ENCEPHALOPATHYDr.Muhammad Yusuf,SpS

DefinisiEncephalopathy adalah istilah yang berarti penyakit, kerusakan, atau malfungsi otak.

> Gejala ringan : kehilangan memori, perubahan kepribadian

> Gejala berat : dementia, seizures, koma, atau kematian.

Encephalopathy dimanifestasikan oleh keadaan mental yang berubah dan adakalanya bersamaan oleh manifestasi-manifestasi fisik (koordinasi yang buruk dari gerakan-gerakan anggota tubuh).

Penyebabinfeksi-infeksi (bakteri, virus,parasit, atau prions), anoxia (kekurangan oksigen pada otak), alkohol, gagal hati, gagal ginjal, penyakit metabolik, tumor otak, kimia Perubahan pada tekanan dalam otaknutrisi yang buruk.

Gejala-GejalaKeadaan mental yang berubahkelesuan, dementia, seizures, tremor-tremor, kejang otot, dan koma.

Diagnosa Encephalopathy Status mental, tes memori, tes koordinasi Complete blood count (CBC ) , infeksi, Tekanan darahPemeriksaan metabolik (elektrolit, glucose, lactate, ammonia, oksigen, dan enzim hati) Obat-obatan atau racun (alkohol, cocaine, amphetamines, DLL) Kultur darah dan cairan tubuh (infeksi) Creatinine (fungsi ginjal) CT dan MRI scansDoppler ultrasoundEncephalogram atau EEGAuto-antibody

PenangananBervariasi tergantung penyebab primer yang mendasarinyaAnoxia : terapi oksigenKeracunan alkohol jangka pendek: cairan-cairan IV (intravena)Penyalahgunaan alkohol jangka panjang (sirosis atau gagal hati kronis: oral lactulose, diet rendah protein, antibiotik Uremic encephalopathy (gagal ginjal): mengkoreksi penyebab fisiologi yang mendasarinya, dialysis, transplantasi ginjal Diabetic encephalopathy: glucose hypoglycemiaHypo- atau hypertensive encephalopathy

Gejala dan KomplikasiHepatic (hati) encephalopathy pembengkakan otak dengan herniation, koma, kematianMetabolic encephalopathy sifat iritabel, kelesuan, depresi, gemetar; adakalanya koma atau kematian Anoxic encephalopathy perubahan kepribadian, kerusakan otak yang parah sampai kematian pada kejadian-kejadian anoxic jangka panjang) Uremic encephalopathy kelesuan, halusinasi, pingsan, kejang otot, seizures, kematian

Hashimoto's encephalopathy kebingungan, dementia Wernicke's encephalopathy kebingungan mental, memori, kemampuan yang berkurang untuk menggerakan mata Bovine spongiform encephalopathy atau "Mad Cow disease" ataxia, dementia dan myoclonus atau kejangShigella encephalopathy sakit kepala, leher yang kaku, delirium, seizures, komainfeksius dari pediatric encephalopathy lekas marah, anoreksia, hypotonia atau floppy baby syndrome, seizures, kematian

Hepatic Encephalopathy

Definition (1) Hepatic encephalopathy (HE) It represents a reversible decrease in neurologic function, based upon the disorder of metabolism which are caused by severe decompensated liver disease

Incidence/prevalence Universal feature of acute liver failure 50%~70% in chronic hepatic failure Difficult to estimate

Etiology Fulminant hepatic failure acute severe viral hepatitis, drug/toxin acute fatty liver of pregnancy Due to acute hepatocellular necrosis Chronic liver disease cirrhosis of all types (70%), primary liver cancer surgically induced portal-cava shunts Due to one or more potentially reversible precipitating factors

HE---common precipitating factorsUremia/azotemiaGastrointestinal bleedingDehydrationMetabolic alkalosisHypokalemiaConstipationExcessive dietary proteinInfectionSedative BenzodiazepinesHypoxiaHypoglycemiaHypothyroidismAnemia

NitrogenousEncephalopathyNon-NitrogenousEncephalopathy

Pathogenesis (1) Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver Caused by several factors act synergistically Several putative gut-derived toxins identified

Pathogenesis (2)Postulated factors/mechanisms:

Ammonnia neurotoxicity Synergistic neurotoxins Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis -Aminobutyric acid hypothesis

Ammonia neurotoxicity Ammonia production resulting from the degradation of urea or protein primary site: gut other site: kidney and skeletal muscles Gut-generating ammonia: 4g/day Equilibrium of ammonia and ammonium:

