major neurocognitive disorders associated with alcohol abuse...this presentation will provide an...
TRANSCRIPT
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Christian Bocti, MD, FRCP(C)Professeur agrégé, Neurologie, Département de médecine,
FMSS, Université de Sherbrooke
Service de Neurologie, Clinique de Mémoire et
Centre de recherche sur le vieillissement
CIUSSS de l’ Estrie - CHUS
10th Canadian Conference on Dementia, 2019
Major Neurocognitive DisordersAssociated with Alcohol Abuse
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Conflicts of interest
Christian Bocti holds
convertible debentures in
I do enjoy a glass of wine
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This presentation will provide an overview of the often
under-recognized contribution of alcohol use on cognitive
functions.
Objectives:
Differentiate the neurocognitive disorders that can be
linked to alcohol
Explain the pathophysiology of NCDs induced by
alcohol
Discuss the management of NCDs induced by alcohol
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Case presentation 1
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Case presentation 2
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Questions
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Key message
If you drink,
your brain will shrink.
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The Alcohol Paradox
Claim: This substance, at low dose,
prevents dementia!
However, at higher doses, it increases
the risk of dementia, cancer and
death…
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Plan
Introduction: statistics, diet, mortality
Drinking, the brain and cognition
Clinical
Imaging
Pathophysiology
Treatment
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Introduction: what is a « drink »?
1 drink = 17 ml of pure alcohol (13g)
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Public Health Agency of Canada 2015
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« At-risk » use = More than 3 (women) or 4 (men) drinks on one occasion, every month.
About 80 % of adults use alcohol in Canada
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People under-report the quantity of
alcohol they use...by how much???
PHAC 2015
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Alcohol for dementia prevention?
1. Vascular prevention: treat hypertension!
2. Physical exercise: at least 3 x 30 min. / week
3. Mediterranean diet (including wine)
4. Cognitive activities: challenge yourself !
5. Social activities: interact with family & friends!
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Medit
err
anean d
iet
EP
IC /
MH
I
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Mediterranean diet :
observational study(NYC)
Scarmeas 2009
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Strength of evidence ?
Daffner 2011
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Estruch et al. NEJM 2013, Martinez-Lapiscina et al. JNNP 2013
PREDIMED: a randomized controlled
trial on the mediterranean diet
After 6 years: + 0,6 MMSE and + 0,5 CDT (score on 7)
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Among participants with high genetic risk, 1.13% (95% CI, 1.01%-1.26%) of those with
a favorable lifestyle developed dementia compared with 1.78% (95% CI, 1.38%-2.28%)
with an unfavorable lifestyle (hazard ratio, 0.68 [95% CI, 0.51-0.90]).
JAMA. 2019;322(5):430-437.
doi:10.1001/jama.2019.9879
Published online July 14,
2019
UK BioBank n=200 000
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Do you recommend
moderate drinking
to prevent cognitive decline?
Wow! These studies really provide Level 1
evidence that alcohol is good for your brain!(as part of MeDi or healthy lifestyle)
…
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Only one glass a day!
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WHAT IS THE EFFECT OF ALCOHOL
ON THE BRAIN ?
A new analysis from a large scale prospective long
term study: Whitehall II (observational)
527 participants followed for 30 years; no
beneficial effect of alcohol on hippocampal
volumes measured on MRI
This was also noted in the Framingham Study (Paul et
al. Arch Neurol 2008)
Even minimal use (1-7 drinks/week) associated
with declining cognitive performance compared
with no use (verbal fluency - 6 )
Topiwala et al. BMJ 2017
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Topiwala et al. BMJ 2017
Catégories :
0 / semaine
1-7
7-14
14-21
21+
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Conclusion from that study
« There was no evidence of a protective effect of light drinking over abstinence on brain structure or function. »
- Topiwala et al, 2017
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But at least, alcohol is
good for your heart, right?
Wood et al. Risk threshold… Lancet 2018
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Wait? What? The same study now
shows the opposite result???
