Correspondence
Embolic strokes of undetermined source: support for a new clinical construct We read with great interest the Personal View by Robert Hart and colleagues of the Cryptogenic Stroke/ ESUS International Working Group, who presented novel ideas about the secondary prevention of cryptogenic ischaemic stroke. 1 Advances in imaging techniques that allow direct visualisation of thrombotic material—eg, susceptibility-weighted imaging 2—and the possibility to retrieve thrombotic material by means of mechanical thrombectomy3 have helped to show that most cryptogenic strokes are caused by thromboembolic events. In a recent study of thrombi visualised with susceptibility-weighted imaging compared with thrombi assessed with digital subtraction angiography in patients with middle cerebral artery occlusion, the cause of stroke remained unknown in 31 of 88 patients (35%).4 In 30 of these patients (96%) with cryptogenic stroke, thrombotic material was visualised with susceptibility-weighted imaging without signs of underlying atherosclerotic disease shown by digital subtraction angiography. These findings—at least in patients with occlusions of the anterior circulation—implicate embolic events as a more probable cause than insitu thrombosis, and support the use of the expression embolic stroke of undetermined source (ESUS). With regard to the prophylactic treatment of patients with ESUS, we need to bear in mind that the composition of the thrombotic material causing the initial stroke can be highly variable.3 The effectiveness of stroke prophylaxis might be influenced by this variability. In a series of 303 patients with ischaemic stroke who were treated at our institution, thrombotic material was retrieved by endovascular means www.thelancet.com/neurology Vol 13 October 2014
and these specimens underwent histopathological analysis. Of the 79 patients (26·1%) with ESUS, ten (12·7%) had erythrocyte-rich thrombi, six (7·6%) had platelet-rich thrombi, and 63 (79·7%) had mixed thrombi (unpublished data). Future trials are needed to assess the optimum prophylactic treatment for patients with ESUS, and to find techniques that help to further decrease the number of stroke patients for whom the source of thromboembolic events is unclear. Histopathological thrombus analyses and neuroimaging techniques might be helpful in achieving this goal.5 JG is global principal investigator of the STAR Study and has received consultancy fees from Covidien. PPG, HPM, and GS declare no competing interests.
*Pascal P Gratz, Jan Gralla, Heinrich P Mattle, Gerhard Schroth [email protected] Department of Diagnostic and Interventional Neuroradiology (PPG, JG, GS), Department of Neurology (HPM), Inselspital, Bern University Hospital and University of Bern, 3010 Bern, Switzerland 1
2
3
4
5
Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–38. Mittal S, Wu Z, Neelavalli J, Haacke EM. Susceptibility-weighted imaging: technical aspects and clinical applications, part 2. AJNR Am J Neuroradiol 2009; 30: 232–52. Marder VJ, Chute DJ, Starkman S, et al. Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke 2006; 37: 2086–93. Weisstanner C, Gratz PP, Schroth G, et al. Thrombus imaging in acute stroke: correlation of thrombus length on susceptibility-weighted imaging with endovascular reperfusion success. Eur Radiol 2014; 24: 1735–41. Niesten JM, van der Schaaf IC, van Dam L, et al. Histopathologic composition of cerebral thrombi of acute stroke patients is correlated with stroke subtype and thrombus attenuation. PloS ONE 2014; 9: e88882.
Authors’ reply The interesting and important observations summarised by Pascal Gratz and colleagues lend support to the embolic strokes of undetermined source (ESUS) construct developed in our recent Personal View. Two large, international randomised trials are underway that will compare new
oral anticoagulants (dabigatran and rivaroxaban, respectively) with aspirin for secondary stroke prevention in ESUS cohorts, and assess the therapeutic implications of this novel construct. Finally, cryptogenic (of unknown cause) stroke will be the subject of these long-overdue, randomised trials that will shed light on this obscure, but common, entity. RGH obtained funding for a meeting of the International Working Group from Bayer, Bristol-Myers Squibb, and Boehringer Ingelheim; he is co-principal investigator of the Bayer-sponsored NAVIGATE ESUS randomized trial involving patients with embolic strokes of undetermined cause and has received research support from Bayer and Boehringer Ingelheim. H-CD has received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daichii-Sankyo, D-Pharm, EV3, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi; he has received financial support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris. SJC has received consultancy fees, speaker’s fees, and research funding from Bayer and Boehringer Ingelheim.
