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Reply to: “Tools and tactics for improving diagnosis of hepatic encephalopathy”
Accepted Manuscript Reply to: Tools and tactics for improving diagnosis of hepatic encephalopathy Sara Montagnese, Michele De Rui, Paolo Angeli, Piero Amodio PII: DOI: Reference:
S0168-8278(17)30102-2 http://dx.doi.org/10.1016/j.jhep.2017.02.008 JHEPAT 6423
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
7 February 2017 9 February 2017
Please cite this article as: Montagnese, S., De Rui, M., Angeli, P., Amodio, P., Reply to: Tools and tactics for improving diagnosis of hepatic encephalopathy, Journal of Hepatology (2017), doi: http://dx.doi.org/10.1016/j.jhep. 2017.02.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Reply to: Tools and tactics for improving diagnosis of hepatic encephalopathy Sara Montagnese, Michele De Rui, Paolo Angeli, Piero Amodio Department of Medicine, University of Padua, Padua, Italy
Correspondence to: Sara Montagnese Dipartimento di Medicina Via Giustiniani, 2 35128 Padova, Italia Tel
+39 049 8218675
Fax
+39 049 7960903
[email protected]
Conflict of interest: None Financial support: None
To the Editor, We have read with interest the letter by Olesen and colleagues [1], and we are grateful to them for acknowledging that our two new proposals [2] have “merit”. Turning to the salient issues they raise, we certainly agree with them that neuropsychiatric performance is multifactorial, hence why we devoted large sections of our manuscript and a figure to discuss the complex interactions between lifelong performance, “baseline” performance at any given moment in time, and different factors contributing to it, including age and comorbidities. While we also agree with Olesen and colleagues [1] that baseline performance may not necessarily be easy to define (discussed in our manuscript), we still think that obtaining it remains the ultimate goal of treatment, and thus the main objective of any diagnostic procedure. That baseline performance at any given moment in time would relate to top lifelong performance (i.e. where a person started from, at their peak) is obvious. Hence, we chose not to state it. The suggestion by Olesen and colleagues that “baseline performance” could be interpreted in a chronological order, as the one the patient presented with when first evaluated, seems improbable. Regarding their comments about Clinical Case 2, the joint EASL-AASLD guidelines on hepatic encephalopathy [3] state that if a patient is clinically abnormal and ammonia levels normal, the diagnosis of hepatic encephalopathy must be questioned, because the underlying liver failure and/or portosystemic shunt are not severe enough to support it [4, 5]. Depending on laboratory cutoffs and on whether the patient was or was not fasting, ammonia levels of Clinical Case 2 were normal/near-normal both in May 2014 and in June 2015. This makes the diagnosis of “intractable, partially responsive chronic hepatic encephalopathy” suggested by Olesen and colleagues unlikely. Also, according to the joint EASL-AASLD guidelines [3], “intractable, partially responsive chronic hepatic encephalopathy” is now called “persistent”. In our view, the electroencephalographic (EEG) abnormalities exhibited by Clinical Case 2 in May 2014 were probably related to nutritional deficits (thus metabolic but not hepatic encephalopathy), and the neuropsychological profile most likely resulting from the mixture of nutritional deficits, alcohol-related dementia and cerebrovascular disease, which was documented on brain imaging. Our hypothesis that alcohol-related dementia and cerebrovascular disease made a contribution is also supported by the fact that between May 2014 and June 2015 Mini Mental State Examination worsened, while indices of hepatic failure and psychomotor slowing all improved. Malnutrition and early dementia offer a reasonable explanation for both psychomotor slowing and inappropriateness, which is what the patient presented with. It is generally accepted that the clinical phenotype of both metabolic encephalopathy [6] and early dementia [7] can be unspecific, and that of their combination even more so [7].
We have read with interest and quoted the recent study by the authors [8] on adjusted EEG thresholds, which first appeared online in April 2016 and was subsequently published in August 2016. About using such adjusted thresholds to reclassify our clinical cases, this is not a sensible proposition. Our Clinical Cases evolved between June 2011 and September 2015 (dates are provided in Tables 1, 2 and 3, and in Figure 1), so can only be described as they were assessed and managed at the time [2]. Finally, we strongly disagree with Olesen and colleagues [1] when they state that risk thresholds have no impact on clinical decisions. On the contrary, should they be validated, which we call for in our own manuscript [2], they may represent the basis for trials evaluating whether patients “at risk” would benefit from early treatment, or closer follow-up. We also find it reassuring that both our exercise on risk thresholds and the authors’ work on diagnostic thresholds [8] indicate that the currently accepted cut-off of abnormality for slow EEG activity (theta) [9] needs lowering. (It is however expected that this may also result in an increased number of false positives.) Where Olesen and colleagues see reasons for concern, we see two separate sets of interesting data leading to the same conclusion. In science, this is always of great comfort.
