This document provides information on various topics related to alcoholism and its effects on the brain and body. It discusses: 1) The phenomenology of alcoholism including definitions of terms like alcoholic, alcohol dependence, binge drinking, craving, and tolerance. 2) How alcohol is metabolized and its effects on neurotransmitters in the brain. Chronic alcohol exposure can affect many genes and neurological systems. 3) The acute and chronic effects of alcoholism including intoxication, withdrawal, blackouts, seizures, nutritional deficiencies like Wernicke-Korsakoff syndrome, cerebellar degeneration, and other neurological complications. 4) Evaluation, diagnosis and treatment approaches for various alcohol-related

1. DR. BHARAT BHUSHAN
(DM-NEUROLOGY)
ASSOCIATE PROFESSOR
GOVERNMENT MEDICAL COLLEGE,KOTA

3. PHENOMENOLOGY
• Alcoholic = Person (T1>25yr M/F, T2<25yr male only)
• Alcoholism =Illness (abuse /dependence)
• Physical Dependence :The development of withdrawal
symptoms once a drug is stopped.
• Binge Drinking: A “binge” is a pattern of drinking alcohol
that brings BAC to 0.08 gm% or above. >5 drinks (male)
or >4 drinks (female) in about 2 hours.
• Craving:- The desire to experience the effects of a
previously experienced psycho-active substance.
• Tolerance:- represents a CNS pharmacodynamic adaptive
response which improves neurologic function at a given
blood alcohol level.

4. METABOLISM
• Role of alcoholism in the development of cognitive and
functional decline has been known since the time of
Hippocrates
• Two-carbon molecule that rapidly diffuses into virtually every
biologic compartment in the body upon ingestion.
• Women have a lower alcohol dehydrogenase blood content
than Men.
Rate of oxidation is
constant(15mg/dl/hr) does
not depend on plasma level.

5. NEUROTRANSMITTER

6. ALCOHOL AND THE BRAIN TRANSCRIPTOME
• Chronic exposure acts by many multiple myelin-
related genes /ligand-gated ion channels /
neuromodulatory molecules /Neuroinflammatory
signaling genes are in both humans and animal
models (Blednov et al., 2011, 2012).
• Genetic predisposition - 50% of the vulnerability
for developing alcohol dependence (Goodwin et
al., 1974; Prescott and Kendler, 1999).
• Polymorphisms in isoforms of ADH and ALD genes,
which influence alcohol metabolism and the risk
for alcoholism (Park et al., 2013).

7. ALCOHOL AND THE BRAIN TRANSCRIPTOME

8. SPECTRUM
Acute
Acute alcoholic intoxication
Alcoholic blackout
Alcohol withdrawal syndromes
• Minor = Tremulousness, 6-
24 hr
• Major = Hallucinosis 10-72
hours
• Withdrawal seizures=Rum fit
, within 6-48 hrs
• Delirium tremens (DTs):-3-10
days
Chronic
Nutritional deficiencies:
Wernicke-Korsakoff syndrome.
Alcoholic polyneuropathy
Pellagra
Uncertain etiology
• Alcoholic cerebellar
degeneration.
• Central pontine myelinolysis.
• Marchiafava-Bignami disease
• Alcoholic myopathy.
• Alcoholic neuropathy

9. ACUTE EFFECTS- INTOXICATION
• Intoxication occurs –d/t readily crosses the BBB
• Facilitation of GABA and Inhibition of Glutmate
• Clinical intoxication is related to the rate of blood
ethanol increase and the individual’s ethanol
tolerance (d/t Zero order kinetics).

10. INTOXICATION
• EEG :- beta (fast) activity ----> slowing.
• Reduces sleep onset latency , sleep efficiency ,
duration of REM sleep and with diminished
perceived sleep quality.
Rx:-Supportive.
• Low dose BZD: Lorazepam PO/IV 1-2mg
• Alternative: Antipsychotic Haloperidol or
Olanzenpine.
• Parenteral thiamine should also used

11. ALCOHOL BLACKOUTS
• Alcohol blackouts occur in the absence of any
loss of consciousness or seizure activity and
represent a type of anterograde amnesia.
• Fragmentary or en bloc alcohol blackouts .
• Perhaps by interfering with septohippocampal
regulation of hippocampal neuronal circuitry
(Givens et al., 2000).