Ammonia neurotoxicity Ammonia elimination Transfer to the liver Metabolized by series of urea cycle enzymes Comsumpted by brain, liver, kidney: to synthesize glutamic acid and glutamine Excreted into the urine Eliminated by lung (trace amounts)

Ammonia neurotoxicity Over production and/or hypoeccrisis Poor hepato-cellular function: incomplete metabolism Portal-systemic encephalopathy: bypass Ammonia intoxication Interfere with cerebral metabolism: Depletion of glutamic acid, aspartic acid and ATP Depression cerebral blood flow and oxigen consumption

Ammonia neurotoxicity Elevation of ammonia: detected in 60%~80% Absolute concentration of ammonia, ammonia metabolites in blood or cerebrospinal fluids, correlates only roughly with the presence or severity of HE Few cases: within normal range

Synergistic neurotoxins Ammonia Mercaptans Short-chain fatty acids Phenols

Excitatory inhibitory neurotransmitterNeurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration of the precursor amino acids Increased aromatic amino acids (AAAs) Tyrosine Phenylalanine Tryptophan Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs) Valine Leucine Isoleucine Due to increased metabolism by skeletal muscle and kidneys or increased insulin

Excitatory inhibitory neurotransmitterImbalance of plasma amino acid: More AAAs enter into blood-brain barrier and CNS Decreased synthesis of normal neurotransmitters L-Dopa Dopamine Noradrenoline Enhanced synthesis of false neurotransmitters Octopamine Tryptophan Serotonin

- Aminobutyric acid hypothesis- Aminobutyric acid (GABA): Principle inhibitory neurotransmitters Generated in the gut by bacteria Bypasses the diseased or shunted liverGABA-receptor complex: Localized to postsynaptic membranes Key contributor to neuronal inhibition in HE GABA-ergic:25% ~ 65% of nerve endings Increased blood-brain barrier permeability Increased number of binding sites Endogenous ligands for the BZ receptor:unknown VEP = induced by BZ or barbiturate Substances in the brain: bind to BZ receptor GABA/BZs receptors antagonists:improve HE symptoms

- Aminobutyric acid hypothesis Endogenous ligands for the BZ receptor: unknown VEP = induced by BZ or barbiturate Substances in the brain: bind to BZ receptor GABA/BZs receptors antagonists: improve HE symptoms

Pathohistology Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral edema is likely the secondly changes In patients with chronic liver disease Astrocytes: increase in number and enlargement In a very long-standing case Thin cortex, loss of neurons fibers, laminar necrosis , pyramidal tracts demyelination

PathoPhisIology CT/MRI : - Cerebral atrophy related to the severity of the liver dysfunction - Marked in chronic persistent encephalopathy

Clinical manifestation In acute liver failure Spontaneously appearing Severe fatal hepatic dysfunction + abrupt mental deterioration + coma/death high fever ,tachycardia , tachypnea hyperventilation

Clinical manifestation In chronic liver disease

Insidious onset Characterized by subtle and/or intermittent changes in consciousness personality intelligence speech Disturbed consciousness: slowness, somnolence, disorientation, confusion deep coma Personality changes: childishness irritability Intellectual deterioration: inability to produce simple designs with blocks or matches Speech: slow slurred monotonous voice Flapping tremor (asterixis) Fetor hepaticus

Clinical manifestationCriteria for clinical stages

Personality and mental changes Abnormal EEG patterns Asterixis

Clinical stages of HE

Clinical stages of HE

Laboratory and other tests Serum ammonia Elevation of serum ammonia: 60%~80% particularly in chronic HE (with portosystemic shunting) Electroencephalogram (EEG) Severe slowing with frequencies in the theta and delta Evoked potentials Variation, lack of specificity and sensitivity

Differential diagnosis Hypoglycemia Uremia Diabetic ketoacidosis Nonketotic hyperosmolar syndrome Subdural hematoma Cerebrospinal infection

TreatmentStrategy for the management of HE Identify and correct the precipitating cause(s) Initiate ammonia-lowering therapy Minimize the potential medical complications of cirrhosis and depressed consciousness

Initiate ammonia-lowing therapyDietary protein restriction: In patients with chronic HE permanent protein restriction: 40~60g/D In patients with acute HE more restricted protein intake: < 40, 20, 10 or 0 g/D Relapse return to the former regime Vegetable protein in priority lower rate of ammonia production contain small amounts of methionine and AAAs

