1. Acute toxic-metabolic encephalopathy in adults

2. Introduction Confusion : the inability to maintain a coherent stream of thought or action Delirium : a confusional state with superimposed hyperactivity of the sympathetic limb of the autonomic nervous system (tremor, tachycardia, diaphoresis, and mydriasis) Acute toxic-metabolic encephalopathy (TME) –delirium and the acute confusional state –an acute condition of global cerebral dysfunction in the absence of primary structural brain disease

3. Most TME is reversible, making prompt recognition and treatment important. Certain metabolic encephalopathies –ex: sustained hypoglycemia and thiamine deficiency (Wernicke's encephalopathy) –may result in permanent structural brain damage if untreated.

4. PATHOPHYSIOLOGY Normal neuronal activity requires –a balanced environment of electrolytes, water, amino acids, excitatory and inhibitory neurotransmitters, and metabolic substrates. –normal blood flow, normal temperature, normal osmolality, and physiologic pH All forms of TME interfere with the function of the –ascending reticular activating system and/or –its projections to the cerebral cortex=> impairment of arousal and/or awareness.

5. The pathophysiology of TME varies according to the underlying etiology: Cerebral edema contributes to acute fulminant hepatic encephalopathy and to hypoosmolar encephalopathies. Drug-induced delirium results from disruption of the normal integration of neurotransmitters, including dopamine, acetylcholine, glutamate, gamma-aminobutyric acid (GABA), and/or serotonin. Electrolyte derangements alter membrane excitability to produce TME. Nutritional disorders disturb cellular energy metabolism and may result in neuronal death. Exogenous toxins, including carbon monoxide and cyanide, cause impaired oxygen delivery and mitochondrial dysfunction.oxygen

6. CLINICAL MANIFESTATIONS Most clinical features of TME are nonspecific, and do not reliably identify a particular etiology. TME is common among patients admitted to an ICU –Older patients + underlying dementia : greatest risk –A single center study –Delirium : 31 % at ICU (> 65 y) -> 70 % of this population (during hospitalization) The presence of delirium is an independent risk factor for six-month mortality and prolonged hospitalization in patients receiving mechanical ventilation.

7. Mental status examination The cardinal feature : impaired attention –Range : subtle cognitive difficulties - florid delirium or coma –Test attention : simple bedside tasks (serial subtraction, naming the months of the year in reverse) –Marked fluctuations in mental status over time are characteristic. Other common findings : –a disturbed sleep-wake cycle –decreased alertness –hallucinations –sensory misperceptions, impaired memory, and disorientation

8. The thought process is often disorganized –manifested by confused or rambling conversation –Paranoid ideation and excessive suspiciousness may occur. Affect is also compromised in TME –apathetic and withdrawn –anxious, agitated, and fearful –Manic The level of alertness reflects the severity of the underlying condition; severely affected patients are comatose.

9. Cranial nerve examination Almost all causes of TME manifest –preservation of pupillary function (even if the pupils are pinpoint) Except : anticholinergic drug or glutethimide(hypnotics) ingestion –Ocular motility remains intact Except : Bell's phenomenon : in comatose patients the eyes may rove randomly and come to rest in a dysconjugate position with upward and outward gaze deviation bilaterally Other brainstem reflexes generally are only affected in severe TME. –Oculocephalic reflex (doll's eye reflex) –Corneal reflex –Gag reflex –Occasional patients with Wernicke's encephalopathy or barbiturate overdose may lose brainstem reflexes, which can mimic death by brain criteria.

10. Motor examination A variety of motor abnormalities may be observed in patients with TME: Tremor is common : coarse and irregular at a rate of 8-10 cycles/s Asterixis, first described in hepatic encephalopathy, is now appreciated to be common to many forms of TME. –almost always bilateral –unilateral asterixis (or any asymmetric response) suggests an occult structural lesion Multifocal myoclonus is common in TME –characterized by sudden, nonrhythmic, gross muscle twitching, particularly involving the face and proximal muscles Other common abnormalities include –paratonia ( 근육긴장병증 / 변속저항증 ), primitive reflexes, brisk deep tendon reflexes, and extensor plantar responses. –In severely obtunded subjects, decorticate and decerebrate posturing can occur.

11. DIAGNOSIS a diagnosis of exclusion within a broad differential diagnosis

12. GENERAL MANAGEMENT Discontinuation of all drugs with potential toxicity to the CNS. Haloperidol IV to treat severe agitation;Haloperidol –elderly subjects usually require only small doses, such as 0.5 mg BID/Day. –IV haloperidol has been associated with clinically significant QT prolongation requiring additional precautions regarding its use. Thiamine should be administered to patients with a history of alcoholism, malnutrition, cancer, hyperemesis gravidarum, or renal failure on hemodialysis.Thiamine

13. SPECIFIC ETIOLOGIES

14. Septic encephalopathy Most common cause of acute TME Its presence and severity correlate with increased mortality. The pathophysiology of septic encephalopathy is multifactorial. –Microcirculatory abnormalities, altered blood-brain barrier permeability, inflammatory cytokines, reductions in monoamine NT(neurotransmitters) –Ischemia secondary to in situ thrombosis in other organs in sepsis A lumbar puncture may be entirely normal or show an elevated protein concentration. The EEG is usually diffusely slow –As the encephalopathy worsens there may be triphasic waves, and a burst-suppression pattern in severe cases –Diffuse muscle weakness due to coexistent polyneuropathy is found in up to 70 % of pts.

