounds
on Cognition

Topics to follow:
– VENTRICULAR ENLARGEMENT / CEREBRAL
ATROPHY
– COGNITIVE DYSFUNCTION
– ALCOHOLIC DEMENTIA
– WERNICKE ENCEPHALOPATHY
– KORSAKOFF SYNDROME
– ALCOHOLIC HALLUCINOSIS
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
VENTRICULAR
ENLARGEMENT/CEREBRAL
ATROPHY
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
What is good for the
heart is good for the brain
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
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
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
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
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
AlcoholRelated
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
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
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
Wernicke’s
Encephalopathy
•
Described in 1881 by
German physician,
anatomist,
psychiatrist and
neuropathologist
Carl Wernicke
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
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
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
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
Why Alcoholics?

Thiamine deficiency in alcohol abusers
results from:
– Inadequate dietary intake
– Reduced gastrointestinal absorption on coconsumption with alcohol (70%)
– Decreased hepatic storage
– Impaired utilization

Other medical conditions not as common:
– Likely only one mechanism at work
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 transketolase
has altered/reduced affinity for thiamine in
alcoholics and persons with other conditions
who develop WE = genetic variant
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
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
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
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
Korsakoff’s
Psychosis
(Syndrome)
•
Described in 1884
by Russian
neuropsychiatrist,
physician and
neuropathologist
Sergei Korsakoff
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
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
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
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
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
Recent Clinical
Experience: Case 1







80yo man referred for evaluation, dx’d AD
Difficulty with memory for 18 months
Gait instability for 3 years, uses walker
OSA, uses CPAP at night, naps daily
PMH: CAD, HTN, DM, Lipids, obesity
No offending medications, all appropriate
CT: moderate microvascular ischemia and
generalized parenchymal volume loss
Recent Clinical
Experience: Case 1

Exam: personable, jovial and appropriate
– Cranial nerves, cerebellar and motor all fine
– Gait wide-based, increased sway with Romberg,
unable to tandem walk / tandem stand
– Distal peripheral sensory loss to vibration in LEs
– Reduced DTRs at knees, absent at ankles

Cognitive:
– Dementia level deficit in new learning and recall
– MCI level deficit in executive, language and VS

Function: dependent for most iADLs, some ADLs
Recent Clinical
Experience: Case 1

Daily alcohol exposure, more after retiring
– 2 bottles of wine and 6 beers



Wife passed away 2012 from liver cirrhosis
Family attempted to reduce alcohol but he
resisted, became angry and aggressive
Interventions
– Thiamine IM in clinic
– Family substituted nonalcoholic beverages

Patient “much better” in 2 weeks per report
Lessons Learned

Case 1
–
–
–
–
–
not all older people have Alzheimer’s
look for alcohol always
use of alcohol often escalates after retirement
alcohol discontinuation can improve behaviors
do not lose the opportunity to start thiamine
immediately, administer that day in clinic
– IM thiamine now available at UNM with order (a
2 year process but ultimately successful)
– F/U injections, then PO, to completely replace
Recent Clinical
Experience: Case 2







81yo man referred from Falls Clinic for
evaluation of memory loss for 1 year
Passed mini-cog screen 6 months ago
Gait instability for 6 months, uses cane
OSA, uses CPAP for sleep at night
PMH: CAD, Afib, CHF, AAA, essential tremor
No offending medications, warfarin for Afib
CT: mild microvascular ischemia and mild
generalized volume loss
Recent Clinical
Experience: Case 2

Exam: personable and appropriate
– Cranial nerves and motor fine
– Cerebellar shows chronic severe essential tremor
– Gait wide-based, increased sway with Romberg,
unable to tandem walk / tandem stand
– Peripheral sensory loss (vibration) at toes

Cognitive:
– Dementia level deficit in executive function
– MCI level deficit in new learning and recall

Function: near independence in iADLs and ADLs
Recent Clinical
Experience: Case 2

Daily alcohol exposure
– 3 drinks per day, not measured

Past alcohol exposure
– Essential tremor for 60 years
– Alcohol helped tremor, escalating use at lunch
– Retired from architectural drafting after 10 years

Interventions
– Thiamine IV in ACC5 Outpatient Treatment Clinic
– Patient reduced use -> nonalcoholic beverage

