2.3: 12. Toxic Metabolic Disease, Salloway

Front 1

Delirium definition and vulnerabilities

Back 1

-Latin for “off the track”
-Acute confusional state.
-Vulnerability to Delirium: Advanced age
-Underlying cognitive impairment or brain disease
-Sleep and sensory deprivation/unfamiliar environment
-Complicated medical and psychiatric problems and multiple medications

Disturbance of mental function that usually involves a diffuse impairment of cortical function with impaired speed, clarity, and coherence of thinking

Front 2

Clinical features of delirium

Back 2

-Usually involves a diffuse impairment of cortical function with impaired speed, clarity,and coherence of thinking.
-Focal neurological findings may be present (hyperglycemia).
-More than one process may be occuring i.e. alcohol withdrawal and head trauma
-Acute delirium may mask an underlying dementia.
-Change in metal status, including:
waxing and waning arousal, psychomotor slowing,
confusion and disorientation, decreased attention and distractability, memory loss, irritability and agitation, restlessness or apathy, psychosis
- Possible associated symptoms: autonomic instability, tremor, asterixes, myoclonus, seizures, dysarthria, incoordination, hyperreflexia

Front 3

Evaluation questions for patients with delirium

Back 3

-Is the process focal, multifocal or diffuse?
-Acute, subacute or chronic
-Trace the history with knowlegeable informants
(a lot can be done by careful observation of the patient and by asking common sense questions)

Front 4

Levels of consciousness

Back 4

-Coma
-Persistent vegitative state
-Locked-in syndrome
-Akinetic mutism
-Stupor
-Confusional state, lethargy, delirium, encephalopathy

Front 5

Causes of encephalopathy

Back 5

-Toxins-Alcohol, street drugs and prescription medications, heavy metals Withdrawal states
-Electrolyte, metabolic and endocrine disturbance
-Nutritional deficiencies, dehydration
-Hypoxia
-Infectious and inflammatory disease
-Neurological disorders-Head trauma, stroke, seizures, dementia
-Other-Unfamiliar environment

Front 6

Values of metabolic homeostasis and causes/issues associated with changes in these values

Back 6

Sodium < 127 meq/dl, >150 meq/dl, central pontine or extrapontine myelinolysis

Glucose < 40 mg/dl, > 450 mg/dl

Calcium < 7.5 mg/dl, >12 mg/dl, tetany, involuntary muscle contractions

Magnesium <1.0 mg/dl, particularly < 0.6 mg/dl, tremor, seizure

Ammonia > 80 mg/dl, particularly >100 mg/dl

pCO2 > 60 mm

BUN/Cr, thyroid function, CO2 response depends upon chronic adaptation

Alcohol Intoxication: Withdrawal tremor, Delerium tremens, seizures, hallucinosis

Electrolyte, nutritional disturbance: Wernicke-Korsakoff, Dementia, Ataxia, Peripheral neuropathy

Front 7

What examination steps do you perform bedside if you suspect delirium?

Back 7

Mental Status: Level and variability of alertness
MMSE- Mini Mental Status Exam reproducible bedside test of mental status
Orientation-name, place, floor, month, year, day of the week, season
Awareness- reason for hospitalization, can they control their behavior?
Attention-do they have a hard time staying on one task or maintaining their train of thought? Test digit span or WORLD forwards and backwards
Memory-3 simple objects immediately and after a few minutes delay Thought process-are thoughts organized or rambling?
Speech-Is speech fluent? Is comprehension normal? Is aphasia present?
Naming-3 simple objects
Spatial-show 2 fingers on the right hand, take the right hand and touch their left ear, have them put numbers on the face of a clock and set the time ten past three.
Abstraction-What does it mean," don't cry over spilt milk?"
Praxis-Getting dressed, doing simple things in their room
Perceptual disturbance-are they paying attention to extraneous stimuli? If so, do they think it is really going on?

Cranial nerves-test for nystagmus, pupillary dysfunction and dysarthria. abnormalities. i.e. unilateral weakness

Motor-Irritability, abnormal movements, tremor, asterixes, weakness

Coordination-finger to nose, thumb to finger, Romberg

Gait-a great neurological test

Front 8

Diagnostic tests for delirium

Back 8

Screening labs: Complete blood count (CBC), Electrolytes, magnesium, calcium, BUN/creatinine, liver function tests, ammonia, toxicology screen

Possibly- Thyroid function tests (T3. T4, TSH, etc), B12, folate, antinuclear antibodies (ANA), erythrocyte sedimentation rate (ESR), arterial blood gas (ABG), heavy metals, CSF cytology, computed tomography of the brain, EEG, MRI

