ALCOHOLISM IN

NEUROLOGY

-Dr. Sachin Adukia

Acute alcoholic intoxication Alcohol withdrawal

Withdrawal seizures Alcohol hallucinosis Delirium tremens

Nutritional deficiencies: Wernicke-Korsakoff syndrome. Alcoholic polyneuropathy. Pellagra.

Neurological complication of uncertain etiology: Alcoholic cerebellar degeneration Central pontine myelinolysis Marchiafava-Bignami disease Alcoholic amblyopia

Encephalopathy: Hepatic encephalopathy

Trauma: SDH Post stroke epilepsy

Others: Stroke brain tumors Headache Hypoglycemia

Alcohol

facilitates inhibitory neurotransmitter GABA

and inhibits excitation induced by NMDA

It has effects on opioid, dopamine, and serotonin systems

Sustained heavy consumption casues dependency and increased tolerance with

reduced sensitivity to GABA

increased sensitivity to NMDA

Blood alcohol concentrations reflect rate of intake, degree of tolerance.

Extreme intoxication (>300 mg/100 ml)

increasing drowsiness and then coma

depressed tendon reflexes

hypotension, hypothermia, and slowed respiration

Alcohol concentrations >400 mg/100 ml.

Death may occur

At < 400 mg/100 ml, look for alternative cause for coma

head injury, other drug usage

hypoglycemia, meningitis

At a cellular level daily alcohol intake induces functional increase in NMDA receptor levels- excitatory

When alcohol is stopped these excess receptors cause large calcium flux into cells,

hyperexcitability, and cell death. alcohol mediated inhibitory action of GABA reduces

Increase in excitatory glutamate and drop inhibitory GABA give noradrenergic ‘‘overdrive’’- sympathetic overactivity.

Alcohol-withdrawal syndrome

with a long history of sustained alcohol use

Symptoms after 4 -12 hrs after last consumption, may start upto 48 to 72 hrs esp.

delirium

Initial symptoms –

insomnia, anxiety, tremulousness, palpitations, diaphoresis

Can appear even when significant alcohol level in blood is present.

Minor symptoms - self-limited, symptoms peaking and resolving within 72 hours.

Moderate to severe - urgent medical attention as they are complicated by withdrawal seizures alcoholic hallucinosis, delirium tremens- DT

Alcohol-withdrawal seizures

Usually GTCS, occuring between 12 -48 hours from the last drink either a single seizure or brief flurry, usually self limiting Age group- Chronic alcoholics, 4th or 5th decade Status epilepticus –rare, but rates upto 9 - 25% observed Outcome more favourable, but recovery may be compounded by prolonged

post-ictal state. Investigation for structural, metabolic, infectious causes if:

status epilepticus focal seizures or focal deficits in the postictal state

recurrent or prolonged seizures require Rx.

Withdrawal seizures

Diagnosis presence of other symptoms of alcohol withdrawal h/o recent alcohol misuse.

?? genetic susceptibility +Other factors presenting as seizure in alcoholics

occult traumatic brain injuries parenchymal contusions subdural haematoma Subarachnoid haemorrhages

Hypoglycemia Other substance abuse

Alcoholic hallucinosis- Distinct from DT

hallucinations that develop within 12 to 24 hrs of abstinenceresolve within 24 - 48 hrs (earliest point at which delirium

tremens develops)usually visual, my be auditory and tactilenot a/w global clouding of sensorium, only specific

hallucinationsVital signs are usually normal

Alcohol withdrawal seizures left untreated progress to delirium tremens in nearly one-third of patients

Delirium Tremens

Defined by hallucinations, disorientation, tachycardia, HTN, hyperthermia,

agitation, and diaphoresis after acute reduction or abstinence from alcohol.

Begins between 48 -96 hrs after last drink,

Lasts 1-5 days

Mortality from DT < 5%, may be due to

arrhythmia,

complicating illnesses- pneumonia,

or failure to identify problem that led to alcohol cessation:

pancreatitis, hepatitis, or CNS injury or infection.

Risk factors for development of DT

sustained drinking

h/o previous DT

Age > 30

concurrent illness

significant alcohol withdrawal in the presence of an elevated alcohol

level

A longer period since the last drink

patients presenting with alcohol withdrawal >2 days after last drink

have DT more likely than those who present within 2 days)

Management

Quiet roomMechanical restraints IVFThiamine, multivitaminsdeficiencies of glucose, potassium, magnesium, phosphate corrected as

neededCaloric supportBenzodiazepines- IV preferred, IM avoided d/t variable absorption

Diazepam , lorazepam, chlordiazepoxide - most frequently used Longacting BZD with active metabolites (eg, diazepam or

chlordiazepoxide) preferred As they result in a smoother course with less chance of recurrent

withdrawal or seizures.