Patient states function “about the same”
Lessons Learned

Case 2
–
–
–
–
unmeasured alcoholic drinks are, unmeasured
moderate alcohol use can cause WE/KS
look for pattern of use disorder when younger
persons may maintain function even while
cognition is deteriorating
– people can change their patterns of alcohol use
– anticoagulation is not a contraindication to
parenteral thiamine
– IV administered in Outpatient Treatment Center
on ACC5, ext 2-2472, fax 2-1920
Recent Clinical
Experience: Case 3







59yo man referred for evaluation of rapidly
progressive dementia
Clinical history of memory loss for 1 year
Difficulty running his business, disoriented
No trouble with driving, gait or falls
PMH: HTN, rotator cuff tear, former smoker
Medication: nicotine patch
MRI: moderate microvascular ischemia and
moderate generalized volume loss
Recent Clinical
Experience: Case 3

Exam: personable, looks to wife for answers
– Cranial nerves, cerebellar, balance and gait,
motor, sensory and DTRs fine

Cognitive:
– Anxiety with testing was limiting factor
– Disoriented to time
– Dementia level deficit in executive, new learning,
language, visuospatial functions

Function: dependent in iADLs, independent in ADL
Recent Clinical
Experience: Case 3

Daily alcohol exposure / previous DUI
– 3-4 beers a day for past few months
– 10 beers, unknown quantity of whiskey previous

Interventions
– Thiamine IM in Clinic
– Stopped use, uses nonalcoholic beverage


Wife states function the same or worse
Patient on full disability, business closed,
attending day care now
Lessons Learned

Case 3
– look for pattern/volume of previous use
– reduction of use may signal development of
neurological or medical illness
– family/friends may not recognize the magnitude
of alcohol use
– family/friends may not recognize the danger of
alcohol use, especially for neurological illness
– determination of prognosis (permanent) allows
for financial, legal and personal care planning
Recent Clinical
Experience: Case 4








66yo woman referred for memory issues
Clinical history of memory loss for 1 year
Lost her business and her home after 2008
housing crisis
Ran stop sign -> crash, cited for DWI
Prior withdrawal seizures, rx’d IM thiamine
PMH: asthma, depression
Medication: albuterol, sertraline, buproprion
MRI: moderate cerebral volume loss
Recent Clinical
Experience: Case 4

Exam: personable, talkative, comes alone
– Cranial nerves, cerebellar, balance and gait,
motor, sensory and DTRs fine

Cognitive:
– Disoriented in 4 of 6 domains
– Dementia level deficit in executive and new
learning/memory functions
– No deficits in language, visuospatial functions
– Minimal current symptoms of depression

Function: self-reported independent in iADLs, ADL
Recent Clinical
Experience: Case 4

Daily alcohol exposure
– unknown quantity of alcohol as she lived alone
– previous legal trouble (MVA while drinking)
– previous medical complications (withdrawal Sz)

Interventions
–
–
–
–

Thiamine IM in Clinic
Supervised living situation
Reduced alcohol use (1/month with supervision)
Better function but not independent
Follow up shows further cognitive decline
Lessons Learned

Case 4
– alcohol is an equal opportunity substance of
abuse: age, gender, education, occupation,
economic circumstances, culture
– need to corroborate volume of alcohol use with
independent observer, difficult if lives alone
– Structured living environment very helpful for
function and elimination of alcohol use
– Further cognitive decline in setting of known
abstinence suggests an additional pathology
– 3 year follow-up -> decline c/w Alzheimer’s
To Test or Not To Test?






There are no diagnostic laboratory studies
WE/KS is a clinical diagnosis
Measurement of erythrocyte thiamine
transketolase (ETKA) before and after the
addition of thiamine pyrophosphate (TPP)
establishes diagnosis of thiamine deficiency
Blood level may not reflect brain level
Normal blood level does not exclude WE
Results not necessary for treatment
Summary







Alcohol Use Disorder is common: 8.5%
Alcohol Use Disorder -> cognitive deficits
10% of dementias are alcohol-related
Wernicke’s Encephalopathy common but
under-recognized by 80%
Korsakoff Psychosis under-recognized
without Wernicke’s
Thiamine is preventative and therapeutic
Thiamine is now accessible, let’s use it