Initiate ammonia-lowing therapyAntibiotics Neomycin: 2~4g/D (4~6g/D) Litter is absorbed Impaired hearing or deafness (in long term use) Long term use (>1 month) is not advisable Metronidozol: 0.2g qid as effective as neomycin

Prognosis HE results from fulminant hepatic failure (FHF): Poor 20% survival rates HE results from chronic liver disease Short-term: better than FHF Long-term: guarded

Hypoxic encephalopathy

Brain perfusion15% of the resting cardiac output 20% of the total body oxygen consumption. 50 ml per minute for each 100 gm of tissueBreathing 10% O2 for 15 to 30 minutes increases the CBF by 35% Breathing 7% O2 (PaO2 35 mm Hg) for 15 minutes increases CBF by 75% Goetz: Textbook of Clinical Neurology, 2nd ed., Copyright 2003 Elsevier

Mekanisme hipoksik

The cause of hypoxic encephalopathyCurrent Opinion in critical care Volume 8(2)April 2002pp 115-120

Symptoms & signs of hypoxic encephalopathyNew skill learning and the processing of complex information are the most vulnerable to hypoxiaPaO2 80 mm Hg impaired dark adaptation55 to 45 mm Hg impaired learning and short-term memory 40 to 30 mm Hg loss of judgment, euphoria, delirium, and muscular incoordination twice light for visual perception < 25 to 20 mm Hg : consciousness is rapidly lostGoetz: Textbook of Clinical Neurology, 2nd ed., Copyright 2003 Elsevier

Myoclonus Delayed anoxic encephalopathyan unexplained phenomenon during recovery (1 to 4 weeks) from an anoxic insultirritability, confusion, apathy, and occasionally agitation or maniaserious mental and motor disturbances, diffuse rigidity, spasticity, weakness, a shuffling gait, incontinence, coma, and death after 1 to 2 weeks major pathological finding : cerebral demyelination. ParkinsonismCerebral palsyGoetz: Textbook of Clinical Neurology, 2nd ed., Copyright 2003 Elsevier Postanoxic encephalopathy syndroms

Treatment

Initial resuscitation and stabilization,Supportive treatment of hypoxic-ischemic Perfusion and Blood Pressure Managementfluid management, hypoglycemia and hyperglycemia treatment of seizures

Encephalopathy, Hypertensive

hypertensive encephalopathy to describe the encephalopathic findings associated with the accelerated malignant phase of hypertension.

Hypertensive crisis 1. hypertensive emergency : Acute or ongoing vital target organ damage, such as damage to the brain, kidney, or heart, in the setting of severe hypertension is considered a hypertensive emergency. It requires a prompt reduction in blood pressure within minutes or hours. 2. hypertensive urgency. The absence of target organ damage in the presence of severe elevation of blood pressure with diastolic blood pressure frequently greater than 120 mm Hg is considered hypertensive urgency, and it requires reduction in blood pressure within 24-48 hours.

The morbidity and mortality associated with hypertensive encephalopathy are related to the degree of target organ damage. Without treatment, the 6-month mortality rate for hypertensive emergencies is 50%, and the 1-year mortality rate approaches 90%.

Manifestasi klinikneurologic symptoms :headache, confusion, visual disturbances, seizures, nausea, and vomiting. Headaches are usually anterior and constant in nature. The onset of symptoms usually occurs over 24-48 hours, with neurologic progression over 24-48 hours.end organ damage. :Cardiovascular symptoms of aortic dissection, congestive heart failure, angina, palpitations, irregular heart beat, and dyspnea , Renal hematuria and acute renal failure

Physical examinationFunduscopic examination: papilledema, hemorrhage, exudates, and cotton-wool spots.Neurologic examination :neurological nonfocal deficits nystagmus to weakness ,mental status ranging from confusion to coma.vascular examinationOther target organ damage that may be found includes the following:Cardiovascular - S3, elevated neck veins, peripheral edema, murmurs, abdominal pulsations, and diminished pulsesRenal - Acute renal failure, pulmonary edema, and peripheral edemaPulmonary - Pulmonary edema, rales, and wheezes

TerapiMedical CareCBF ---60-90 mm HgLowering the mean arterial pressure by 25% and the diastolic blood pressure to 100-110 mm HgPharmacologic agents selected for use in hypertensive encephalopathy should have few or no CNS adverse effects. Avoid agents such as clonidine, reserpine, and methyldopa.