Use of sedatives

Benzodiazepines First line therapy for ALL alcohol withdrawal syndrome Diazepam, 5-10 mg IV, repeat every 5 -10 min, Max 160/d OR Lorazepam, 2 to 4 mg IV, repeat every 15 to 20 minutes esp. in cirrhosis or acute

alcoholic hepatitis - due to short action and absence of active metaboite, no oversedation Barbiturates

Synergistic with benzodiazepines; if refractory to high-dose BZD 130 to 260 mg IV, repeat every 15 to 20 minutes Intubation frequently required with concurrent benzodiazepine and barbiturate use ALL patients requiring barbiturates – monitor in ICU

Propofol Excellent agent if refractory to BZD and barbiturates Intubation almost always 1 mg/kg IV push as induction agent for intubation and titrate

Refractory DT

Is not clearly defined. May be present if > 50 mg diazepam or 10 mg lorazepam is

required to control withdrawal during 1st hour of treatment,or if > 200 mg of diazepam or 40 mg of lorazepam cant control

symptoms during initial 3 to 4 hrs of RxRequire

Additional Phenobarbitone or propofol ICU admission

Not to be used in acute setting

Such drugs include: Ethanol Antipsychotics (eg, haloperidol) Anticonvulsants (eg, carbamazepine) Centrally acting alpha2 agonists (eg, clonidine, dexmedetomidine) Beta blockers (eg, propranolol) Baclofen

They can reduce freq and intensity of minor withdrawal symptoms, but more data supports BZD for Sz, DT

PROPHYLAXIS

Patients with a history of seizures, delirium tremens, prolonged, heavy alcohol consumption, minimally symptomatic or asymptomatic but admitted for other

reasons

Can be prophylactically treated with oral chlordiazepoxide. If severe symptoms develop, manage in standard fashion.

Wernicke’s encephalopathy

Thiamine deficiency

In 1881, Carl Wernicke described an acute encephalopathy characterized by

mental confusion, ophthalmoplegia, gait ataxia

associated it with autopsy findings - punctate hemorrhages around 3rd and 4th

ventricles and the aqueduct

Prevalence at autopsy

0.4 to 2.8 % - general population in the West

majority are alcoholic

Upto 12.5% of alcohol abusers have WE

Susceptibilty- F>M

Conditions associated with WE

Chronic alcoholism Anorexia nervosa or dieting Hyperemesis GravidaProlonged intravenous feeding without proper supplementation Prolonged fasting or starvation, or unbalanced nutrition, esp.

with refeeding GI surgery (especially bariatric surgery) Systemic malignancy Transplantation Hemodialysis or peritoneal dialysis AIDS

PATHOPHYSIOLOGY

Thiamine is a cofactor for many enzymes in energy metabolism, transketolase, alpha-ketoglutarate dehydrogenase, pyruvate dehydrogenase

Thiamine requirements depend on metabolic rate, greatest during periods of high metabolic demand and high glucose intake. Thus the precipitation of WE in susceptible pts by IV glucose before

thiamine supplementation Deficiency initiates neuronal injury by inhibiting metabolism in brain regions

with high metabolic requirements BBB breakdown, NMDA receptor mediated excitotoxicity and increased

reactive O2 species induce neurotoxicity Deficiency in alcoholics results from:

inadequate dietary intake, reduced GI absorption, decreased hepatic storage and impaired utilization

Pathology

Acute WE lesions - vascular congestion, microglial proliferation, petechial hemorrhages.

Chronic cases- demyelination, gliosis, and loss of neuropil with relative preservation of neurons.

Neuronal loss most prominent in the relatively unmyelinated medial thalamus Atrophy of the mamillary bodies - highly specific in chronic WE and Korsakoff

syndrome :- up to 80 percent of cases Lesions occur symmetrically surrounding 3rd and 4th ventricle, aqueduct Virtually all cases - The mamillary bodies Commonly affected - Dorsomedial thalamus, locus ceruleus, periaqueductal

gray, ocular motor nuclei, vestibular nuclei Less frequently - colliculi, fornices, septal region, hippocampus, cerebral

cortex, which may show patchy, diffuse neuronal loss and astrocytic proliferation selective loss of Purkinje cells at anterior superior cerebellar vermis

Clinical features

Classic triad: (< 33%) Encephalopathy Oculomotor dysfunction Gait ataxia

Encephalopathy

Profound disorientation, indifference, inattentiveness

If these are less severe, higher cognitive testing shows impaired memory

and learning

Some exhibit agitated delirium d/t concomitant ethanol withdrawal.