References [1] Olesen SS, Jackson CD, Morgan MY. Tools and tactics for improving diagnosis of hepatic encephalopathy. J Hepatol., in press [2] Montagnese S, De Rui M, Angeli P, Amodio P. Neuropsychiatric Performance in Patients with Cirrhosis: Who is "Normal"? J Hepatol., in press [3] Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. J Hepatol. 2014;61:642-59. [4] van de Poll MC, Ligthart-Melis GC, Olde Damink SW, van Leeuwen PA, Beets-Tan RG, Deutz NE, et al. The gut does not contribute to systemic ammonia release in humans without portosystemic shunting. Am J Physiol Gastrointest Liver Physiol. 2008;295:G760-5. [5] Gerritzen-Bruning MJ, van den Ingh TS, Rothuizen J. Diagnostic value of fasting plasma ammonia and bile acid concentrations in the identification of portosystemic shunting in dogs. J Vet Intern Med. 2006;20:13-9. [6] Weiss N, Barbier Saint Hilaire P, Colsch B, Isnard F, Attala S, Schaefer A, et al. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol. 2016;65:1120-1130. [7] Morandi A, Davis D, Bellelli G, Arora RC, Caplan GA, Kamholz B, et al. The Diagnosis of Delirium Superimposed on Dementia: An Emerging Challenge. J Am Med Dir Assoc. 2017;18:12-18. [8] Jackson CD, Gram M, Halliday E, Olesen SS, Sandberg TH, Drewes AM, et al. New spectral thresholds improve the utility of the electroencephalogram for the diagnosis of hepatic encephalopathy. Clin Neurophysiol. 2016;127:2933-41. [9] Van der Rijt CC, Schalm SW, De Groot GH, De Vlieger M. Objective measurement of hepatic encephalopathy by means of automated EEG analysis. Electroencephalogr Clin Neurophysiol. 1984;57:423-6.
S0168-8278(17)30102-2 http://dx.doi.org/10.1016/j.jhep.2017.02.008 JHEPAT 6423
To appear in:
Journal of Hepatology
Received Date: Accepted Date:
7 February 2017 9 February 2017
Please cite this article as: Montagnese, S., De Rui, M., Angeli, P., Amodio, P., Reply to: Tools and tactics for improving diagnosis of hepatic encephalopathy, Journal of Hepatology (2017), doi: http://dx.doi.org/10.1016/j.jhep. 2017.02.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Reply to: Tools and tactics for improving diagnosis of hepatic encephalopathy Sara Montagnese, Michele De Rui, Paolo Angeli, Piero Amodio Department of Medicine, University of Padua, Padua, Italy
Correspondence to: Sara Montagnese Dipartimento di Medicina Via Giustiniani, 2 35128 Padova, Italia Tel
+39 049 8218675
Fax
+39 049 7960903
[email protected]
Conflict of interest: None Financial support: None
To the Editor, We have read with interest the letter by Olesen and colleagues [1], and we are grateful to them for acknowledging that our two new proposals [2] have “merit”. Turning to the salient issues they raise, we certainly agree with them that neuropsychiatric performance is multifactorial, hence why we devoted large sections of our manuscript and a figure to discuss the complex interactions between lifelong performance, “baseline” performance at any given moment in time, and different factors contributing to it, including age and comorbidities. While we also agree with Olesen and colleagues [1] that baseline performance may not necessarily be easy to define (discussed in our manuscript), we still think that obtaining it remains the ultimate goal of treatment, and thus the main objective of any diagnostic procedure. That baseline performance at any given moment in time would relate to top lifelong performance (i.e. where a person started from, at their peak) is obvious. Hence, we chose not to state it. The suggestion by Olesen and colleagues that “baseline performance” could be interpreted in a chronological order, as the one the patient presented with when first evaluated, seems improbable. Regarding their comments about Clinical Case 2, the joint EASL-AASLD guidelines on hepatic encephalopathy [3] state that if a patient is clinically abnormal and ammonia levels normal, the diagnosis of hepatic encephalopathy must be questioned, because the underlying liver failure and/or portosystemic shunt are not severe enough to support it [4, 5]. Depending on laboratory cutoffs and on whether the patient was or was not fasting, ammonia levels of Clinical Case 2 were normal/near-normal both in May 2014 and in June 2015. This makes the