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Contribution of alcohol to early-
onset dementia (France)
This graph shows that alcohol is the main etiology in 39 % of early-onset dementias
and contributes to another 18% - from a nationwide hospital discharge database
Schwarzinger 2018
HR for AUD
= 3.36
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What is alcohol-related
dementia? Terminology
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“KS is a largely irreversible residual syndrome, caused by severe
thiamine deficiency and occurring after incomplete recovery from
a Wernicke encephalopathy, predominantly in the context of
alcohol abuse and malnutrition, characterized by an abnormal
mental state in which episodic memory is affected out of all
proportion to other cognitive functions in an otherwise alert and
responsive patient, whose psychological make-up may be further
distinguished by executive dysfunction, flattened affect, apathy,
lack of illness insight, and possibly by fantastic confabulations in
the early stage.”
« Polyneuritic psychosis » Original publications from 1887-1891
Sergei Korsakoff
Aarts, Walvoort, Kessels. Korsakoff’s syndrome: a critical review, 2017
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Korsakoff’s syndrome
Severe anterograde amnesia*
Retrograde amnesia(many years)
Executive dysfunction
Apathy
Flat affect
Lack of insight
Confabulation possible
Often follows Wernicke’s (= WKS)
* See next slide
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Is it justified to distinguish between
WKS and other alcohol-related
cognitive problems ?
The common research strategy to define WKS
by critieria that emphasize severe anterograde
amnesia might have created a
neuropsychological stereotype that is NOT
representative of the whole clinical picture.
(circular reasoning)
Bowden 1990
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Wernicke’s Encephalopathy
Classical definition :
CONFUSION
ATAXIA
NYSTAGMUS
??? How many have the classic triad ???
16 %Harper et al. 1998
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Poor sensitivity of the clinical
diagnosis of WE
Population-based autopsy stuydy in Australia
1996-97: 25 cases WKS out of 2200 (1.1%)
Only 16 % (4 cases) had WKS in their chart
2 others had a diagnosis of « alcoholic dementia »
And 5 others had unspecified memory problems
documented
Suggests that the majority of acute cases are
missed, and/or repeated acute low grade injuries?
Harper et al. 1998
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1. Dietary deficiencies
– Undernutrition (BMI <2 SD below normal)
– A history of grossly impaired dietary intake
– An abnormal thiamine status
2. Oculomotor abnormalities
– Ophthalmoplegia
– Nystagmus
– Gaze palsy
3. Cerebellar dysfunction
– Unsteadiness or ataxia
– Abnormalities of past pointing
– Dysdiadokokinesia
– Impaired heel-shin testing
Improving the diagnosis of WE
You need 2 out of 4:4. Altered mental state
– Disorientation in two of three fields
– Confused
– An abnormal digit span
– Comatose
or
Mild memory impairment
– Failure to remember two or more words
in the four-item memory test
– Impairment on more elaborate
neuropsychological tests of memory
function
Caine et al 1997
excellent sensitivity
excellent specificity if no HE
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Comparison of WKS alcoholics and
« uncomplicated » alcoholics
1. On neuroimaging structural substrates of amnesia are
similar but volume loss is less severe
2. On neuropsychological assessment, non-memory
domains are as similarly affected
3. Amnesia is present but less severe than observed in WKS
(but is it by definition?)
In summary: quantitative rather than qualitative differences
Fama et al. Neuropsychol review 2012
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Ove
rlap Z
ones W
KS
vs W
KS
am
ong a
lcoholic p
ati
ents
Pitel 2012
Gray matter
atrophy
on MRI:
More
similarities
than
differences
KS Korsakoff
CS Controls
AL: alcohol users
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Structures of the Human Memory System
hippocampus (1) > fornix (2; loop around the thalamus), with one branch (3) to the anterior
thalamic nuclei (7), another (4) to the mammillary bodies > mammillary bodies (5) >
mammillothalamic tract (6) > anterior thalamic nuclei (7); projections to the cingulate cortex
(8) > cingulate cortex (9) > retrosplenial cortex (10) > parahippocampal gyrus (11)
Aarts, Walvoort, Kessels. Korsakoff’s syndrome: a critical review, 2017
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Control
subject
AL w/o
WKS
AL w
WKS
Age=63 for all
T1 MRI Pitel 2012
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Volume of mamillary bodies, thalamus and
cerebellum in Controls, AL, WKS
Alcohol users without WKS are right in
between Controls and WKS, suggesting
a « dose–response curve »Sullivan 2009
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Reduced cortical thickness and
glucose metabolism in AUD
19 AUD (12 drinks/d)vs 20 controls (0-2 drinks/d); cognitive measures
not different ( CANTAB); dose-response relationship of total lifetime
alcohol with both CT and rCMRGlu = evidence of neurotoxicity
Tomasi et al. 2019
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Non-WKS alcoholics Striking similarity in patterns of atrophy for WKS and non-
WKS alcoholics
Supports a continuity hypothesis
Diencephalic structures are more severely affected in WKS,
but essentially the same structures are reduced in volume
Either we miss many (most) cases of acute WE
Maybe there was no acute WE
Maybe alcohol has direct neurotoxicity
Pitel 2012
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The most important
difference…on neuropathology
Neuronal counts in the anterior thalamic
nuclei best discriminate between WKS and
non WKS alcoholics. All other regions are
affected to a similar degree!