15. Hepatic encephalopathy Two forms of hepatic encephalopathy are recognized. –Acute HE associated with marked cerebral edema is seen in patients with the acute onset of hepatic failure. –Chronic HE occurs in subjects with chronic liver disease and portosystemic shunting of blood. The pathophysiology of HE is multifactorial –increased ammonia concentration –false neurotransmitters –endogenous benzodiazepine-like substances –abnormal fatty acid metabolism –free radical damage –cerebral edema –increased mercaptans

16. N/Ex –However, if the patient is comatose, false localizing signs such as hemiparesis, ocular bobbing, dysconjugate eye movements, and tonic downward deviation of the eyes may appear => suggesting a focal or structural lesion

17. Uremic encephalopathy TME is a sign of advanced renal failure. Encephalopathy typically occurs –later in younger, otherwise healthy patients –sooner in older patients or those with underlying central nervous system disease. Brain amino acid metabolism also may be impaired –causing an imbalance between excitatory and inhibitory neurotransmitters, or –the accumulation of false neurotransmitters such as methylguanidine and "middle molecules”.

18. Early clinical features of uremic encephalopathy include lethargy, irritability, disorientation, hallucinations, and rambling speech. Coma is unusual but may occur in patients with acute renal failure. Most uremic patients have mild diffuse weakness and show unsteadiness in their movements. Tremor, myoclonus, and asterixis are common and tend to vary in parallel with mental status; tetany may be present.

19. Rarely, focal signs such as hemiparesis or reflex asymmetry may occur. Such focal signs tend to be transient, alternate from side to side, and resolve with hemodialysis. Generalized seizures may occur, particularly when uremia is acute, and myoclonus, psychosis, and coma can also be seen. The EEG in uremia reflects the severity of encephalopathy. –The most common EEG finding is prominence of slow waves.

20. Neuroimaging may be required to exclude the presence of a subdural hematoma. Acute uremic encephalopathy reverses with dialysis, although a lag time of 1 to 2 days usually is required before mental status clears. Subtle cognitive difficulties may persist even after dialysis in patients with chronic renal failure. Failure to improve substantially following dialysis should alert the physician to other possible etiologies of encephalopathy.

21. Wernicke's encephalopathy –Due to dysfunction of central gray structures surrounding the third and fourth ventricles secondary to thiamine deficiency –Predisposing factors: fasting, TPN, GI surgery, being fed after a period of starvation, hemodialysis, or advanced cancer –Triad : confusion, ataxia, and ophthalmoplegia –Ocular signs : hallmark of the disease (horizontal nystagmus, bilateral abducens palsy, complete ophthalmoplegia, and pupillary abnormalities) –Apathy, impaired awareness, disorientation, mental sluggishness, and restlessness

22. Post-transplantation encephalopathy –underlying conditions, operative procedures, –immunosuppressive medications –opportunistic infections

23. Cyclosporine : somnolence, headache, dysarthria, depression, and visual hallucinations. Neurologic complications of cyclosporine toxicity are often associated with a characteristic posterior leukoencephalopathy which is reversible.Cyclosporine Tacrolimus (FK 506) : anxiety, tremor, vivid nightmares, and restlessness.Tacrolimus Corticosteroids : insomnia, irritability, impaired concentration, and mood changes including a florid steroid psychosis. (substituting dexamethasone) Corticosteroidsdexamethasone –Affective symptoms may respond to lithium.lithium OKT3 : acute aseptic meningitis with seizures, fever, lethargy, increased muscle tone, myoclonus, and a diffuse encephalopathy with cortical blindness.OKT3 –Imaging studies may show mild cerebral edema. –Anti-thymocyte and antilymphocyte globulins can produce a similar encephalopathy.

24. Infection : 5 to 10 %of all transplant recipients develop a CNS infection –Some may present with encephalopathy without meningeal signs or focal deficits. –Listeria, Toxoplasma, Varicella zoster virus, Strongyloides stercoralis, and Cryptococcus neoformans tend to present with encephalitis, mimicking TME.

25. PROGNOSIS Acute TME as a fully reversible event However, severe TME(coma) is a marker for significant morbidity and mortality. Poor outcomes : –Absent corneal or pupillary response at 24 hours –Motor response poorer at three days –Absent roving eye movements at seven days

26. Among unselected patients followed after discharge from ICU, significant, persistent neurological and psychiatric disturbances are prevalent, in 32 %. –Cognitive impairment is usually diffuse, but more prominent in the areas of psychomotor speed, verbal fluency, visual and working memory, and visuoconstruction abilities –Depression occurs in up to 36 % of patients discharged from the ICU. –Duration of delirium during the acute hospital stay is longer among patients that develop neuropsychological impairment. –Advanced age, low premorbid intelligence, cerebrovascular and peripheral vascular disease, and hypoxia are also risk factors The end. 감사합니다.