Lumbar puncture don't forget to measure and record the opening pressure

Front 9

Treatment for delirium

Back 9

Correction of the underlying problem
Careful management of fluid and electrolytres
Safety and reassurance to patient. and family. Orient patient frequently.
Return to familiar surroundings as soon as possible
Low protein diet in hepatic and renal disease and bowel prep in hepatic disease Possibly benzodiazepines or neuroleptics
Experimental- benzodiazepine antagonists in hepatic disease, dopamine agonists Follow-up evaluation for underlying dementia

Front 10

List of Toxic and Metabolic Causes of Disorders of the Central Nervous System

Back 10

A. Organic Toxins (alcohol, organic solvents, etc)
B. Inorganic toxins (e.g., lead and other heavy metals)
C. Biologic toxins (e.g., snake venom, ciguatera)
D Pharmacologic toxicity (e.g., sedatives, anticonvulsants, antidepressants
E. Withdrawal states
F. Nutritional deficiencies (e.g., Vitamins B1, B6, B12)
G. Electrolyte imbalance (e.g., hyper- and hypo-natremia)
H. Metabolic encephalopathy secondary to organ failure (e.g., uremia, hepatic encephalopathy)
I. Encephalopathies secondary to endocrine disorders (e.g., hypothyroidism, hyperparathyroidism)

Front 11

When a confused alcohol patient comes into the ED, what potential causes should you investigate?

Back 11

-intoxication
-delirium tremens
-post-ictal confusion after a withdrawal seizure
-a global confusional state presaging the Wernicke-Korsakoff syndrome due to thiamine deficiency
-hypoglycemia, hypothermia, hyponatremia, hepatic encephalopathy or any combination of these.
-head trauma and meningitis are more frequent in alcoholics
-other exogenous toxins: alcohol and sedatives are often abused together
-Destitute alcoholics may seek alcohol from cheap alcohol containing substances and risk, for
example, blindness and brain damage from ingestion of methyl alcohol
- In some areas where moonshine whiskey is made in stills from old plumbing, lead poisoning may lead to encephalopathy (moonshine madness) or a peripheral neuropathy (e.g., wrist drop)

Front 12

Main toxic and nutritional disorders associated with alcohol abuse

Back 12

A. Intoxication and alcoholic “blackouts”
B. Alcoholic dementia
C. Withdrawal states (tremulousness, hallucinosis, seizures, “delerium tremens”)
D. Thiamine and/or niacin deficiency (Wernicke-Korsakoff complex): Ophthalmoparesis, Global confusional or amnestic state, “Cerebellar” ataxia, Peripheral neuropathy
E. Hepatic failure

Front 13

Alcohol intoxication: metabolism, clinical effects and tolerance/addiction

Back 13

Metabolism: rapidly absorbed from the G.I. tract. Metabolized by the liver to acetaldehyde by alcohol dehydrogenase; NAD is required as a co-factor and is reduced to NADH

Clinical effects: Euphoria and disinhibited behavior, Mild incoordination evident (c.a. 50 mg/dl), Ataxia of gait (c.a. 100 mg/dl), Confusion (c.a. 200 mg/dl), Stupor (c.a. 300 mg/dl), Coma (c.a. 400 mg/dl), May be fatal (L.D. 50 = 500 mg/dl)
Individuals may be amnestic for events during intoxication -- so-called "alcoholic blackouts"

Tolerance and addiction: with regular and protracted alcohol use, the dose (and blood level) required to achieve the same clinical effects gradually increases. The cycle of increasing tolerance and physical dependence proceeds to addiction.

Front 14

Alcoholic dementia: location in the brain, cause, difference between this and Wernicke-Korsakoff, accompanied findings, reversibility

Back 14

Location: Chronic alcohol abuse can lead to the development of a progressive dementia which takes the form of a "frontal lobe" syndrome with poor judgement, inappropriate behavior, apathy and perseveration.

Cause: This dementia seems most likely due to the direct toxic effects of alcohol on the cerebral cortex.

W-K: It should be distinguished from the amnestic syndrome of the Wernicke-Korsakoff complex (see below) which is caused by the associated nutritional thiamine deficiency.

Associated findings: Alcoholic dementia is frequently accompanied by lobar atrophy of the frontal lobes on CT disproportionate for the patient's age.

Reversibility: Early in the course, both cognitive impairment and atrophy may be at least partially reversible with abstinence from alcohol.