*Robert G Hart, Hans-Christoph Diener, Stuart J Connolly [email protected] McMaster University and Population Health Research Institute, Hamilton, ON, L8L 2X2, Canada (RGH, SJC); University Duisburg-Essen, Essen, Germany (H-CD)
Sepsis-associated encephalopathy versus sepsis-induced encephalopathy We read with interest the Review by Widmann and Heneka on the longterm consequences of sepsis.1 Sepsis and its associated complications are thought to be the foremost causes of morbidity and mortality in patients in intensive-care units (ICU) worldwide. Sepsis, a potentially fatal sequel to infection, results from a cascade 967
Correspondence
of pro-inflammatory compounds released in response to infection. Consequently, multiple-organ systems might be affected, leading to their failure. Sepsis-associated encephalopathy, a life-threatening yet reversible deterioration of mental status that occasionally accompanies sepsis, is the most common type of encephalopathy encountered in patients in the intensive care unit; sepsis-associated encephalopathy contributes to increased mortality in these patients, and those who survive often have long-term, disabling, cognitive dysfunction or other devastating outcomes, including impaired memory, attention, mentalprocessing speed, and visual-spatial abilities. This long-term disabling state can affect all aspects of a patient’s life, including the ability to return to normal daily activity or work, imposing a further burden to their families and healthcare providers.2 Clinically, sepsis-associated encephalopathy manifests as acute altered mental status, inattention, disorientation, agitation, stupor, and coma. It is characterised by leukoencephalopathy, abnormalities in somatosensory-evoked potentials and electroencephalogram activity, and an increase in brain-injury biomarkers, such as neuron-specific enolase and S100B protein. 3 The magnitude of brain dysfunction and deterioration in cognitive performance is difficult to measure through bedside assessments. The pathophysiology of encephalopathy in patients with sepsis is multifaceted, encompassing both inflammatory and noninflammatory insults that lead to direct brain-cell damage, impaired neurotransmission, and mitochondrial or endothelial dysfunction. 4 Furthermore, the complex balance between proinflammatory and anti-inflammatory responses induced by sepsis, known as the mixed antagonistic response 968
syndrome, will shift towards either the inflammatory or the antiinflammatory response during the course of sepsis. Sepsis can also lead to impairment of the function of individual organs; this impairment might be sepsisassociated or sepsis-induced. The pathophysiology underlying sepsisinduced multi organ failure is a severely compromised, rather than an overactive, immune system.5 It is this subsequent impaired balance in immune response that leads to multiorgan failure. Critically ill patients might also develop iatrogenic organ dysfunction. Renal dysfunction is a common scenario noted in patients, due to the use of nephrotoxic drugs such as aminoglycosides, and is therefore termed as sepsis-associated, rather than sepsis-induced, renal dysfunction. Despite the organ impairment noted throughout sepsis, any brain damage originates directly from the systemic infection. Sepsis-associated encephalopathy is associated with diffuse or multifocal cerebral dysfunction prompted by the systemic response to the infection without any evident direct infection of the brain. The brain has a central role in sepsis, both mediating the immune responses and being a target endorgan for the pathological process. Hence, cerebral involvement is a result of progression to severe sepsis, rather than being an adjuvant occurrence. Therefore, the term sepsis-associated encephalopathy used by most authors1 should be substituted with the more appropriate term sepsis-induced encephalopathy. We declare no competing interests.
Samad EJ Golzari, *Ata Mahmoodpoor [email protected] Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, 5157698616, Iran 1
Widmann CN, Heneka M. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36.
2
3
4
5
Hurley RA, Hayman LA, Taber KH. Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci 2011; 23: 236–41 Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37 (10 suppl): S331–36. Zampieri FG, Park M, Machado FS, Azevedo LCP. Sepsis associated encephalopathy. Clinics 2011; 66: 1825–31. Hotchkiss RS, Opal S. Immunotherapy for sepsis: a new approach against an ancient foe. N Engl J Med 2010; 363: 87–89.