12. ALCOHOL WITHDRAWAL SYNDROME
Withdrawal
A physiological state, d/t cessation/reduction in
amount of drug ,Generally opposite of drug’s
normal effects.
Spectrum AWS
• Minor withdrawal= Tremulousness, 6-24 hrs
• Major withdrawal= Hallucinosis 10-72 hours
• Withdrawal seizures=Rum fit ,within 6-48 hrs
• Delirium tremens (DTs):-3-10 days

13. ALCOHOLIC HALLUCINOSIS
Alcoholic hallucinosis:
– Occurs in about 2% of patients
– Characterized by presence of hallucinations
[usually auditory] during partial or complete
abstinence, following regular alcohol intake.
Treatment:
– Lorazepam oral 3-10 mg every 4-6 hr
– Correction of electrolyte disorders: hypokalemia
and hypomagnesemia, hyperthermia,

14. ALCOHOLIC SEIZURE (RUM FITS)
– GTCS & multiple seizures occur in about 10% of
alcohol dependence patients, usually 12 to 48 hrs
after abstinence.
– Sometimes status epileptics can be precipitated
(less than 3%)
– Unless an underlying neuropathology exists,
seizures are rarely focal.
– Seizures sometimes occur during heavy drinking or
after more than a week without alcohol
– Arrhythmias and sudden cardiac death can occur.
– EEG are mildly abnormal and usually revert to
normal within few days

15. EFNS- RECOMMENDATION(2011)
Treatment: BDZ: Diazepam: IV 0.5 mg/kg at 2.5 mg/ min
No WS/Mild to Moderate symptoms no routine seizure prevention(Level B ).
Severe alcohol withdrawal symptoms, regardless of seizure occurrence, should
be treated pharmacologically (Level C recommendation).
Status epilepticus: i.v. lorazepam is safe and efficacious. When unavailable, i.v.
diazepam is a good alternative (Level A recommendation).
Primary Preventions
BZD for primary prevention of seizures in a person with alcohol withdrawal,
as well as for treatment of the alcohol withdrawal syndrome. Other drugs for
detoxification should only be considered as add -on (Level A).
Secondary prevention
BZD should be used for the secondary prevention of AWS (Level A).
Phenytoin is not recommended for prevention of AWS recurrence (Level A
recommendation).
The efficacy of other antiepileptics for secondary prevention of AWS is
undocumented.

16. DELIRIUM TREMENS
Occurs within 3 to 4 days
Features of:-
- Clouding of consciousness with disorientation
in time and place with tremulousness of body
- Poor attention span and distractibility
- Visual hallucinations and illusions
- Marked autonomic disturbances
- Insomnia
- Dehydration with electrolyte imbalance
Treatment: 50-100 mg Chlordiazepoxide every 4
hrs orally or Lorazepam IV 0.1 mg/kg at 2 mg/min.
 Prevention: 25-50 mg of Chlordiazepoxide every 2-4 hrs until out of
danger.
 High calorie, high carbohydrate diet given with Thiamine
suppliment.

17. CHRONIC COMPLICATIONS
Alcoholic Pellagra
• Disease of cerebral function attributed to
deficiency of nicotinic acid or tryptophan (Serdaru et al
1988; Victor 1994).
• Rare now because of widespread practice of
niacin supplementation of cereals and bread
• Initial symptoms are mood changes and
neurasthenia.May progress to lethargy and
confusion, variably accompanied by spastic
paresis, paratonia, or myoclonus.