Front 15

Withdrawal states

Back 15

1. Tremulousness -- the most common withdrawal symptom, "the shakes," often begin "the morning after." If alcohol is not ingested to quiet the tremor, they steadily increase and peak in 24 - 36 hours. They are often associated with nausea which may prevent drinking and precipitate the further evolution of the abstinence syndrome.
The tremor is fast, postural (e.g., when the hands are outstretched) and can involve all four limbs. There is associated irritability, insomnia, gastrointestinal distress. Tachycardia is present, the face is flushed and the conjunctiva are injected.

2. Hallucinosis -- about 25% have hallucinations. They may begin as "bad dreams," but then manifest during wakefulness. Visual hallucinations, especially of animate creatures, are most common, but they may occur in auditory or any other modality. Usually the sensorium is otherwise clear; the patient is not confused or disoriented and usually knows that the hallucinations are not "real."

3. Delirium tremens -- the symptom complex described above -- tremulousness, sympathetic hyperactivity, insomnia and hallucinations -- is a harbinger of delirium tremens. The term should be reserved to describe a more severe and ominous (c.a. 15% mortality) abstinence syndrome in which these symptoms are very severe with florid confusion and disorientation - i.e. delirium. This syndrome usually begins 3 - 4 days after the cessation of drinking but can begin even later.

4. Seizures ("Rum Fits") -- occur 6 - 48 hours after cessation of drinking with peaking at about 24 hours. These are generalized "grand mal" convulsions. Focal onset should suggest an underlying structural CNS lesion. There may be a single seizure or a flurry of several over the period of a few hours. Rarely, status epilepticus occurs. The EEG is usually normal. Focal slowing or epileptic abnormalities on the EEG should prompt a search for some other cause of seizures.

Front 16

Pathogenesis of Wernicke-Korsakoff Syndrome

Back 16

-Malnutrition is common in alcoholics --> state of negative nitrogen balance and deficiencies of multiple vitamins.
-Available thiamine is necessarily used to metabolize alcohol, further depleting thiamine stores. A co-factor for several enzymes involved in carbohydrate metabolism, thiamine deficiency produces a diffuse decrease in brain glucose utilization.
-This leads to impaired neural function and, if prolonged, necrosis of susceptible regions: the periventricular regions of the brain stem and diencephalons, the anterior lobe of the cerebellum.
-Although most commonly seen in alcoholics, the Wernicke-Korsakoff Syndrome can occur in any condition leading to thiamine deficiency: (eg. cachexia from cancer; starvation from gastric stapling for obesity; anorexia, etc.)
-In classic thiamine deficiency, "Beri-Beri," neurologic symptoms are accompanied by high output cardiac failure. Alcoholics with Wernicke-Korsakoff Syndrome encountered in civilian practice seldom have florid congestive; nevertheless, tachycardia, orthostatic hypotension and exercise intolerance are frequent signs of cardiovascular embarrassment.
-Wernicke-Korsakoff Syndrome has often been an iatrogenic illness: Administration of glucose containing IV fluids without co-administration of thiamine to thiamine-depleted alcoholics causes acute depletion of remaining stores of thiamine to metabolize the glucose.
***ALWAYS GIVE THIAMINE AND MULTIVITAMINS TO ANY ALCOHOLIC OR MALNOURISHED INDIVIDUAL.***
***NEVER START AN INTRAVENOUS SOLUTION WITH GLUCOSE WITHOUT GIVING THIAMINE TO ANY INDIVIDUAL WHO MAY BE MALNOURISHED OR AN ALCOHOLIC.***

Front 17

Pathology of Wernicke-Korsakoff Syndrome

Back 17

necrotic degeneration, occasionally with petechial hemorrhages and reactive gliosis in the diencephalon (the dorsomedial nucleus of the thalamus and the mammillary bodies) causes the mental disorders (global confusional state evolving into the classic amnestic syndrome). Lesions in the periventricular regions of the midbrain and pons cause oculomotor dysfunction. Lesions in the medulla affect the vestibular nuclei contributing to the gait.

Front 18

Clinical signs and symptoms of Wernicke-Korsakoff Syndrome

Back 18

1) Opthalmoparesis: isolated or with any other manifestations; sensitive to therapy, gets better with thiamine given; nystagmus + paresis of conjugate gaze (horiz > vertic) and CNVI weakness; CNIII NOT COMMON

2) Korsakoff Amnesia: dorso-medial nuc of thalamus/mammillary bodies --> unable to learn or remember new info, but other cognitive operations preserved; occurs more slowly, 20-25% left with severe, permanent amnesia

3) Acute confusional state: begins with this, associated with withdrawal

4) Alcoholic cerebellar degeneration: cerebellar degeneration, individual vulnerability important; effects cerebellar cortex; anterior lobe or vermis (hemispheres spared); truncal ataxia, balance poor; acute, improves with time; repeated episodes --> chronic, disabling, damage to cortex in all layers

