uremic encephalopathy...

Uremic Encephalopathy (UE)Uremic Encephalopathy (UE)

1.

Rusdidjas, Rafita Ramayati, Oke Rina dan Rosmayanti

Divisi Nefrologi Anak, Dept. Ilmu Kes. Anak FK-USU/ RSHAM

Medan

INTRODUCTION / PENDAHULUAN INTRODUCTION / PENDAHULUAN

�� Uremia (= Urine in the blood)Uremia (= Urine in the blood)�� the final stage of progressive Renal failure the final stage of progressive Renal failure �� the resultant multiorgan failurethe resultant multiorgan failure�� accumulating metabolites of proteins and amino acids and accumulating metabolites of proteins and amino acids and

concomitant failure of renal catabolic, metabolic, and concomitant failure of renal catabolic, metabolic, and endocrinologic processesendocrinologic processes

�� Uremic encephalopathy (UE) is one of many manifestations Uremic encephalopathy (UE) is one of many manifestations of renal failure (RF).of renal failure (RF).

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of renal failure (RF).of renal failure (RF).

Uremia:Uremia:Hasil akhir dari Renal failureHasil akhir dari Renal failure

Merupakan resultante dari gagal MultiorganMerupakan resultante dari gagal Multiorgan

Penumpukan hasil Metab. Protein, Asam amino danPenumpukan hasil Metab. Protein, Asam amino dan

Kegagalan klatabolik renal.Kegagalan klatabolik renal.

UE. Salah satu manifestasi Kegagalan ginjalUE. Salah satu manifestasi Kegagalan ginjal

AIMS of this paper:AIMS of this paper:

Talking aboutTalking about::

�� EtiologyEtiology

�� PatophysiologyPatophysiology

�� Clinical featuresClinical features

�� DiagnosisDiagnosis

TreatmentTreatment

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�� TreatmentTreatment

�� TUJUAN, membicarakan : Penyebab, Patofisiologi,TUJUAN, membicarakan : Penyebab, Patofisiologi,

�� Gejala Klinis, Diagnosis dan Pengobatan UE.Gejala Klinis, Diagnosis dan Pengobatan UE.

UEUE

�� USUALLY due to USUALLY due to

�� ARF (most difficult to treat / PALING SULIT DIOBATI)ARF (most difficult to treat / PALING SULIT DIOBATI)

�� CRFCRF

�� ESRDESRD

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�� ESRDESRD

SEMUA RENAL FAILURE SEMUA RENAL FAILURE �� MENGSAHILKANMENGSAHILKAN

--SISASISA--SISA METAB. PROTEIN mis UREUM, CREATININ,SISA METAB. PROTEIN mis UREUM, CREATININ,

URIC ACID, URIC ACID, DLL SUBSTANSDLL SUBSTANS �� MEMBUAT KELAINAN MEMBUAT KELAINAN

OTAK (= UE).OTAK (= UE).

Tabel 1. Beberapa substans lainnya sebagai Uremic Toxins,yang implikasinya merupakan toxisitas dari Uremic.1

---------------------------------------------------------------------------------1. Organic metabolit

Urea (cyanide)CreatinineGuanethidine

Aliphatic aminesPhenol dan aromatic amineUric acid

Oxalic acidMyoinositol2.3 Buthylene glycol

2. Peptides dan Protein Degradasi products

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2. Peptides dan Protein Degradasi productsMiddle moleculeAmono acidBeta1 mucroglubulines

3. EnzymesReninRibonucleaseLysozymes

4. HormonesParathyroid hormoneGlucagonGrowth hormonesCalcitonineNariuretic hormones

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Neurological complications in renal failureNeurological complications in renal failure

�� The incidence and severity of uremic encephalopathy, The incidence and severity of uremic encephalopathy, atherosclerosis, neuropathy and myopathy atherosclerosis, neuropathy and myopathy have have declineddeclined but many patients fail to fully respond to but many patients fail to fully respond to dialytic therapy.dialytic therapy.

�� Dialytic therapy or kidney transplantation induce Dialytic therapy or kidney transplantation induce neurological complicationsneurological complications..

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Dialytic therapy or kidney transplantation induce Dialytic therapy or kidney transplantation induce neurological complicationsneurological complications..

�� Insidens dan keparahan UE, atherosclerosis, Neuropati Insidens dan keparahan UE, atherosclerosis, Neuropati dan Myopati, dan Myopati, sudah menurunsudah menurun, tetapi banyak pasien yg , tetapi banyak pasien yg gagal dgn terapi dialysis.gagal dgn terapi dialysis.