18. Wernicke-Korsakoff Syndrome
German neurologist and
psychiatrist, born May 15, 1848,
Tarnowskie Gory, Poland; died
June 15, 1905,
Russian neuropsychiatrist,
born January 22, 1853,
Gus estate, Vladimirsk; died
May 1, Moscow, 1900.
Karl Wernicke(1848-1905)

19. WERNICKE ENCEPHALOPATHY
• WE is an acute, potentially reversible,
neuropsychiatric disorder caused by thiamine
deficiency (Donnino et al., 2007; Isenberg-Grzeda et al., 2012).
• The incidence can be as high as 12.5%
• The altered cognition of WE can progress to
KS, a chronic and usually permanent.(Toth et al., 2002).
• Approximately 80% of patients with acute WE
will develop KS (Donnino et al., 2007).
• Mechanism:- Chronic alcoholism– Malnutrition –
reduced thiamine uptake and utilization

20. PHYSICAL EXAMINATION
• The diagnosis of Wernicke syndrome is often suspected
based on clinical grounds.
• Theclassicaltriadofsymptoms–only1/3rd ofcases
• Ocularabnormalities–nystagmus,bilaterallateral
rectuspalsies,conjugategazepalsies,sluggishpupils,
ptosis,andanisocoria
• Encephalopathy– globalconfusionalstate,disinterest,
inattentiveness,or agitation;Comaisrare.
• Gaitataxia– cerebellardamage,andvestibularparesis
• Peripheralneuropathy– foot drop,anddecreased
proprioception
20

21. Figure 1. [A and B] FLAIR images depicting hyperintensities in the periaqueductal
region [A] and medial thalamus [B]. Pre- [C] and Post- [D] contrast T1-weighted images
showing contrast enhancement of the mammillary bodies.
Wernicke-Korsakoff Syndrome

22. Differential Diagnosis
• Psychosis
• Normal pressure hydrocephalus
• Cerebrovascularaccident
• Chronic hypoxia
• Closed-head injury
• Hepatic encephalopathy
• Postictal state

23. WORK-UP
• Erythrocyte transketolase activity assay,
Thiamine assay – very specific tests – not
widely available – reserved for diagnostic
dilemmas
• EEG and CSF analysis may exclude other
explanatory or concomitant conditions.

24. TREATMENT
• Emergencydepartmentcare–Parenteralthiamine–Requirementin
chronicalcoholicsmaybeas highas500mgsingledoseormultipledaily
doses.
• NeverstartonDextrose
• Treatment with thiamine repletion, currently recommended at 1 gram of
IV thiamine per 24 hours for alcoholics with suspected Wernicke
encephalopathy , should not be delayed.
• Death occurs in nearly 20 % of patients with delayed treatment.
• Parenteralmagnesiumsulfateasthiaminetherapyineffectivein
presenceofhypomagnesemia.
• In-Patientcare–Watchforcomplications–Korsakoffpsychosis–Alcohol
withdrawal–Congestiveheartfailure–Lacticacidosis
• Out-PatientCare–Thiamine100mgPOdaily,startalcoholcessation
program,Adviseonimportanceofbalanceddiet.
24

25. KORSAKOFF SYNDROME:-
• Another CNS syndrome resulting from thiamine
deficiency in alcoholics.
• It manifests with Psychosis, memory loss and confabulation,
abulia.
• Korsakoff syndrome is distinguished from acute
Wernicke syndrome by prominent anterograde and
retrograde amnesia without substantially impaired
alertness and attention or extraocular movement
disturbance.
• 85% of the survivors of the acute phase of Wernicke
encephalopathy who remain untreated go on to develop
Wernicke-Korsakoffsyndrome.
• 20% eventuallyrecovercompletelyduring long-termF/U care.

26. KORSAKOFF SYNDROME
• Epidemiologicallly cases of undiagnosed Wernicke
syndrome can progress to Korsakoff syndrome.
• Patients may have a significant degree of
vacuous spontaneous speech and abulia that
may be mistaken for depressive symptoms when
inadequately explored.
• Thalamus (particularly the anterior thalamic
nucleus) and hypothalamus (medial mammillary
nucleus) are injured , but other cortical and
subcortical areas modulate this process.

27. PROGNOSIS OF WKS
• 10-20% mortality rate (in acute stages)
• In general, full recovery of ocular function occurs. Fine
horizontal nystagmus can persist in - 60% of cases.
• Approximately 40% of patients have complete recovery
from ataxia.
• Of patients surviving WE 80% have Korsakoff psychosis.
• KS 25% do not recover, require long-term admission.
• Only about 20% eventually recover completely during
long-term follow-up care.
• Only 20% of patients recover completely from amnestic
deficit.
• Despite appropriate treatment ,measureable memory
deficiency may persist for upto 2 years in patients with
Wernicke encephalopathy.