< 5 % present with depressed consciousness,

Untreated - progress through stupor and coma to death

Oculomotor dysfunction

Reflect lesions of oculomotor, abducens, and vestibular nuclei. Usually occur in combinationNystagmus - MC, horizontal gaze evoked to both sides

Vertical nystagmus may occur- evoked by upward, rather than downward gaze

LR palsy is virtually always bilateral. Conjugate gaze palsies, isolated vertical gaze palsy, INO, complete

ophthalmoplegia are rare. Pupillary abnormalities- sluggish or unequal pupilsAdvanced cases- complete loss of eye movements with miotic,

nonreactive pupils. Ptosis is uncommon.

Gait ataxia

Primarily involves stance and gait likely d/t combination of

Polyneuropathy Cerebellar involvement and vestibular dysfunction

When severe, walking is impossible. Less affected patients walk with

widebased gait and slow, short spaced steps. appreciated only on tandem gait in some

Cerebellar pathology - restricted to the anterior and superior vermis; thus, ataxia of the legs or arms and dysarthria or scanning speech are uncommon

Vestibular dysfunction - major cause of acute gait ataxia in WE also explains dissociation between gait and limb abnormalities

Other signs

Evidence of protein calorie malnutrition Vestibular dysfunction without hearing loss is a common finding Peripheral neuropathy is common and typically involves just the lower

extremities gradual onset of weakness, paresthesias, and pain affecting the distal lower

extremities examination reveals diminished or absent ankle jerks and patchy distal sensory

loss. Hypothermia may cause unreactive pupils, rarely encountered in normothermic

patients with WE Lesions in the posterior and posterolateral hypothalamus - consistent with

thermoregulatory functions of the hypothalamus. While overt beriberi heart disease is rare in WE, other cardiovascular signs and

symptoms are common tachycardia, exertional dyspnea, elevated cardiac output, and EKG abnormalities

Diagnosis

WE is diagnosed in patients with two of the following four Caine criteria Dietary deficiency Oculomotor abnormalities Cerebellar dysfunction Either altered mental status or mild memory impairment Caine criteria increased the diagnostic sensitivity for WE from 22% using the

classic triad, to 85% There are no laboratory studies that are diagnostic of WE. Thiamine deficiency - reliably detected by

erythrocyte thiamine transketolase (ETKA) before and after thiamine pyrophosphate (TPP).

A low ETKA, along with a more than 25 percent stimulation, establishes the diagnosis of thiamine deficiency

Not necessary for diagnosis and management

Others

CSF - normal or may show a mild protein elevation

Pleocytosis or protein >100 mg/dL - alternative diagnoses

EEG if NCSE suspected.

In WE, only ½ pts demonstrate EEG abnormalities,

usually diffuse mild to moderate slow wave activity

Imaging

Not essential to diagnosis, shoud not delay RxMRI is more sensitive than CT Typical findings include

areas of increased T2 and FLAIR signals decreased T1 signal diffusion abnormality

surrounding the aqueduct and third ventricle within medial thalamus, dorsal medulla, tectal plate, and mamillary bodies

Atypical areas - cerebellum, CN nuclei, dentate nuclei, caudate, red nuclei, splenium and cerebral cortex

Treatment

Immediate IV thiamine 500 mg over 30 minutes, TID for 2 days

Then 250 mg IV or IM OD for an additional five days

other B vitamins and magnsium

Glucose without thiamine precipitates or worsen WE;. thus, thiamine

administered before glucose.

GI absorption of thiamine is erratic in alcoholic and malnourished

patients, thus oral administration - unreliable initially

Daily oral Thiamine 100 mg be continued

Treatment Outcomes

Prompt thiamine - improvement in ocular signs within hours to days

If ocular palsies fail to respond, other diagnoses should be considered.

recovery of vestibular function may begin during 2nd week after thiamine

gait ataxia coincides with recovery of vestibular function

Confusion subsides over days and weeks.

