Alcoholic Encephalopathy - - A Neurologic Disease

A presentation on Alcoholic Enceph

1. Alcoholic Brain Alcoholic Brain
DiseaseDisease
Presented by:Presented by:
Dr. Jessie ColacionDr. Jessie Colacion
Dr. Randolf FangoniloDr. Randolf Fangonilo

2. ObjectivesObjectives

To present a case of a patient with To present a case of a patient with
Alcoholic EncephalopathyAlcoholic Encephalopathy

To discuss the role of Thiamine (or To discuss the role of Thiamine (or
the lack of it) in Alcoholic Brain the lack of it) in Alcoholic Brain
DiseaseDisease

To emphasize the importance of To emphasize the importance of
early treatment of a patient early treatment of a patient
suspected to have Wernicke’s suspected to have Wernicke’s
encephalopathyencephalopathy

3. ThiamineThiamine

Vitamin BVitamin B
11

Source – Diet (minimum of 0.33 gm Source – Diet (minimum of 0.33 gm
for every 1,000 Kcal of energy for every 1,000 Kcal of energy
consumed)consumed)

Found mostly in skeletal muscles, Found mostly in skeletal muscles,
heartheart, liver, kidney, and , liver, kidney, and brainbrain

Required for the assembly and Required for the assembly and
proper functioning of several proper functioning of several
enzymesenzymes

4. ThiamineThiamine

Required for the assembly and Required for the assembly and
proper functioning of several proper functioning of several
enzymes that are important for:enzymes that are important for:
•Metabolism of carbohydrates.Metabolism of carbohydrates.
•Numerous critical biochemical reactions Numerous critical biochemical reactions
in the body (including the synthesis of in the body (including the synthesis of
Neurotransmitters) Neurotransmitters)

5. ThiamineThiamine

Required for the assembly and Required for the assembly and
proper functioning of several proper functioning of several
enzymes that are important for:enzymes that are important for:
•Production of Nucleic acidsProduction of Nucleic acids
•Production of fatty acids, steroids, and Production of fatty acids, steroids, and
complex carbohydratescomplex carbohydrates
•Defense against Oxidative stressDefense against Oxidative stress

6. ThiamineThiamine

Deficiency is an established cause of Deficiency is an established cause of
•Wernicke-Korsakoff’s Syndrome (WKS)Wernicke-Korsakoff’s Syndrome (WKS)
•Various degrees of cognitive impairmentVarious degrees of cognitive impairment
•Alcohol-induced persisting dementia Alcohol-induced persisting dementia
(Alcoholic Dementia)(Alcoholic Dementia)

7. Alcohol IntoxicationAlcohol Intoxication
Alcohol IntoxicationAlcohol Intoxication

recent ingestion of alcoholrecent ingestion of alcohol

clinically significant maladaptive behavior or clinically significant maladaptive behavior or
psychological changes that develop during, or psychological changes that develop during, or
shortly after, alcohol ingestionshortly after, alcohol ingestion

one (or more) of the following signs, one (or more) of the following signs,
developing during, or shortly after, alcohol use:developing during, or shortly after, alcohol use:
Slurred speechSlurred speech NystagmusNystagmus
IncoordinationIncoordination
Impairment in attention or memoryImpairment in attention or memory
Unsteady gaitUnsteady gaitStupor or comaStupor or coma

8. Alcohol IntoxicationAlcohol Intoxication

Blood ethanol concentration estimateBlood ethanol concentration estimate
320 ml x 6 x 10% x 800mg/ml320 ml x 6 x 10% x 800mg/ml
-------------------------------- / 10-------------------------------- / 10
0.6 L/mg x 55 kg0.6 L/mg x 55 kg

BEC = BEC = 465 mg/dl465 mg/dl

Rate of metabolismRate of metabolism
15-20 mg/dL/hr for novice drinkers15-20 mg/dL/hr for novice drinkers
30 mg/dL/hr for regular drinkers30 mg/dL/hr for regular drinkers

Out of intoxication = Out of intoxication = 15 hours15 hours

9. Alcohol IntoxicationAlcohol Intoxication
•Dose-response relationshipDose-response relationship
BECBEC Effects Effects
50-100 mg/dL50-100 mg/dL mild intoxicationmild intoxication
100-300 mg/dL100-300 mg/dLmoderate moderate
intoxicationintoxication
300-500 mg/dL300-500 mg/dLsevere intoxicationsevere intoxication
>500 mg/dL>500 mg/dL very severe very severe
intoxicationintoxication