diagnosis of “intractable, partially responsive chronic hepatic encephalopathy” suggested by Olesen and colleagues unlikely. Also, according to the joint EASL-AASLD guidelines [3], “intractable, partially responsive chronic hepatic encephalopathy” is now called “persistent”. In our view, the electroencephalographic (EEG) abnormalities exhibited by Clinical Case 2 in May 2014 were probably related to nutritional deficits (thus metabolic but not hepatic encephalopathy), and the neuropsychological profile most likely resulting from the mixture of nutritional deficits, alcohol-related dementia and cerebrovascular disease, which was documented on brain imaging. Our hypothesis that alcohol-related dementia and cerebrovascular disease made a contribution is also supported by the fact that between May 2014 and June 2015 Mini Mental State Examination worsened, while indices of hepatic failure and psychomotor slowing all improved. Malnutrition and early dementia offer a reasonable explanation for both psychomotor slowing and inappropriateness, which is what the patient presented with. It is generally accepted that the clinical phenotype of both metabolic encephalopathy [6] and early dementia [7] can be unspecific, and that of their combination even more so [7].
We have read with interest and quoted the recent study by the authors [8] on adjusted EEG thresholds, which first appeared online in April 2016 and was subsequently published in August 2016. About using such adjusted thresholds to reclassify our clinical cases, this is not a sensible proposition. Our Clinical Cases evolved between June 2011 and September 2015 (dates are provided in Tables 1, 2 and 3, and in Figure 1), so can only be described as they were assessed and managed at the time [2]. Finally, we strongly disagree with Olesen and colleagues [1] when they state that risk thresholds have no impact on clinical decisions. On the contrary, should they be validated, which we call for in our own manuscript [2], they may represent the basis for trials evaluating whether patients “at risk” would benefit from early treatment, or closer follow-up. We also find it reassuring that both our exercise on risk thresholds and the authors’ work on diagnostic thresholds [8] indicate that the currently accepted cut-off of abnormality for slow EEG activity (theta) [9] needs lowering. (It is however expected that this may also result in an increased number of false positives.) Where Olesen and colleagues see reasons for concern, we see two separate sets of interesting data leading to the same conclusion. In science, this is always of great comfort.
References [1] Olesen SS, Jackson CD, Morgan MY. Tools and tactics for improving diagnosis of hepatic encephalopathy. J Hepatol., in press [2] Montagnese S, De Rui M, Angeli P, Amodio P. Neuropsychiatric Performance in Patients with Cirrhosis: Who is "Normal"? J Hepatol., in press [3] Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. J Hepatol. 2014;61:642-59. [4] van de Poll MC, Ligthart-Melis GC, Olde Damink SW, van Leeuwen PA, Beets-Tan RG, Deutz NE, et al. The gut does not contribute to systemic ammonia release in humans without portosystemic shunting. Am J Physiol Gastrointest Liver Physiol. 2008;295:G760-5. [5] Gerritzen-Bruning MJ, van den Ingh TS, Rothuizen J. Diagnostic value of fasting plasma ammonia and bile acid concentrations in the identification of portosystemic shunting in dogs. J Vet Intern Med. 2006;20:13-9. [6] Weiss N, Barbier Saint Hilaire P, Colsch B, Isnard F, Attala S, Schaefer A, et al. Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy. J Hepatol. 2016;65:1120-1130. [7] Morandi A, Davis D, Bellelli G, Arora RC, Caplan GA, Kamholz B, et al. The Diagnosis of Delirium Superimposed on Dementia: An Emerging Challenge. J Am Med Dir Assoc. 2017;18:12-18. [8] Jackson CD, Gram M, Halliday E, Olesen SS, Sandberg TH, Drewes AM, et al. New spectral thresholds improve the utility of the electroencephalogram for the diagnosis of hepatic encephalopathy. Clin Neurophysiol. 2016;127:2933-41. [9] Van der Rijt CC, Schalm SW, De Groot GH, De Vlieger M. Objective measurement of hepatic encephalopathy by means of automated EEG analysis. Electroencephalogr Clin Neurophysiol. 1984;57:423-6.