Cognitive abnormalities in cirrhosis

Transcription

1 AISF Young Investigator Lecture Cognitive abnormalities in cirrhosis Sara Montagnese

2 Disclosures I have received lecture fees from Merz Pharmaceuticals GmbH and Norgine The University of Padova has received research funding for me and my team from Merz Pharmaceuticals GmbH

3 Vignette Patient with cirrhosis Referred to our clinic for cognitive disorders in medicine HE or pre-transplant work-up

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6 Neuropsychiatric Evaluation Structured interview Clinical evaluation/neurological examination Electroencephalogram (EEG) Set of neuropsychological tests (including PHES)

7 Weissenborn et al., J Hepatol 2001 Amodio et al., J Hepatol 2008

8 Neuropsychiatric Evaluation Structured interview Clinical evaluation/neurological examination Electroencephalogram (EEG) Set of neuropsychological tests (including PHES) Critical Flicker Frequency (CFF)

9 Neuropsychiatric Evaluation Structured interview Clinical evaluation/neurological examination Electroencephalogram (EEG) Set of neuropsychological tests (including PHES) Critical Flicker Frequency (CFF) Set of laboratory tests Repeat after treatment / brain imaging

10 Vignette - 26/05/ year old male Alcohol-related cirrhosis (off 3 yrs) Child B, MELD 17 No history of overt HE Fasting, venous ammonia 41 µmol/l (<35)

11 Vignette - 26/05/2014 Clinically normal MMSE 23/30 (memory) PHES=-10 (>-4) Computer tests x CFF 38 (> 39 Hz)

12 Vignette - 26/05/2014

13 Vignette - 26/05/2014 Clinically normal MMSE 23/30 (memory) PHES= -10 Computer tests x CFF 38

14 Vignette - 26/05/2014..The features of the neuropsychological profile together with borderline ammonia levels suggest a mixture of minimal HE and cerebral damage of a different origin (prolonged alcohol misuse? Malnutrition-related encephalopathy?) in a patient with refractory ascites, malnutrition, sarcopenia.

15 Vignette - 24/09/ year old male Alcohol-related cirrhosis (off 3 yrs) Child C, MELD 20 Recovering from HE-related hospitalisation Two episodes of precipitated HE over the summer Fasting, venous ammonia 191 µmol/l (<35)

16 Vignette - 24/09/2014 Clinically normal Slow, blurred speech MMSE 23/30 16/30 PHES= Computer tests x CFF 38 x

17 Vignette May 2014 Sept 2014

18 Vignette - 29/05/2014..The current neuropsychiatric profile is compatible with overt HE, in a patient with additional risk factors for neuropsychiatric dysfunction (see May 2014 evaluation). It would be useful to discuss with family/carers preventable precipitants.

19 Cognitive dysfunction Clinically normal Slow, blurred speech MMSE 23/30 16/30 PHES= Computer tests x CFF 38 x

20 Hepatic Encephalopathy Clinically normal Slow, blurred speech MMSE 23/30 16/30 7 PHES= Computer tests x CFF 38 x

21 Cognitive dysfunction Clinically normal Slow, blurred speech MMSE 23/30 16/30 PHES=-10 (>-4) -12 Computer tests x CFF 38 (> 39 Hz) x

22 Cognitive dysfunction Clinically normal Slow, blurred speech MMSE 23/30 16/30 PHES=-10 (>-4) -12 Computer tests x CFF 38 (> 39 Hz) x

23 Reversibility TMTA DS LTt TMT-A * * * TMT-B DS SD LTT-t LTT-e Controls nohe prelt HE prelt * P<0.05 Sotil et al, Liver Transpl 2009

24 Predisposition / Co-morbidity Campagna et al, Liver Transpl 2014

25 Hepatic Encephalopathy...and What Else? 276 patients (58±11 yrs, Child A 37%, B 41%, C 22%) 99 (36%) neuropsychiatrically unimpaired 90 (33%) clinically obvious neuropsychiatric abnormalities (OHE) 87 (32%) PHES and/or EEG and/or CFF abnormalities (MHE) Montagnese et al. Hepatology, 2015