Authors’ reply Cognitive and cerebral damage after sepsis could have many causes, and whether sepsis-associated encephalopathy is the only cause is unclear. Furthermore, whether encephalopathy during sepsis is a result of sepsis itself or due to myriad other factors during acute illness is also unclear. Potentially contributing factors during acute disease include immunological weakness; neurological or psychiatric diseases (especially post-traumatic stress disorder, depression, and anxiety); other comorbidities; the presence and type of infection, and severity and duration; the type of treatment given at the intensive-care unit (especially analgesia and sedation); delirium; which, if any, diagnostic and rehabilitative measures were taken; and pre-existing physical disabilities. These factors vary between patients, and are likely to interact. In our Personal View,1 we sought to outline the best-known mechanisms that directly or indirectly affect the brain— systemic and cerebral blood flow, permeability of the blood–brain barrier, oxidative stress, neuronal dysfunction and neuronal death, and immunosuppression. Golzari and Mahmoodpoor are correct that, in addition to the mechanisms we outlined, dysfunction in and failure of organs other than the brain will have an indirect effect on brain function. In view of the fact that sepsis and the inflammatory response are highly dynamic processes, and despite the
www.thelancet.com/neurology Vol 13 October 2014
Embolic strokes of undetermined source: support for a new clinical construct We read with great interest the Personal View by Robert Hart and colleagues of the Cryptogenic Stroke/ ESUS International Working Group, who presented novel ideas about the secondary prevention of cryptogenic ischaemic stroke. 1 Advances in imaging techniques that allow direct visualisation of thrombotic material—eg, susceptibility-weighted imaging 2—and the possibility to retrieve thrombotic material by means of mechanical thrombectomy3 have helped to show that most cryptogenic strokes are caused by thromboembolic events. In a recent study of thrombi visualised with susceptibility-weighted imaging compared with thrombi assessed with digital subtraction angiography in patients with middle cerebral artery occlusion, the cause of stroke remained unknown in 31 of 88 patients (35%).4 In 30 of these patients (96%) with cryptogenic stroke, thrombotic material was visualised with susceptibility-weighted imaging without signs of underlying atherosclerotic disease shown by digital subtraction angiography. These findings—at least in patients with occlusions of the anterior circulation—implicate embolic events as a more probable cause than insitu thrombosis, and support the use of the expression embolic stroke of undetermined source (ESUS). With regard to the prophylactic treatment of patients with ESUS, we need to bear in mind that the composition of the thrombotic material causing the initial stroke can be highly variable.3 The effectiveness of stroke prophylaxis might be influenced by this variability. In a series of 303 patients with ischaemic stroke who were treated at our institution, thrombotic material was retrieved by endovascular means www.thelancet.com/neurology Vol 13 October 2014
and these specimens underwent histopathological analysis. Of the 79 patients (26·1%) with ESUS, ten (12·7%) had erythrocyte-rich thrombi, six (7·6%) had platelet-rich thrombi, and 63 (79·7%) had mixed thrombi (unpublished data). Future trials are needed to assess the optimum prophylactic treatment for patients with ESUS, and to find techniques that help to further decrease the number of stroke patients for whom the source of thromboembolic events is unclear. Histopathological thrombus analyses and neuroimaging techniques might be helpful in achieving this goal.5 JG is global principal investigator of the STAR Study and has received consultancy fees from Covidien. PPG, HPM, and GS declare no competing interests.
*Pascal P Gratz, Jan Gralla, Heinrich P Mattle, Gerhard Schroth [email protected] Department of Diagnostic and Interventional Neuroradiology (PPG, JG, GS), Department of Neurology (HPM), Inselspital, Bern University Hospital and University of Bern, 3010 Bern, Switzerland 1
2
3
4
5
Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–38. Mittal S, Wu Z, Neelavalli J, Haacke EM. Susceptibility-weighted imaging: technical aspects and clinical applications, part 2. AJNR Am J Neuroradiol 2009; 30: 232–52. Marder VJ, Chute DJ, Starkman S, et al. Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke 2006; 37: 2086–93. Weisstanner C, Gratz PP, Schroth G, et al. Thrombus imaging in acute stroke: correlation of thrombus length on susceptibility-weighted imaging with endovascular reperfusion success. Eur Radiol 2014; 24: 1735–41. Niesten JM, van der Schaaf IC, van Dam L, et al. Histopathologic composition of cerebral thrombi of acute stroke patients is correlated with stroke subtype and thrombus attenuation. PloS ONE 2014; 9: e88882.
Authors’ reply The interesting and important observations summarised by Pascal Gratz and colleagues lend support to the embolic strokes of undetermined source (ESUS) construct developed in our recent Personal View. Two large, international randomised trials are underway that will compare new
oral anticoagulants (dabigatran and rivaroxaban, respectively) with aspirin for secondary stroke prevention in ESUS cohorts, and assess the therapeutic implications of this novel construct. Finally, cryptogenic (of unknown cause) stroke will be the subject of these long-overdue, randomised trials that will shed light on this obscure, but common, entity. RGH obtained funding for a meeting of the International Working Group from Bayer, Bristol-Myers Squibb, and Boehringer Ingelheim; he is co-principal investigator of the Bayer-sponsored NAVIGATE ESUS randomized trial involving patients with embolic strokes of undetermined cause and has received research support from Bayer and Boehringer Ingelheim. H-CD has received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daichii-Sankyo, D-Pharm, EV3, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi; he has received financial support for research projects from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, and Talecris. SJC has received consultancy fees, speaker’s fees, and research funding from Bayer and Boehringer Ingelheim.