�� Terapi dialysis dan Tranplantasi mengTerapi dialysis dan Tranplantasi meng--induksi kominduksi kom--plikasi neurologi.plikasi neurologi.

Pathophysiology of Uremic Encephalopathy..1Pathophysiology of Uremic Encephalopathy..1

�� Complex and poorly understoodComplex and poorly understood�� 1. Accumulation of metabolites1. Accumulation of metabolites�� 2. Disturbance of the intermediary metabolism2. Disturbance of the intermediary metabolism�� 3. Imbalance in excitatory and inhibitory 3. Imbalance in excitatory and inhibitory �� neurotransmitters neurotransmitters

�� 4. Hormonal disturbance4. Hormonal disturbance

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�� PATOFISIOLOGI UE: komplek dan sedikit yg PATOFISIOLOGI UE: komplek dan sedikit yg diketahui.diketahui.

�� 1.Ada penumpukan hasil metabolisme1.Ada penumpukan hasil metabolisme�� 2.Ada gangguan dari intermediari metabolisme2.Ada gangguan dari intermediari metabolisme�� 3.Imbalans antara perangsangan dan penghambatan 3.Imbalans antara perangsangan dan penghambatan

neuro transmiter.neuro transmiter.4.Ada ganggaun Hormon4.Ada ganggaun Hormon

��

Pathophysiology of uremic encephalopathy..2Pathophysiology of uremic encephalopathy..2

�� .Accumulation of numerous organic substances, e.g..Accumulation of numerous organic substances, e.g.�� 5. Uremic neurotoxins ,urea, guanidino compounds, uric acid, 5. Uremic neurotoxins ,urea, guanidino compounds, uric acid,

hippuric acid, various amino acids, polypeptides, hippuric acid, various amino acids, polypeptides, polyamines, phenols polyamines, phenols

�� 6. and conjugates of phenol, phenolic and indolic acids, 6. and conjugates of phenol, phenolic and indolic acids, acetone, glucuronic acid, carnitine, myoinositol, sulphates, acetone, glucuronic acid, carnitine, myoinositol, sulphates, phosphates and middle molecules.phosphates and middle molecules.

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phosphates and middle molecules.phosphates and middle molecules.

�� PENUMPUKAN Organik substans yg banyak:PENUMPUKAN Organik substans yg banyak:

�� 5. Uremic neurotoxins, uric acid, hipurric acid, ber 5. Uremic neurotoxins, uric acid, hipurric acid, ber bagai Amino acid, polypeptides, polyamines, bagai Amino acid, polypeptides, polyamines, phenol. danphenol. dan

�� 6. conjugate phenols, phenolic dan indolic acid 6. conjugate phenols, phenolic dan indolic acid acetone, glucorobic acid, carnitine, myoinositol, acetone, glucorobic acid, carnitine, myoinositol, sulfat, phosphate, dan molekul2 sedangsulfat, phosphate, dan molekul2 sedang..


�� 7. Guanidino compounds 7. Guanidino compounds �� guanidinosuccinic acid, methylguanidine, guanidine and guanidinosuccinic acid, methylguanidine, guanidine and

creatinine : highly increased in serum, CSF and braincreatinine : highly increased in serum, CSF and brain�� Inhibited responses to GABA and glycine (inhibitory amino Inhibited responses to GABA and glycine (inhibitory amino

acids)acids)�� Guanidinosuccinic acid : inhibits transketolase, a thiamineGuanidinosuccinic acid : inhibits transketolase, a thiamine--

dependent enzyme of the pentose phosphate pathwaydependent enzyme of the pentose phosphate pathwayInhibition of transketolase : demyelinative changes to both Inhibition of transketolase : demyelinative changes to both

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dependent enzyme of the pentose phosphate pathwaydependent enzyme of the pentose phosphate pathway�� Inhibition of transketolase : demyelinative changes to both Inhibition of transketolase : demyelinative changes to both

central and peripheral nervous systemcentral and peripheral nervous system�� Methylguanidine : seizures and uremic twitchMethylguanidine : seizures and uremic twitch--convulsive convulsive

syndromesyndrome

�� 7. GUANIDINO COMPUNDS, meningkat dlm serum, peng 7. GUANIDINO COMPUNDS, meningkat dlm serum, peng hambat GABA (Gamma Amino Butyric Acid) dan glycinehambat GABA (Gamma Amino Butyric Acid) dan glycine

�� Penghambat jalur transketolase dan menghambatPenghambat jalur transketolase dan menghambat��perobahan demyelinasi dari syaraf sentral dan perifer. perobahan demyelinasi dari syaraf sentral dan perifer. Methylguanine Methylguanine �� kejang, twiching.kejang, twiching.