10. Alcohol IntoxicationAlcohol Intoxication
•Ethanol effects at various BAC levels for Ethanol effects at various BAC levels for
nonhabituated drinkers are as follows: nonhabituated drinkers are as follows:

20-50 mg/dL – Decreased fine motor 20-50 mg/dL – Decreased fine motor
function function

50-100 mg/dL – Impaired judgment and 50-100 mg/dL – Impaired judgment and
coordination coordination

100-150 mg/dL – Difficulty with walking and 100-150 mg/dL – Difficulty with walking and
balance balance

150-250 mg/dL – Lethargy 150-250 mg/dL – Lethargy

300 mg/dL – Coma 300 mg/dL – Coma

400 mg/dL – Respiratory depression 400 mg/dL – Respiratory depression

500 mg/dL – Potential death500 mg/dL – Potential death

11. Alcoholic EncephalopathyAlcoholic Encephalopathy
Alcohol-Induced Persisting DementiaAlcohol-Induced Persisting Dementia

the development of multiple the development of multiple
cognitive deficits manifested by both cognitive deficits manifested by both
•memory impairment memory impairment
•one (or more) of the following cognitive one (or more) of the following cognitive
disturbances:disturbances:

aphasia aphasia

apraxia apraxia

agnosia agnosia

disturbances in executive functioning disturbances in executive functioning

12. Alcoholic Brain DiseaseAlcoholic Brain Disease

Alcohol consumption can damage the Alcohol consumption can damage the
brain through numerous mechanismsbrain through numerous mechanisms

Thiamine deficiency resulting from Thiamine deficiency resulting from
chronic alcohol consumption is one chronic alcohol consumption is one
factor underlying alcohol-induced factor underlying alcohol-induced
brain damage.brain damage.

13. Alcoholic Brain DiseaseAlcoholic Brain Disease

Chronic alcoholism can result in Chronic alcoholism can result in
thiamine deficiency by causing:thiamine deficiency by causing:
•Inadequate thiamine intakeInadequate thiamine intake
•Decreased thiamine from the GI tractDecreased thiamine from the GI tract
•Impaired thiamine utilization in the Impaired thiamine utilization in the
cells.cells.

14. Alcoholic Brain DiseaseAlcoholic Brain Disease

Susceptibility to thiamine deficiency Susceptibility to thiamine deficiency
differs for people, as well as for differs for people, as well as for
different brain regionsdifferent brain regions

15. Differential Sensitivity Among Differential Sensitivity Among
PeoplePeople

Genetic Predisposition?Genetic Predisposition?
•Patients with KP had “less active” Patients with KP had “less active”
Transketolase compared to controlsTransketolase compared to controls

Blass and Gibson 1977
•TransketolaseTransketolase from the alcoholic men
and their sons also bound ThDP less
strongly than did the enzyme from the
healthy volunteers and their sons

Mukherjee et al. 1987

16. Differential Sensitivity Among Differential Sensitivity Among
PeoplePeople
•Other investigators, however, have found no
differences in the ability of transketolase from
Korsakoff ’s patients and healthy subjects to
bind ThDP

Nixon et al. 1984
•Overall, researchers to date have found no
consistent correlation between genetically
determined transketolase variants and a
person’s sensitivity to thiamine deficiency

McCool et al. 1993

17. Differential Sensitivity Among Differential Sensitivity Among
PeoplePeople
•Another possible explanation has
focused on the assembly of functional
transketolase, aided by an as yet
unidentified “assembly factor”

Wang et al. 1997

18. Differential Sensitivity Among Differential Sensitivity Among
PeoplePeople

Variability in the capacity for
thiamine uptake into the cells or in
the overall sensitivity to cell damage
induced by oxidative stress

19. Differential Sensitivity of Various Differential Sensitivity of Various
Brain RegionsBrain Regions

Autopsy studies have found that a
region of the cerebellum known as
the anterior superior cerebellar
vermis most frequently exhibits
alcohol-induced damage

(Baker et al. 1999)

20. 
In a recent study, investigators used
an imaging technique called proton
magnetic resonance spectroscopy
(proton MRS) to determine the levels
of certain molecules (metabolites)
that reflect the functionality of the
cells in various brain regions of
alcoholics and nonalcoholics

22. Effects of Alcohol on ThiamineEffects of Alcohol on Thiamine
In chronic alcohol misusers, malnutrition
can reduce intestinal thiamine absorption
by ~70%, decreasing serum levels from
30 to 98% below the lower level
established for normal subjects.
Alcohol itself alone can also decrease
absorption by 50% in one-third of patients
who are not malnourished (Thomson,
2000).