Harding 2000
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Korsakoff Syndrome
Ethanol neurotoxicity vs nutritional deficiency
Wernicke’s Encephalopathy
B1 (thiamine) deficit, associated or not to excessive
alcohol use (bariatric surgery, hypermesis
gravidarum…).
Upwards of 20 % mortality if untreated
Korsakoff Syndrome
Theoretically follows WE but « de novo » quite often
probably due to the fact that WE diagnosis is difficult
Occasionally same clinical picture after trauma,
hemorrhage to diencephalic structures
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Exact etiology ? Controversy
Many pitfalls in this discussion
Effect of alcohol on absorption of thiamine and metabolism of
thimaine
Lifestyle of heavy alcohol drinkers often does not include
optimal nutrition, management of health and chronic conditions
Indirect effects vis hepatic encephalopathy
Comorbidities such as other substance abuse, psychiatric, TBI
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Deficiency of thiamine or direct alcohol toxicity?
In an animal model, alcohol aggravates
damages due to thiamine deificiency in the
thalamus and maillary bodies
= detrimental synergy
Pfefferbaum et al. 2007
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Pereira et al. 2015
Many ways in which
alcohol may be toxic for
neurons
Deficiency of thiamine or direct alcohol toxicity?
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Nutritional deficiency or
biochemical predisposition?
There clearly is a genetic predisposition to WE
Genetic variants of « transketolase » have been associated
with susceptibility to WE
Other genetic variants implicated as well (thiamine
transporters)
ApoE4 (here too!!!)
Multiple metabolic roles of thimaine pyrophosphate (co-
enzyme) in the brain
Body reserves are about 3 weeks for thiamine
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Wernicke’s: role of MRI
T2 / FLAIR Hyperintensities T2 around the
3rd ventricle (thalamus), mamillairy bodies,
periaqueductal grey matter and tectal plate
(mesencephalon)
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Example MRI: Wernicke
Sullivan & Pfefferbaum 2009
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Example MRI/neuropathology:
Wernicke
Liu 2005
Haemorragic necrosis of mamillary bodies
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TREATMENT
James Prochaska et Carlo DiClemente (1982)
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Arrêt de l’abus d’alcool: amélioration de « l’atrophie » octobre 2012 - MoCA 28
Troubles cognitifs -
abus d’alcool, atrophie cérébrale:
mars 2012 - MoCA 21
La modification du comportement, ça marche (parfois)
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Wernicke: medical emergency
High Dose I.V. Thiamine
Various suggestions : 100 mg IV daily for a week
Guidelines from EFNS. 200 mg I.V. tid
According to review in Lancet Neurology (Secchi & Serra
2007): doses as high as 500 mg IV for 3 days
Usual daily needs = 1.5 mg
For various reasons heavy alcohol use impairs the body’s
ability to absorb and metabolize thiamine
Sechi 2007
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Conclusions• There is no minimal intake of alcohol that is beneficial, or
even safe, for the brain.
• Chronic use has a dose-response relationship with some
cognitive decline and colume loss of the hippocampus
• Some positive prevention results from observational studies
are likely explained by confounders.
• Lower your threshold for diagnosis of WE and use high dose
I.V. Thiamine liberally
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Conclusions -2If you drink
Your brain will shrink
Cardiac benefits appear trivial in the face
of increased overall mortality, above a
certain threshold
Nutritional advice and national guidelines, should
be revised downwards to reflect this.
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5e Congrès Québécois sur la
maladie d’Alzheimer!
4-6 Novembre 2020
Centre des Congrès de Québec
Le futur de la maladie d’Alzheimer
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