�� 8.Decrease in brain metabolic function8.Decrease in brain metabolic function

�� Increased levels of creatine phosphate, adenosine triphosphat(ATP) and glucoseIncreased levels of creatine phosphate, adenosine triphosphat(ATP) and glucose

�� Decreased levels of monophosphate(AMP), adenosine diphosphate(ADP) and Decreased levels of monophosphate(AMP), adenosine diphosphate(ADP) and lactatelactate

9.Activation of the excitatory N9.Activation of the excitatory N--methylmethyl--dd--aspartate receptors and concomitant inhibition aspartate receptors and concomitant inhibition of inhibitoryGABA(A)ergic neurotransmissionof inhibitoryGABA(A)ergic neurotransmission

88. Fungsi Brain Metabolik berkurang . Fungsi Brain Metabolik berkurang ��

meningkat; creatin phosp. ; ATP; Glukosa, meningkat; creatin phosp. ; ATP; Glukosa,

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meningkat; creatin phosp. ; ATP; Glukosa, meningkat; creatin phosp. ; ATP; Glukosa,

Berkurang : monop[hosphate AMP; ADP dan LactoseBerkurang : monop[hosphate AMP; ADP dan Lactose

9. Aktifasi reseptor N9. Aktifasi reseptor N--methylmethyl--dd--aspartat dan bersamaan dgnaspartat dan bersamaan dgn

inhibisi GABA [Gamma Amino Butyric Acid) (A)lergeic inhibisi GABA [Gamma Amino Butyric Acid) (A)lergeic

neurotransmissionneurotransmission


�� 10. Hormonal disturbances10. Hormonal disturbances

�� parathyroid hormone, insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing parathyroid hormone, insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing hormone and gastrin are elevatedhormone and gastrin are elevated

�� PTH : promote the entry of calcium into neuronsPTH : promote the entry of calcium into neurons

�� Calcium : essential mediator of neurotransmitter release and plays a major role in Calcium : essential mediator of neurotransmitter release and plays a major role in intracellular metabolic and enzymatic processesintracellular metabolic and enzymatic processes

→ → disrupt cerebral functiondisrupt cerebral function by interfering with any of these processes.by interfering with any of these processes.

10. Gangguan Hormonal. 10. Gangguan Hormonal.

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10. Gangguan Hormonal. 10. Gangguan Hormonal.

Meningkat : PTH; Insulin; Growth Hormon; Glucagon; Thyrotoxin; Meningkat : PTH; Insulin; Growth Hormon; Glucagon; Thyrotoxin;

Prolactin; Luteinizing hormon; dan Gastrin.Prolactin; Luteinizing hormon; dan Gastrin.

PTH : Mendesak masuknya Ca kedalam Neuron. Ca adalah mediato PTH : Mendesak masuknya Ca kedalam Neuron. Ca adalah mediato

essential utk neurotransmitter.essential utk neurotransmitter.

�� merusak fungsi CEREBRUMmerusak fungsi CEREBRUM oleh karena salah satu oleh karena salah satu

proses tersebut diatas (1proses tersebut diatas (1--10)10)

Incidence Incidence

�� The prevalence of UE is difficult to determine. The prevalence of UE is difficult to determine. �� Depends on the number of ESRD patientsDepends on the number of ESRD patients

�� In the 1990s : > 165,000 people In the 1990s : > 165,000 people

�� In the 1980s : 158,000 In the 1980s : 158,000

�� In the 1970s : 40,000In the 1970s : 40,000

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�� In the 1970s : 40,000In the 1970s : 40,000

�� As the number of patients with ESRD increased, As the number of patients with ESRD increased, presumably so did the number of cases of UE. presumably so did the number of cases of UE.

�� Sex: Incidences are equal in men and woman. Sex: Incidences are equal in men and woman.

�� Age: People of all ages can be affectedAge: People of all ages can be affected

Symptoms and signsSymptoms and signs

�� Symptoms begin insidiously. (tibaSymptoms begin insidiously. (tiba--tiba)tiba)

�� Progress slowly or rapidly.Progress slowly or rapidly.

�� Changes in sensorium : loss of memory, impaired concentration, depression, Changes in sensorium : loss of memory, impaired concentration, depression, delusions, lethargy, irritability, fatigue, insomnia, psychosis, stupor, catatonia, and delusions, lethargy, irritability, fatigue, insomnia, psychosis, stupor, catatonia, and coma.coma.

�� Slurred speech, pruritus, muscle twitches, or restless legs.Slurred speech, pruritus, muscle twitches, or restless legs.