23. Effects of Alcohol on ThiamineEffects of Alcohol on Thiamine

Inadequate Nutritional IntakeInadequate Nutritional Intake
•Alcoholics tend to consume less than Alcoholics tend to consume less than
0.29mg/1,000 Kcal0.29mg/1,000 Kcal

Woodhill and Nobile 1972Woodhill and Nobile 1972
•40% exhibit periodic deficiency during 40% exhibit periodic deficiency during
drinking bingesdrinking binges
•25% exhibit prolonged thiamine 25% exhibit prolonged thiamine
deficiency deficiency
•35% exhibit continuous thiamine 35% exhibit continuous thiamine
deficiencydeficiency

Leevy and Baker 1968Leevy and Baker 1968

24. Effects of Alcohol on ThiamineEffects of Alcohol on Thiamine

Decreased uptake from the GI tractDecreased uptake from the GI tract
•Acute alcohol exposure interferes with
the absorption of thiamine from the
gastrointestinal tract at low, but not at
high, thiamine concentrations
(Hoyumpa 1980).
•TPK enzyme from various tissues
decreased with acute alcohol exposure
to about 70 percent of the activity level
in control animals, and with chronic
alcohol exposure to about 50 percent
(Laforenza et al. 1990)

25. Effects of Alcohol on ThiamineEffects of Alcohol on Thiamine

Impaired Thiamine UtilizationImpaired Thiamine Utilization
•Phosphorylated Thiamine (ThDP) is Phosphorylated Thiamine (ThDP) is
required by other enzymes in order to required by other enzymes in order to
function.function.

The reaction requires MagnesiumThe reaction requires Magnesium
•Chronic alcohol consumption frequently Chronic alcohol consumption frequently
leads to Magnesium deficiencyleads to Magnesium deficiency

Morgan 1982; Rindi et al. 1992

26. Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

Acute and Short-lived Acute and Short-lived

Severe (Life-Threatening)Severe (Life-Threatening)

Symptoms include:Symptoms include:
•Mental confusionMental confusion
•Oculomotor disturbancesOculomotor disturbances
•AtaxiaAtaxia
* Many do not exhibit these 3 symptoms * Many do not exhibit these 3 symptoms

27. 
Other less common etiologiesOther less common etiologies
•Forced or self-imposed starvationForced or self-imposed starvation
•Protein-energy malnutrition resulting from Protein-energy malnutrition resulting from
inadequate diet or malabsorptioninadequate diet or malabsorption
•Conditions associated with protracted vomitingConditions associated with protracted vomiting
•Chronic renal failureChronic renal failure
•Carbohydrate loading in the presence of Carbohydrate loading in the presence of
marginal thiamine stores (feeding after marginal thiamine stores (feeding after
starvation)starvation)
•Transketolase function abnormalitiesTransketolase function abnormalities
Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

28. Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

Postmortem neuropathological Postmortem neuropathological
studies indicate that many cases of studies indicate that many cases of
thiamine deficiency-related thiamine deficiency-related
encephalopathy may not be encephalopathy may not be
diagnosed in life because not all the diagnosed in life because not all the
classic signs and symptoms are classic signs and symptoms are
present or recognized.present or recognized.

29. Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

the characteristic lesions of WE seen
in ~1.5% of patients representative
of the general population

…in 12.5% of alcohol misusers
coming to post-mortem

(Harper et al., 1986, 1995;Cook et al., 1998).

30. Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

the classic triad of signs (confusion,
ataxia and ophthalmoplegia) occurs
in only 10% of cases

(Harper et al., 1986)

Only 5–14% of patients with WE are
diagnosed in life

(Torvik et al., 1982;Blansjaar
and Van Dijk, 1992)

31. Wernicke’s Encephalopathy (WE)Wernicke’s Encephalopathy (WE)

Other clinical signs such as acute
mental impairment, obtundation,
pre-coma and coma occur in 82% of
patients with WE, which may easily
be attributed to intoxication, alcohol
withdrawal or to concurrent
morbidity such as head injury.