26 Hepatic Encephalopathy...and What Else? Of 90 OHE 55 (61%) had co-morbidities that could contribute/fully explain their neuropsychiatric profiles Of 87 MHE, 40 (46%) had co-morbidities that could contribute/fully explain their neuropsychiatric profiles 95/177 (54%)

27 Hepatic Encephalopathy...and What Else? Cerebrovascular disease (17) Recent alcohol misuse (15) Malnutrition (6) Infection/Sepsis (5) Psychoactive drugs (4) Severe hyponatremia, hypoglycemia, hypothyroidism (2 each) Other plus various combinations (42) These patients were older (59.8±10.8 vs. 56.8±11.5 yrs, p=0.04)

28 Hepatic Encephalopathy...and What Else? Montagnese et al. Hepatology, 2015

29 Hepatic Encephalopathy Substantially aspecific neurological and psychiatric symptoms/signs Attribution to liver failure and/or portalsystemic shunt

30 Hepatic Encephalopathy...and What Else? Montagnese et al. Hepatology, 2015

31 Hepatic Encephalopathy...and What Else? HE associated with ACLF occurs in younger cirrhotics with severe liver failure, in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. HE not associated with ACLF occurs in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction, and in relation to diuretic use. Prognosis is extremely poor in the first and relatively preserved in the second group. Cordoba et al. J Hepatol 2014;60:

32 Comorbidity and Predisposition CIRRHOSIS OLTX CIRRHOSIS OLTX

33 Predisposition to Delirium Inouye et al, Lancet 2014

34 Reversibility and Predisposition CIRRHOSIS OLTX CIRRHOSIS OLTX

35 Hepatic Encephalopathy Caused associated by liver disease and/or shunt

36 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance

37 Hepatic Encephalopathy Weissenbrn et al, Metabolic Brain Disease 2005

38 Sleepiness and HE Bersagliere et al., 2011

39 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance Largely reversible

40 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance Largely reversible Persistent HE Riggio O., Hepatology 2005

41 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance Largely reversible Persistent HE Irreversible HE Riggio O., Hepatology 2005

42 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance Largely reversible Persistent HE Irreversible HE Ammonia levels normal, diagnosis in question Should respond to ammonia-lowering treatment Sherlock S, Diseases of the Liver and Biliary System, 1955

43 Hepatic Encephalopathy Caused associated by liver disease Psychomotor slowing and decreased vigilance Largely reversible Persistent HE Irreversible HE Ammonia levels normal, diagnosis in question Should respond to ammonia-lowering treatment..and can therefore be removed from the picture! Sherlock S, Diseases of the Liver and Biliary System, 1955

44 Overt Hepatic Encephalopathy (Vilstrup et al, Hepatology, 2015)

45 Covert Hepatic Encephalopathy Relates to the degree of liver failure Relates to ammonia levels/inflammatory markers Test is more often abnormal in OHE Predicts OHE

46 Covert Hepatic Encephalopathy Relates to the degree of liver failure Relates to ammonia levels/inflammatory markers Test is more often abnormal in OHE Predicts OHE PHES, Scan test, Stroop test Critical Flicker Frequency Electroencephalogram

47 Differential Diagnosis INPATIENT OUTPATIENT Metabolic encephalopathy Drugs Malnutrition

48 Iron-deficiency Female HV 66 responders 47 non-responders Murray-Kolb & Beard Am J Clin Nutr 2007

49 Differential Diagnosis INPATIENT OUTPATIENT Metabolic encephalopathy Drugs Malnutrition Environment

50 Read and Finfer, NEJM 2014

51 Cognitive Impairment INPATIENT Metabolic encephalopathy Drugs Malnutrition Environment OUTPATIENT MCI/Dementia (Memory)

52 Syndrome Pathophysiology and DD