MRI abnormality resolves with clinical improvement

This early therapeutic response likely represents the recovery from a

biochemical rather than a structural lesion.

Korsakoff syndrome Due to Thiamine deficiency in alcoholics, pts as a rule unaware of their illness Epidemiology- not well known undiagnosed Wernicke syndrome can progress to Korsakoff syndrome. Is distinguished from acute WE by

prominent anterograde and retrograde amnesia without substantially impaired alertness and attention Without extraocular movement disturbance.

Manifestations include anterograde amnesia, impaired ability to acquire or retain new information; prominent confabulation is due to inability to recall even a brief, simple story or recent

information. Retrograde amnesia is identified by the inability to recall elements of both recent and

remote memory

significant degree of vacuous spontaneous speech and abulia - mistaken for depressive symptoms

Attention and social behavior are relatively preserved

May result when both the thalamus (particularly the anterior thalamic nucleus)and hypothalamus (medial mammillary nucleus) are injured

Patients with KS rarely recover. With thiamine, confabulation nmay resolv, amnesia persists Many patients require at least some form of supervision and social support,

Alcoholic polyneuropathy: Nutritional , direct toxic effect of alcohol

Peripheral distal sensorimotor neuropathy Chronic, well-fed alcoholics without vitamin deficiency

develop slowly progressive sensory loss affecting small fiber- mediated functions, especially nociception

pain and burning paresthesia are common no ataxia or weakness from neuropathy

Non-alcoholic thiamine deficiency produces prominent subacute weakness and sensory ataxia from large-diameter > small-diameter fiber sensory neuropathy

Malnourished chronic alcoholics have features of both Patients may disregard minor paresthesia or anesthetic areas until significant

pain or gait difficulties evolve Ataxia difficult to differentiate from Alcoholic Cerebellar degeneration

Autonomic symptoms, including orthostatic hypotension, impotence, incontinence, hyper- or hypohidrosis :- May be present

difficult to demonstrate at the bedside unless frank orthostatic hypotension is present

Electrodiagnostic testing shows typical evidence of an axonal sensorimotor neuropathy. Sensory distal amplitudes are reduced, or potentials are unrecordable. Motor evoked amplitude may be reduced, but to a lesser degree.

Patients may have behaviors, such as prolonged immobility or adverse body positions :- increased risk of compression neuropathy

Biopsy (Sural nerve) shows typical changes, but not indicated Adequate nutrition, multivitamin supplements and thiamine Ususally good recovery but some residual deficits persist

ALCOHOLIC CEREBELLAR DEGENERATION

Chronic cerebellar syndrome related to degeneration of Purkinje cells in

the cerebellar cortex : Midline cerebellar structures-

anterior and superior vermis predominantly affected, identical to WE

Develops only after 10 or more years of excessive ethanol

may be d/t combination of nutritional deficiency and alcohol neurotoxicity

Majority complain of gait impairment- weakness, unsteadiness, or

incoordination in the legs

Later, a minority incoordination and tremor in the arms, dysarthria, and

intermittent diplopia or blurred vision.

Examination demonstrates features of midline cerebellar lesion ataxia of stance and gait, resembling that of acute alcohol intoxication Tandem walking is typically impossible, even with mild disease. Heel-knee-shin is abnormal, but finger-nose may show mild

abnormalities, more severe impairment of handwriting

Mild dysarthria- slow, slurred speechSome have a coarse, rhythmic, 3 to 5 Hz postural tremor affecting the

fingers, arms, or thighs. Cognitive function usually unimpaired, except if prior WE.

Absence of CN abnormalities differentiates from vascular

disorders of posterior circulation, mass lesions, and demyelinative disease.

age of onset and clinical course differentiates from some of the SCA;

MSA, including olivopontocerebellar degeneration, may be difficult to distinguish on clinical

grounds alone

Diagnosis - clinical history and neurologic examination

CT or MRI scans may show cerebellar cortical atrophy,

but one half of alcoholic patients with this finding are not ataxic on examination

PET - shows reduction in cerebral metabolic rate for glucose and decrease in BZD receptor

binding in the superior cerebellar vermis :

magnitude of hypometabolism correlates with the clinical severity

Treatment: Cessation and supplementation, but ataxia persists in most

Ventricular Enlargement and Cognitive Dysfunction

50 to 70 % alcohol abusers have cognitive deficits on neuropsychological testing

Ethanol neurotoxicity may contribute to this CT / MRI show enlargement of the cerebral ventricles and sulci in majority

of alcohol abusers. But do not correlate consistently with duration of drinking or severity of

cognitive impairment hypothesized that changes in brain parenchyma, but not brain water, accounts

for reversible radiographic and cognitive abnormalities of alcoholics Regional vulnerability:-