32. Mechanisms of DamageMechanisms of Damage
thiamine-dependent enzyme transketolase
involved in the pentose phosphate pathway, the
maintenance of myelin sheaths in the nervous
system, lipid and glucose metabolism and
branched chain amino acid production.
Thiamine deficiency also reduces the conversion
of pyruvate to acetyl co-enzyme A.
This increases lactic acid production, and the
accompanying pH change may damage the apo-
enzyme, making it less efficient
(Butterworth, 1989; Todd et al., 1999).

34. Role of Neuroimaging Role of Neuroimaging (Scroop et.al. 2002)(Scroop et.al. 2002)

Cerebral atrophy
•degree of ventricular enlargement and
cortical atrophy does not appear to
correlate with the degree of functional
impairment
•magnitude is, in part, correlated with
the level of exposure

Rebecca Scroop, Australasian Radiology (2002)

35. Role of NeuroimagingRole of Neuroimaging

Cerebral atrophy
•positron emission tomography (PET) is
more sensitive and has a better
correlation with neuropsychological
testing.
•The frontal lobes are the most severely
affected and result in poorer planning
and organizational skills

36. Role of NeuroimagingRole of Neuroimaging

Cerebral atrophy
•Computed tomography and MRI
demonstrate enlargement of the
subarachnoid space and ventricular
system in chronic alcoholics relative to
age-matched controls

Cooper M. J Nucl Med 1993

38. Role of NeuroimagingRole of Neuroimaging

Cerebellar atrophy
•higher correlation with alcohol abuse
than cerebral atrophy

Brumberg AJR 1991
•However, there is poor correlation
between the clinical severity and degree
of atrophy

Shear PK, Alcohol Clin Exp Res 1996

39. Role of NeuroimagingRole of Neuroimaging
Cerebellar atrophy
•atrophy is more marked in the rostral
vermis and the adjacent superior
cerebellar surfaces with narrowing of
the folia and widening of the interfolial
sulci
•Hayakawa et al. demonstrated that the
most consistent finding of alcohol-
related cerebellar changes was
dilatation of the fourth ventricle with an
increase in both width and height

41. Role of NeuroimagingRole of Neuroimaging
White-matter lesions
•One of the earliest pathological changes
of alcohol abuse is generalized mild
myelin degeneration
•supported by postmortem and, more
recently, MRI findings in clinically
asymptomatic patients who abuse
alcohol
Zeneroli NIL Map Res Imag 1998

42. Role of NeuroimagingRole of Neuroimaging

White-matter lesions
•The MRI morphology and signal
characteristics of the observed lesions
are similar to those of multiple sclerosis.
•They are almost exclusively located in
the periventricular white matter

44. Role of NeuroimagingRole of Neuroimaging
Marchiafava–Bignami disease
•a rare complication of chronic massive
alcoholism
•characterized by degeneration of the
corpus callosum with edema and
demyelination progressing in the chronic
stages to atrophy
•appear similar with CPM but they have
not been documented to occur in the
same individual, and it is unclear if they
are the result of the same etiological
process.

45. Role of NeuroimagingRole of Neuroimaging
Marchiafava–Bignami disease
•acute form
massive neurological changes and reduced
conscious state, which is often fatal and a
chronic form characterized by
interhemispheric disconnection that might
last for years
the corpus callosum is diffusely enlarged
with increased signal on T2 and proton
density weighted examinations
• In the chronic stages
there is atrophy that might appear quite
focal.

47. Role of NeuroimagingRole of Neuroimaging

Central Pontine MyelinolysisCentral Pontine Myelinolysis
•Magnetic resonance imaging allows earlier
detection of central pontine myelinolysis, with
prolongation of T1 and T2 relaxation
•In the acute stages there is enhancement
following gadolinium as a reflection of blood-
brain barrier breakdown
•The pontine white matter is primarily involved
which, when florid, appears mass-like unlike
the transverse T2 hyperintensity seen in
hypertensive perivascular hyalinosis.