28. ALCOHOL RELATED DEMENTIA
• Represent approximately 10% of all cases of dementia
(Gupta and Warner, 2008).
• With advancing age , patients who are chronic
alcoholics may develop cognitive impairment or
dementia without demonstrable micronutrient
deficiency.
• Synergistic in the expression of other cognitive
disorders of aging.
• Clinically, patients with alcohol related dementia
typically present at an earlier age than other acquired
or late-onset forms of dementia.

29. ALCOHOL RELATED DEMENTIA
Pathogenesis
• Withdrawal-induced glutamate excitotoxicity
(Hoffman, 1995) or oxidative stress (Brust, 2010).
• Alter expression of numerous brain gene expression
networks
• Alcohol metabolite acetaldehyde binds to select
proteins, resulting in the formation of adducts. These
adducts led to brain damage (Nakamura et al., 2000).
• Neurotoxic glutamatergic excitation that leads to
hippocampal and neocortical neuronal loss.

30. ALCOHOL RELATED DEMENTIA
• AD may have symptoms that overlap with other
common neurodegenerative cognitive disorders(e.g)
• Contrast to the other dementia AD more typically
have a rather globally impaired neuropsychological
profile , with similar impairment in most or all
domains even in early disease stages.
• The evaluation :-Likewise other dementia
• Rx:- Partially reversible on cessation of drinking.
Gazdzinski et al. (2005)

31. MARCHIAFAVA BIGNAMI DISEASE
“red wine drinker’s encephalopathy,”
• Acute:- severe impairment of consciousness, seizures, and
muscle rigidity often result in death after several days.
• Chronic :-An interhemispheric disconnection syndrome,
such as limb apraxia, tactile agraphia, unilateral agraphia,
hemialexia, and dementia, can be seen and can last for
months to years (Kim et al., 2007).
• Corpus callosum demyelination is the hallmark of MBD
diseaseParticular involvement of the splenium.(Tozakidou et al., 2011)
• Rx:-Strongly associated with thiamine deficiency (and
recovery may therefore occur with early recognition and
repletion)
• Other clinical conditions such as ischemia, multiple
sclerosis, lupus, and posterior reversible encephalopathy
syndrome.

32. Sandwich sign

33. CEREBELLAR DEGENERATION
• CD with or without micronutrient deficiency
states , such as thiamine deficiency. Depends
on duration and severity of alcohol intake
(Nicolas et al., 2000)
• Typically occurs after 10 or more years of
alcohol abuse (Baker et al., 1999; Andersen,
2004).
• Thought to be the most common CNS
complication of alcoholism, affecting 10% to
25% of alcoholics.

34. CEREBELLAR DEGENERATION
• Most typically, the superior cerebellar vermis is
principally involved, with multilayer neuronal loss
(particularly affecting Purkinje cells) and cerebellar
white matter loss.
• The number of years of heavy alcohol abuse may be
the strongest single determinant of alcoholic ataxia
development.
• Treatment of this disorder , aside from thiamine and
other micronutrient repletion , is largely supportive
once developed.
• Cerebellar dysfunction may improves or stabilizes
with abstinence and improved nutrition (Diener et al., 1984).

35. CENTRAL PONTINE MYELINOLYSIS
• Possibility that alcoholics are predisposed to myelin
disorders by environmental insults such as
hyponatremia with CPM.
• CPM is C/b a loss of oligodendrocytes and myelin in the
central pons (Adams et al., 1959).
• EPM has also been described most often involving the
white matter of the cerebellum, lateral geniculate
body, putamen, thalamus, hippocampus, and cerebral
transition of white and gray matter (Martin, 2004).
• C/F confusion, impaired cognition, dysarthria,
dysphasia, gait instability, weakness or paralysis, and
generalized seizures (Hurley et al., 2011).
• Rx :-Correction of Na & Vitamin supplementation.