�� SYMPTOM DAN SIGNSYMPTOM DAN SIGN

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�� SYMPTOM DAN SIGNSYMPTOM DAN SIGN

�� Mulai mendadak / tibaMulai mendadak / tiba--tibatiba

�� Berlanjut Lambat atau CepatBerlanjut Lambat atau Cepat

Timbul perubahan Sensorium, kehilangan memory, gangguan consentrasiTimbul perubahan Sensorium, kehilangan memory, gangguan consentrasi

depressi, dilusi, letargi, irritabel, lelah, insomia, psychosis, stupor, catatoniadepressi, dilusi, letargi, irritabel, lelah, insomia, psychosis, stupor, catatonia

dan Coma.dan Coma.

�� Sukar Berbicara, Pruritus, muscle twiching, atau kaki restlesness.Sukar Berbicara, Pruritus, muscle twiching, atau kaki restlesness.

�� Findings include the following;Findings include the following;

�� Myoclonic jerks, twitches, or fasciculations (ie, uremic twitchMyoclonic jerks, twitches, or fasciculations (ie, uremic twitch--convulsive convulsive syndrome postulated by Adams et al in 1997)syndrome postulated by Adams et al in 1997)

�� DysarthriaDysarthria

�� AgitationAgitation

�� TetanyTetany

�� Seizures, usually generalized tonicSeizures, usually generalized tonic--clonicclonic

�� Confusion, stupor, and comaConfusion, stupor, and coma

�� TEMUAN YANG LAIN:TEMUAN YANG LAIN:

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�� TEMUAN YANG LAIN:TEMUAN YANG LAIN:

�� Myoclonik Jerk, Twiching, atau faciculationMyoclonik Jerk, Twiching, atau faciculation

( Uremic( Uremic--TwichingTwiching--convulsion)convulsion)

�� DysarthriaDysarthria

�� AgitasiAgitasi

�� TetanyTetany

�� Kejang, biasanya TonikKejang, biasanya Tonik--KlonikKlonik

�� Confusi, Stupor dan ComaConfusi, Stupor dan Coma

Imaging studiesImaging studies�� Brain imaging : limited value.Brain imaging : limited value.

�� CT and MRI :cerebral atrophy and secondary ventricular dilatation.CT and MRI :cerebral atrophy and secondary ventricular dilatation.

�� ExcludingExcluding ICH (Intra Cranial Hemorrhage) and ICH (Intra Cranial Hemorrhage) and

SDH (Sub Dural Hemorrhage(SDH (Sub Dural Hemorrhage(

�� Increased signal intensity in the cortical and subcortical areas of the Increased signal intensity in the cortical and subcortical areas of the parietal and occipital lobesparietal and occipital lobes

→ → resolved after dialysis (Sembuh sesudah Dialysis)resolved after dialysis (Sembuh sesudah Dialysis)

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→ → resolved after dialysis (Sembuh sesudah Dialysis)resolved after dialysis (Sembuh sesudah Dialysis)

PENCITRAAN:

Pencitraan otak, hasilnya terbatas

CT Scan dan MRI, terlihat atrophy Cerebral, dilatasi sekunder Vebtricle

Exclusi : ICH ( Intra Cranial Hemorrhage) dan

SDH ( Sub Dural Hemorrhage)

Intensitas signal meningkat pada area Cortex dan Subcortex dari

Lobus Parietal dan Occipital.

�� Sembuh sesudah Dialysis

EEG EEG �� Serial EEG : useful in assessing patients and in monitoring their progressSerial EEG : useful in assessing patients and in monitoring their progress

�� Generalized slow wave : more severe as the condition worsensGeneralized slow wave : more severe as the condition worsens

�� In acute uremia, In acute uremia,

�� irregular low voltage with slowing of the posterior dominant alpha rhythm and occasional theta bursts. irregular low voltage with slowing of the posterior dominant alpha rhythm and occasional theta bursts.

�� prolonged bursts of bilateral, synchronous slow and sharp waves or spike wavesprolonged bursts of bilateral, synchronous slow and sharp waves or spike waves

�� Bilateral spike discharge : myoclonic jerksBilateral spike discharge : myoclonic jerks

�� After dialysis begins, EEG may worsen for up to 6 months before slowly normalizing as renal function After dialysis begins, EEG may worsen for up to 6 months before slowly normalizing as renal function improvesimproves

�� EEG sangat bermanfaat utk penderita,dan utk monitor progresifitas.EEG sangat bermanfaat utk penderita,dan utk monitor progresifitas.