49. Role of NeuroimagingRole of Neuroimaging

Wernicke’s EncephalopathyWernicke’s Encephalopathy
•Coronal fluid attenuated inversion
recovery image shows increased signal
in the periventricular white matter of
the third ventricle.
•Axial proton density section show
increased signal intensity in the
mamillary bodies and less so in the
periaqueductal grey matter

51. Wernicke’s EncephalopathyWernicke’s Encephalopathy

Although cranial MRI detected no Although cranial MRI detected no
pathology, brain SPECT revealed bilateral pathology, brain SPECT revealed bilateral
frontal and frontoparietalfrontal and frontoparietal hypoperfusion as hypoperfusion as
well as right well as right basal gangliabasal ganglia hypoperfusion. hypoperfusion.
(Celik Y, Kaya M. 2004)(Celik Y, Kaya M. 2004)

52. Laboratory Tests (?)Laboratory Tests (?)

Serum Pyruvate levels + Lactate Serum Pyruvate levels + Lactate
Levels (Peters 1936)Levels (Peters 1936)
•However, these measurements are
limited by a lack of specificity and
technical difficulty
(Victor et al., 1989)

1964 – Baker et.al.1964 – Baker et.al.
•Measured thiamine levels in the blood
(HPLC), and RBC Transketolase activity

53. Laboratory Tests (?)Laboratory Tests (?)
• However, these tests are not However, these tests are not
available routinely on an emergency available routinely on an emergency
basis.basis.
• It is more important to make a It is more important to make a
presumptive diagnosis and to treat the presumptive diagnosis and to treat the
patient as soon as possiblepatient as soon as possible

(Cook et al., 1998)

54. ComplicationsComplications

The subdural space is larger and often, in
addition, clotting time is prolonged from
liver dysfunction due to alcohol misuse.

Therefore they are at greater risk of
developing subdural hematoma secondary
to head injuries.

The initial signs of a developing
intracranial bleed may be masked by
drunkenness.

55. TreatmentTreatment

Ambrose et al.(2001) - First
randomized double-blind multidose
study into the therapeutic benefits of
thiamine in an alcohol-dependent
sample without clinically apparent
WE.

56. TreatmentTreatment

intramuscular dose of ≥200 mg of
thiamine may be required to show
improvement

Improvement was statistically
marginal and there was a high rate
of noncompletion

57. Treatment Treatment

There is There is insufficientinsufficient evidence from evidence from
randomized controlled clinical trials randomized controlled clinical trials
to guide clinicians in the dose, to guide clinicians in the dose,
frequency, route or duration of frequency, route or duration of
thiamine treatment for prophylaxis thiamine treatment for prophylaxis
against or treatment of WKS due to against or treatment of WKS due to
alcohol abuse.alcohol abuse.
(Day E, et al Cochrane, 2004)(Day E, et al Cochrane, 2004)

58. TreatmentTreatment

The dose of thiamine required to
prevent or treat WE in most alcoholic
patients is believed to be >500 mg
once or twice daily, given
parenterally for 3–5 days

(Cook et al., 1998).

59. TreatmentTreatment

Don’t forget to correct Magnesium (only if Don’t forget to correct Magnesium (only if
it is found to be abnormally low)it is found to be abnormally low)
•Traviesa (1974) has demonstrated that patients
with WE may be unresponsive to parenteral
thiamine in the presence of hypomagnesemia,
but after correction of this deficit, the blood
transketolase activity returns to normal, and
there is clearing of the clinical signs
Consider Vit.BConsider Vit.B
66 and Nicotinic Acid and Nicotinic Acid
deficienciesdeficiencies

60. TreatmentTreatment

Oral therapy is inadequate in
patients who are considered to be at
risk and thiamine must be given i.v.
for prompt, effective correction of its
depleted brain levels.

Oral thiamine is poorly absorbed and
ineffective in both prophylaxis and
treatment of WE

Royal College of Physicians (2001)

61. Cholinesterase Inhibitors (?)

Cholinergic treatment with Donepezil does
not seem to provide marked beneficial
effects in patients with WKD in this small,
descriptive study.

This may be because pathways mediating
channel and state-dependent functions are
impaired in this disease, and enhancement
of state-dependent cholinergic
transmission may not be sufficient.

Hüseyin A. Sahin,2002

62. PrognosisPrognosis

if inadequately treated with thiamine
(given by the wrong route, in too
small a dose or too late), leads to
irreversible structural changes
producing loss of short-term memory
andan impaired ability to acquire
new information.

Victor et al. (1989)

64. PrognosisPrognosis
Only 16% of WE patients treated with
inappropriately low parenteral doses of
50–100 mg of thiamine daily recovered
fully, with a reported death rate of 17–
20%
84% developed KP
Only 21% of these patients with KP
showed complete recovery
26% showed no improvement
28% only slight improvement

65. PrognosisPrognosis

25% showed significant recovery from the
amnesic state which may take from 2
months to 10 years.

Twenty-five per cent of patients with KP
require long-term institutionalization

(Cook et al., 1998).