36. ALCOHOLIC NEUROPATHY
ACUTE ALCOHOLIC NEUROPATHY:-
• Rare cases have been reported of alcoholics with severe
acute or subacute neuropathy that mimics Guillain Barre´
syndrome.(causal but unproven)
• Biopsy and electrodiagnostic data show an axonal pattern
(not demyelinating) with normal CSF protein.
COMPRESSIVE NEUROPATHIES
• Susceptibility to compression is a feature of most axonal
neuropathies , and acute radial neuropathy , or Saturday
night palsy, in alcoholics is well reported.
• However , alcoholics with a generalized peripheral
neuropathy are prone to compression neuropathy at many
different sites , including ulnar neuropathy at the elbow ,
radial or axillary nerve injury in the axilla ( crutch-type
compression ) , and fibular ( peroneal) neuropathy at the
fibular head .

37. ALCOHOLIC NEUROPATHY
CHRONIC ALCOHOLIC NEUROPATHY:-
• Painful sensory neuropathy in association with alcoholism was
recognized in the late 1700s.
• However , the question of the cause due to ethanol as a
putative direct nerve toxin or due to nutritional deficiency or
both, was debated until recently.
• Malnutrition and vitamin deficiency are common in chronic
alcoholics , and thiamine has been the primary focus of
investigation.
• Clear association between reduction of thiamine levels or
transketolase activity and alcoholic peripheral neuropathy has
not been conclusively established.

38. CHRONIC ALCOHOLIC NEUROPATHY
• Peripheral distal sensorimotor neuropathy with distal
axonopathy that is a common finding in alcoholic
patients (90%).
• Distal weakness and atrophy are usually late findings
following sensory disturbance and are less profound ,
with weakness that may be limited to toe extensors.
• Differences in thiamine levels or enzyme activity
between alcoholics with and without neuropathy
have not been consistently identified , even though
alcoholic neuropathy patients often do have reduced
levels of various vitamins.

39. CHRONIC ALCOHOLIC NEUROPATHY:-
• Chronic well fed alcoholics without vitamin
deficiency - slowly progressive sensory loss
affecting small-fiber-mediated functions, but
not ataxia or weakness from neuropathy.
• Primary non-alcoholic thiamine deficiency-
subacute weakness and sensory ataxia from
large-diameter > small-diameter fiber sensory
neuropathy.
• Autonomic symptoms are not uncommon

40. ALCOHOLIC NEUROPATHY-Rx
• Cessation from ethanol is paramount to
improvement .
• Despite apparently adequate nutrition,
multivitamin supplements and thiamine are
indicated for all alcoholic neuropathy patients.
• Long-term follow-up of reformed alcoholics
demonstrates that significant improvement of
alcoholic neuropathy is possible, although often
incomplete.
• Patients with mild to moderate neuropathy can
significantly improve ,but the improvement is
usually incomplete in those with severe findings.

41. ALCOHOLIC MYOPATHY
ACUTE
• Develops over hours to days
following a recent binge.
• Painful, Proximal, may regional or
even focal, swollen muscles ,
variable weakness,
• Usually with myoglobinuria and
markedly elevated CK that
normalizes within 1 to 2 weeks.
• Muscle destruction –
Fasting/drinking
• Attacks can be recurrent,
correlating with additional
episodes of heavy drinking.
• Recovery following cessation of
drinking and repletion of
electrolytes is usually rapid and
dramatic.
CHRONIC
• Develops in an indolent manner
over many months. Roughly 2% of
all adults.
• Painless , proximal weakness with
wasting (up to 30%)
• Myoglobinuria is absent, and
creatine kinase(CK) is normal,
reduced, or mildly elevated, unless
an acute myopathy is
superimposed.
• Muscle Bx- atrophy of type II fibers,
which contain a higher content of
glycolytic enzymes.
• Prolonged abstinence can improve
clinical weakness and is associated
with significant improvement

42. TAKE HOME MESSAGE
• Alcoholism can produces a diverse spectrum
of neurologic disease when abused.
• Alcohol interacts acutely predominantly with
GABA-A and NMDA receptors, but triggers
diverse signaling events within well-defined
neural pathways.
• Early recognition and despite apparently
adequate nutritional deficiency one should
supplements thiamine and multivitamin for all
alcoholic patients.

43. THANK YOU