Superior frontal cortex corrobrated by regional hypometabolism on PET studies

correlates with deficits in working memory in alcohol abusers White matter regional pathology is reveersible with abstinence

Cetral pontine myelinolysis As they have poor energy reserves, Na-K-ATPase pump which

regulates osmolyte transport across neuronal membrane fails, demyelination ensues

Marchiafava Bignami disease rare disorder of demyelination or necrosis of corpus callosum and

adjacent subcortical white matter predominantly in malnourished alcoholics acute, subacute, or chronic marked by dementia, spasticity, dysarthria, inability to walk Patients may lapse into coma and die

Alcohol amblyopia

far less common

presents as a painless bilateral loss of vision in alcohol abusers

Almost all c/o blurring or dimness of vision and of difficulty in reading small

prints.

disease usually evolves over several weeks to months

Fundus- may be normal or

mild to moderate pallor of optic nerve heads; most apparent in temporal

half

stigmata of undernutrition is encountered

Improvement almost always with adequate dietary and vitamin intake.

Acute and chronic alcoholic myopathy In two different studies, > 50 to 60 % alcoholi abuusrs had biopsy evidence of myopathy Skeletal muscle can be damaged by the administration of alcohol to wellnourished

volunteers ? Direct toxicity Electrolyte abnormalities - ?? hypokalemia, also impair skeletal muscle function

Acute myopathy

develops over hours to days, often in relation to an alcoholic binge characterized by weakness, pain, tenderness, and swelling of affected

muscles. ?? fasting during a binge may precipitate muscle injury majority are men Proximal most severely involved, but can be asymmetric or focal. Dysphagia and CCF may occur Laboratory findings- moderate to severe elevation of CK, myoglobinuria, EMG- fibrillations and myopathic changes Biopsy - muscle fiber necrosis on biopsy Treatment is directed at correcting cardiac arrhythmias, renal failure due to

rhabdomyolysis, and electrolyte distr. Abstinence - gradual, often partial, recovery

Chronic alcoholic myopathy

evolves over weeks to months, is more common Pain < than in acute alcoholic myopathy, but muscle cramps may occur. Examination major findings are muscle weakness and atrophy, which affect

predominantly hip and shoulder girdles polyneuropathy coexists in many But clinical and laboratory features indicate a primary disturbance of muscle. Serum CK < in acute alcoholic myopathy, and myoglobinuria does not occur. Cessation improvement, continued alcohol abuse clinical deterioration

Hepatic encephalopathy

Clinical triadWest Haven stages of hepatic encephalopathy & Rx

Stroke

Light to moderate use (up to two drinks a day for men and one for

women)

elevates HDL concentration and reduced risk

heavy alcohol consumption - increased risk for total stroke.

cardiogenic brain embolism.

Increased risk for hemorrhagic stroke

alcohol-induced hypertension predisposes to spontaneous ICH

active drinkers - higher freq. OSA with more severe hypoxemia.

recommended to cease or reduce consumption for heavy drinkers.

Headache- Immediate or delayed

May trigger cluster headache Immediate alcohol related headache:- Defined by HIS

Occuring within 3 hrs of ingestion, resolving within 72 hrs of cessation of alcohol

Atleast one of the following: Bilateral Fronto-temporal Pulsatile Aggravtion by physical activity

Amount independent of previous h/o migraine Delayed headache:

Same character, but occurs when blood alcohol level drops or reduces to zero

Brain tumor

Because beer and liquor contain nitrosamines, ?? Alcohol may increase the risk However, no consistent association between different types of alcohol and risk

of gliomas or meningiomas in childhood (maternal consumption) or adulthood.

References

Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL. Bradley's neurology in

clinical practice. Elsevier Health Sciences; 2015 Oct 25.

McIntosh C, Chick J. Alcohol and the nervous system. Journal of Neurology,

Neurosurgery & Psychiatry. 2004 Sep 1;75(suppl 3):iii16-21.

Noble JM, Weimer LH. Neurologic complications of alcoholism.

CONTINUUM: Lifelong Learning in Neurology. 2014 Jun 1;20(3, Neurology of

Systemic Disease):624-41.

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