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�� EEG sangat bermanfaat utk penderita,dan utk monitor progresifitas.EEG sangat bermanfaat utk penderita,dan utk monitor progresifitas.

�� Umumnya: Gelombang lambat, makin lambat makin parahUmumnya: Gelombang lambat, makin lambat makin parah

�� Pada akut uremia:Pada akut uremia:

�� Ada Low voltage yang irregulerdgn gelombang lambat diposterior, Ada Low voltage yang irregulerdgn gelombang lambat diposterior, rythme alfa dan kadang gelombang theta yg kacau, kalau bilateral rythme alfa dan kadang gelombang theta yg kacau, kalau bilateral ��twichingtwiching

�� Sesudah dialysis dimulai, EEG masi jelek Sesudah dialysis dimulai, EEG masi jelek ––6 mgg mulai normal sesudah6 mgg mulai normal sesudah

�� Fungsi gijal membaikFungsi gijal membaik

EEG EEG

�� In chronic uremia, In chronic uremia,

�� the EEG stabilizes during longthe EEG stabilizes during long--term dialysis treatment. term dialysis treatment.

�� Deterioration corresponding to fluctuations in blood urea Deterioration corresponding to fluctuations in blood urea levels : diffuse delta and theta activity, generalized spikelevels : diffuse delta and theta activity, generalized spike--wave activity, and heightened sensitivity to photic wave activity, and heightened sensitivity to photic stimulation.stimulation.

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�� PADA KRONIK UREMIA. EEG stabil selama dilysisPADA KRONIK UREMIA. EEG stabil selama dilysis

�� Kekacauan sesuai dgn kadar ureum dlm darah,Kekacauan sesuai dgn kadar ureum dlm darah,

�� Umumnya ada aktifitas Spike waves dan sensitif terUmumnya ada aktifitas Spike waves dan sensitif ter

�� hadap stimulasi cahayahadap stimulasi cahaya

Brain histologic findings in UEBrain histologic findings in UE

Meningeal fibrosis, glial changes, edema, vascular degeneration, Meningeal fibrosis, glial changes, edema, vascular degeneration,

focal and diffuse neuronal degeneration, and focal focal and diffuse neuronal degeneration, and focal

demyelination. demyelination.

�� Small infarcts : due to hypertension or focal necrosis. Small infarcts : due to hypertension or focal necrosis.

�� Cerebellar acute granule cell necrosisCerebellar acute granule cell necrosis

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�� GAMBARAN HISTOLOGI OTAK PADA UEGAMBARAN HISTOLOGI OTAK PADA UE

�� Meningeal fibrosis, Gial berobah, Vascular degenerasi, Meningeal fibrosis, Gial berobah, Vascular degenerasi,

�� fokal dan diffuse neuronal dan fokal demyelinsasifokal dan diffuse neuronal dan fokal demyelinsasi

�� Dan infact kecil, ok. Hipertensi dan fokal necrosisDan infact kecil, ok. Hipertensi dan fokal necrosis

�� Cereberal akut granule sel necrosis.Cereberal akut granule sel necrosis.

ATROPHY OTAK, dan KELAINAN VASCULAR pd UE

Ada small necrosis, ada demyelinisasi ada fibrosis19.

Neuroimage. 2007;34(2):694-701

DIAGNOSISDIAGNOSIS

�� HistoryHistory

�� Clinical symptom and signClinical symptom and sign

�� EEGEEG

�� IMAGING STUDIESIMAGING STUDIES

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IMAGING STUDIESIMAGING STUDIES

�� ANAMNESISANAMNESIS

�� GEJALA KLINISGEJALA KLINIS

�� EEGEEG

�� PENCITRAANPENCITRAAN

TREATMENT TREATMENT

�� Correct the metabolic disturbance Correct the metabolic disturbance

�� Dialysis (hemodialysis or peritoneal dialysis) Dialysis (hemodialysis or peritoneal dialysis)

�� Renal transplantation Renal transplantation

�� Symptoms improve as renal function improves Symptoms improve as renal function improves

�� Seizures may be treated with anticonvulsantsSeizures may be treated with anticonvulsants

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�� PENGOBATAN.PENGOBATAN.

�� Koreksi ganggaun MetabolikKoreksi ganggaun Metabolik

�� Dialysis (HD atau PD)Dialysis (HD atau PD)

�� Transplantasi GinjalTransplantasi Ginjal

�� Gejala hilang kl fungsi ginjal membaikGejala hilang kl fungsi ginjal membaik

�� Kejang bisa diobati dgn anticonvulsanKejang bisa diobati dgn anticonvulsan

Thank youThank you

Terima KasihTerima Kasih

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uremic encephalopathy...

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