*Robert G Hart, Hans-Christoph Diener, Stuart J Connolly [email protected] McMaster University and Population Health Research Institute, Hamilton, ON, L8L 2X2, Canada (RGH, SJC); University Duisburg-Essen, Essen, Germany (H-CD)
Sepsis-associated encephalopathy versus sepsis-induced encephalopathy We read with interest the Review by Widmann and Heneka on the longterm consequences of sepsis.1 Sepsis and its associated complications are thought to be the foremost causes of morbidity and mortality in patients in intensive-care units (ICU) worldwide. Sepsis, a potentially fatal sequel to infection, results from a cascade 967
Correspondence
of pro-inflammatory compounds released in response to infection. Consequently, multiple-organ systems might be affected, leading to their failure. Sepsis-associated encephalopathy, a life-threatening yet reversible deterioration of mental status that occasionally accompanies sepsis, is the most common type of encephalopathy encountered in patients in the intensive care unit; sepsis-associated encephalopathy contributes to increased mortality in these patients, and those who survive often have long-term, disabling, cognitive dysfunction or other devastating outcomes, including impaired memory, attention, mentalprocessing speed, and visual-spatial abilities. This long-term disabling state can affect all aspects of a patient’s life, including the ability to return to normal daily activity or work, imposing a further burden to their families and healthcare providers.2 Clinically, sepsis-associated encephalopathy manifests as acute altered mental status, inattention, disorientation, agitation, stupor, and coma. It is characterised by leukoencephalopathy, abnormalities in somatosensory-evoked potentials and electroencephalogram activity, and an increase in brain-injury biomarkers, such as neuron-specific enolase and S100B protein. 3 The magnitude of brain dysfunction and deterioration in cognitive performance is difficult to measure through bedside assessments. The pathophysiology of encephalopathy in patients with sepsis is multifaceted, encompassing both inflammatory and noninflammatory insults that lead to direct brain-cell damage, impaired neurotransmission, and mitochondrial or endothelial dysfunction. 4 Furthermore, the complex balance between proinflammatory and anti-inflammatory responses induced by sepsis, known as the mixed antagonistic response 968
syndrome, will shift towards either the inflammatory or the antiinflammatory response during the course of sepsis. Sepsis can also lead to impairment of the function of individual organs; this impairment might be sepsisassociated or sepsis-induced. The pathophysiology underlying sepsisinduced multi organ failure is a severely compromised, rather than an overactive, immune system.5 It is this subsequent impaired balance in immune response that leads to multiorgan failure. Critically ill patients might also develop iatrogenic organ dysfunction. Renal dysfunction is a common scenario noted in patients, due to the use of nephrotoxic drugs such as aminoglycosides, and is therefore termed as sepsis-associated, rather than sepsis-induced, renal dysfunction. Despite the organ impairment noted throughout sepsis, any brain damage originates directly from the systemic infection. Sepsis-associated encephalopathy is associated with diffuse or multifocal cerebral dysfunction prompted by the systemic response to the infection without any evident direct infection of the brain. The brain has a central role in sepsis, both mediating the immune responses and being a target endorgan for the pathological process. Hence, cerebral involvement is a result of progression to severe sepsis, rather than being an adjuvant occurrence. Therefore, the term sepsis-associated encephalopathy used by most authors1 should be substituted with the more appropriate term sepsis-induced encephalopathy. We declare no competing interests.
Samad EJ Golzari, *Ata Mahmoodpoor [email protected] Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, 5157698616, Iran 1
Widmann CN, Heneka M. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36.
2
3
4
5
Hurley RA, Hayman LA, Taber KH. Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci 2011; 23: 236–41 Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37 (10 suppl): S331–36. Zampieri FG, Park M, Machado FS, Azevedo LCP. Sepsis associated encephalopathy. Clinics 2011; 66: 1825–31. Hotchkiss RS, Opal S. Immunotherapy for sepsis: a new approach against an ancient foe. N Engl J Med 2010; 363: 87–89.
Authors’ reply Cognitive and cerebral damage after sepsis could have many causes, and whether sepsis-associated encephalopathy is the only cause is unclear. Furthermore, whether encephalopathy during sepsis is a result of sepsis itself or due to myriad other factors during acute illness is also unclear. Potentially contributing factors during acute disease include immunological weakness; neurological or psychiatric diseases (especially post-traumatic stress disorder, depression, and anxiety); other comorbidities; the presence and type of infection, and severity and duration; the type of treatment given at the intensive-care unit (especially analgesia and sedation); delirium; which, if any, diagnostic and rehabilitative measures were taken; and pre-existing physical disabilities. These factors vary between patients, and are likely to interact. In our Personal View,1 we sought to outline the best-known mechanisms that directly or indirectly affect the brain— systemic and cerebral blood flow, permeability of the blood–brain barrier, oxidative stress, neuronal dysfunction and neuronal death, and immunosuppression. Golzari and Mahmoodpoor are correct that, in addition to the mechanisms we outlined, dysfunction in and failure of organs other than the brain will have an indirect effect on brain function. In view of the fact that sepsis and the inflammatory response are highly dynamic processes, and despite the
www.thelancet.com/neurology Vol 13 October 2014