4) Peripheral neuropathy: common; absent ankle reflexes, dec. pain in feet, stocking-glove paresthesisas, muscles tenderness; distal motor impairment if severe

Front 19

Niacine deficiency

Back 19

(Pellagra)
-Triad: "dermatitis, dementia, diarrhea" progressing to death
-Co-exists with other nutritional deficiencies
-Can --> Wernicke-Korsakoff

Front 20

Pyridoxine (B6) deficiency

Back 20

Cause of neonatal seizures
Babies are irritable, startle easily, convulsions
Inherited metabolic error in ability to use vitamin OR inadequate dietary intake; reduces GABA in brain
Severe retardation & spastic quadriparesis if not treated
Surplus of B6 -- necrosis of dorsal root ganglion, sensory neuropathy

Front 21

B12 deficiency

Back 21

-Subacute combined degeneration of spinal cord
-Pathogenesis: rarely due to malnutrition; impaired absorption due to lack of gastric intrinsic factor, veggie diet, tropical sprue, bowel bacteria overgrowth, tapeworm;
-CNS path: demyelinating degeneration extending thru lateral and dorsal columns of spinal cord - Subacute Combined Degeneration of the Spinal Cord - accounts for gait disorder which is a cardinal neurologic sign; spinal cord + peripheral nerves + brain affected (can have mental deterioration)
- Clinical: parasthesias, ataxia (bad proprioception, long tracks in spine effected, + Romberg), mental deterioration (subacute, dramatic w/ marked sudden personality changes)
-Diagnosis/treatment: demonstrate lo levels of B12, give B12 for rest of life; may be reversible

Front 22

Signs that are common to all metabolic encephalopathies

Back 22

- altered mentation: spectrum ranges from somnolence and apathy to delirium, psychosis or coma
- seizures: common in all
- abnormal movements: tremor & multifocal myoclonus
- asterixis: distinctive sign; unable to maintain voluntary muscular contractions; hold arms outstretched with wrists extended produces flapping motion instead of steady
- Electroencephalographic abnormalities: hallmark on EEG is slowing posterior background rhythm

Front 23

Electrolyte disturbances: Sodium, Calcium and Magnesium

Back 23

1) Sodium: dehydration, diabetes insipidus from hypothalamus lesions, iatrogenic causes; most freq iatrogenic b/c of diuretics or Syndrome of Inappropriate Antidiuretic Hormone Secretion or psychogenic polydipsia b/c of mental retardation; delirium --> coma, seizures common; central pontine myelinolyis caused by excessive correction of hyponatremia (stupor, quadriparesis, bulbar dysfunction, death)

2) Calcium: hypoparathyrodism--> HYPOcalcemia; tetany, irritability & seizures; HYPER: caused by hyperparathyroid, met. cancers, sarcoid; psychosis, delirium, other derangements

3) Magnesium: hypo- is similar to hypocalcemia - twitching, irritability, delirium, seizures, occasionally abnormal involuntary movements, tremor, chorea

Front 24

Metabolic encephalopathies due to organ failure: 1) pulmonary failure 2) hepatic encephalopathy 3) uremia

Back 24

1) pulmonary failure: hypoxia causes somnolence, confusion; dyspnea is caused by hypercapnia (also causes headache); in COPD, CO2 respiratory drive may be lost, patients develop severe CNS depression w/o overt respiratory distress
2) Hepatic encephalopathy: port-systemic shunting --> absorption of intestinal amino acid metabolites into circulation; somnolence, agitation, confusion, delirium, prominent asterixis, hyperactive DTRs, Babinksi --> coma, generalized flaccidity; seizures; EEG slow backgrnd and b/l hi amp triphasic waves; hard to diagnose in patients with lo level chronic liver disease who may have normal liver enzymes; treat with protein restriction, elimination of protein with lactulose, sterilization of gut flora w/ neomycin; permanent structural CNS lesions and chronic progressive cerebral degeneration w dementia, dysarthria, myoclonus, ataxia w spastic quadriparesis, extrapyramidal signs
3) uremia: chronically --> lethargy, confusion, delirium, seizures, coma reversible with dialysis; but do it slowly or else disequilibium syndrome; chronic dialysis dementia now rare causes death in motnhs - pruritus, twitching, myoclonus, confusion --> irreversible dementia; also risk for electrolyte and Ca derangements, cerebrovascular insults related to hypertension, coagulopathy, accelerated atherosclerosis, anemia, CNS infections