DR. BHARAT BHUSHAN (DM-NEUROLOGY) ASSOCIATE PROFESSOR GOVERNMENT MEDICAL COLLEGE,KOTA
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Transcript of DR. BHARAT BHUSHAN (DM-NEUROLOGY) ASSOCIATE PROFESSOR GOVERNMENT MEDICAL COLLEGE,KOTA
ALCOHOL RELATED NEUROLOGICAL COMPLICATIONS AND MANAGMENT
DR. BHARAT BHUSHAN(DM-NEUROLOGY)
ASSOCIATE PROFESSOR GOVERNMENT MEDICAL COLLEGE,KOTA
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.
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.
NEUROTRANSMITTER
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).
ALCOHOL AND THE BRAIN TRANSCRIPTOME
SPECTRUM Acute
Acute alcoholic intoxicationAlcoholic blackoutAlcohol 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 PellagraUncertain etiology• Alcoholic cerebellar
degeneration.• Central pontine myelinolysis.• Marchiafava-Bignami disease• Alcoholic myopathy.• Alcoholic neuropathy
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).
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
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).
ALCOHOL WITHDRAWAL SYNDROMEWithdrawal
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
ALCOHOLIC HALLUCINOSISAlcoholic 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,
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
EFNS- RECOMMENDATION(2011)Treatment: BDZ: Diazepam: IV 0.5 mg/kg at 2.5 mg/ minNo 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 preventionBZD 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.
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.
CHRONIC COMPLICATIONSAlcoholic 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.
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)
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
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PHYSICAL EXAMINATION• The diagnosis of Wernicke syndrome is often suspected
based on clinical grounds.• The classical triad of symptoms – only 1/3rd of cases• Ocular abnormalities – nystagmus , bilateral lateral rectus palsies, conjugate gaze palsies, sluggish pupils, ptosis, and anisocoria
• Encephalopathy – global confusional state, disinterest, inattentiveness, or agitation; Coma is rare.
• Gait ataxia – cerebellar damage, and vestibular paresis
• Peripheral neuropathy – foot drop, and decreased proprioception
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
Differential Diagnosis
• Psychosis• Normal pressure hydrocephalus• Cerebrovascular accident• Chronic hypoxia• Closed-head injury• Hepatic encephalopathy• Postictal state
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.
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TREATMENT• Emergency department care – Parenteral thiamine –Requirement in
chronic alcoholics may be as high as 500mg single dose or multiple daily doses.
• Never start on Dextrose• 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.• Parenteral magnesium sulfate as thiamine therapy ineffective in
presence of hypomagnesemia. • In-Patient care – Watch for complications – Korsakoff psychosis –
Alcohol withdrawal – Congestive heart failure – Lactic acidosis• Out-Patient Care – Thiamine 100 mg PO daily, start alcohol cessation
program, Advise on importance of balanced diet.
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-Korsakoff syndrome.
• 20% eventually recover completely during long-term F/U care.
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.
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.
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.
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.
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)
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.
Sandwich sign
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.
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).
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.
ALCOHOLIC NEUROPATHYACUTE 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 .
ALCOHOLIC NEUROPATHYCHRONIC 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.
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.
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
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.
ALCOHOLIC MYOPATHYACUTE
• 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
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.
THANK YOU