Comment
immunotherapies, and by a presumptive role of neuralcell adhesion molecules in the modulation of REM-sleep in animals.10 The presence of unique HLA alleles in four of four patients tested suggests their necessity for presentation of peptides to T cells and for the triggering of immune responses via activation of T-cell receptors. The identity of this presumptive antigen and its relation to IgLON5 needs further delineation. Alternatively, the pathophysiological basis of symptoms of the patients described by Sabater and colleagues might have as much to do with the widespread deposition of hyperphosphorylated tau in brainstem and subcortical neurons that the authors report in post-mortem samples from two patients. If accumulation of hyperphosphorylated tau in neurons is ultimately established as the primary as opposed to a secondary pathological feature, this tauopathy will be unique from that of Alzheimer’s disease, frontotemporal dementia, corticobasal degeneration, or progressive supranuclear palsy, in which parasomnias, especially RBD, are rarely encountered. In either instance, this seminal work from Sabater and colleagues will enhance appreciation for sleep and sleepiness as windows for assessment of brain health, and will advance understanding of the diversity in molecular pathways leading to neurodegeneration.
David Rye Department of Neurology, Emory University, Atlanta, GA 30322, USA [email protected] I have served as a consultant and advisor to Jazz Pharmaceuticals, UCB Pharma, and Xenoport. I am listed as inventor on a patent application about the use of GABA receptor antagonists for excessive sleepiness and related disorders. 1
2 3
4 5
6
7
8
9
10
Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 2014; published online April 3. http://dx.doi.org/10.1016/ S1474-4422(14)70051-1. Peever J, Luppi PH, Montplaisir J. Breakdown in REM sleep circuitry underlies REM sleep behavior disorder. Trends Neurosci 2014; 37: 279–88. De la Herran-Arita AK, Kornum BR, Mahlios J, et al. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med 2013; 5: 216ra176. Lancaster E, Dalmau J. Neuronal autoantigens–pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 2012; 8: 380–90. Compta Y, Iranzo A, Santamaria J, Casamitjana R, Graus F. REM sleep behavior disorder and narcoleptic features in anti-Ma2-associated encephalitis. Sleep 2007; 30: 767–69. Adams C, McKeon A, Silber MH, Kumar R. Narcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma. Arch Neurol 2011; 68: 521–24. Iranzo A, Graus F, Clover L, et al. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 2006; 59: 178–81. Cornelius JR, Pittock SJ, McKeon A, et al. Sleep manifestations of voltage-gated potassium channel complex autoimmunity. Arch Neurol 2011; 68: 733–38. Stamelou M, Plazzi G, Lugaresi E, Edwards MJ, Bhatia KP. The distinct movement disorder in anti-NMDA receptor encephalitis may be related to Status Dissociatus: a hypothesis. Mov Disord 2012; 27: 1360–63. Black MA, Deurveilher S, Seki T, et al. Role of polysialylated neural cell adhesion molecule in rapid eye movement sleep regulation in rats. Eur J Neurosci 2009; 30: 2190–204.
A population perspective on the IWG-2 research diagnostic criteria for Alzheimer’s disease See Position Paper page 614
532
The International Working Group (IWG) for New Research Criteria for the Diagnosis of Alzheimer’s Disease has produced a revision of its earlier 2007 criteria, updating the diagnostic algorithm with novel measurement methods.1 The IWG-2 criteria, which join other new diagnostic criteria in the dementia field, cover clinical aspects of Alzheimer’s disease and new biological and imaging methods, including preclinical, clinical, and atypical presentations. The IWG-2 criteria, along with other new criteria, at last acknowledge the much reported fact that the component features of criteria exist along continua when measured in older populations.2 The new criteria also explicitly note that clinical expression of dementia, particularly in individuals in their ninth decade and above, does not
always reflect underlying neurobiology. The stated intention of these IWG-2 criteria is for use within research settings. How are researchers and clinicians to cope with several sets of criteria from highly respected leaders in the field? Certainly, they should not be implemented in the research or clinical setting without careful consideration. A helpful harmonisation exercise done by many of these leaders suggested basic principles: Alzheimer’s disease should be defined as a brain disorder, regardless of clinical status; the clinically expressed disorder, including its prodromal stages, should be referred to as symptomatic Alzheimer’s disease; after the successful completion of standardisation efforts, incorporation of biomarkers into diagnostic algorithms www.thelancet.com/neurology Vol 13 June 2014
Comment
for Alzheimer’s disease should be considered; and nonamnestic, atypical presentations should be included as symptomatic Alzheimer’s disease, especially when there is supportive biomarker evidence.3 This last statement segues to this IWG-2 update. However, the implicit message remains that if Alzheimer’s disease pathology could be detected early enough and effectively treated, the assumed appearance of a later dementia syndrome would be averted. Through these efforts, most dementia cases worldwide (assuming that Alzheimer’s-type pathology is the cause) would be prevented and a global catastrophe averted. Is this simply wishful thinking? The wider implications of the adoption of a biological Alzheimer’s disease diagnosis have been emphasised by many researchers.4 In view of the known propensity for new diagnostic criteria to be adopted in clinical settings, are the IWG-2 criteria ready for roll out? For now, they will be applied to those selected individuals—relatively young and fit—attending highly specialised clinics.5 Will the use of these criteria in such settings generate relevant evidence for dementia as a whole? These and other criteria still rely on the dominant Alzheimer’s paradigm, despite ample evidence that this paradigm does not survive well outside highly selective specialist environments.6 Thus, comorbidity and the relation with ageing of the brain are mentioned only briefly in the new criteria, but remain elephants in the room for societally relevant outcomes from dementia research.7 Taking this, and the responses to earlier sets of criteria, into account, a key recommendation could be that researchers should welcome the new criteria, but also follow, as a community, the approach suggested by Hachinski and colleagues8 in recognition of the confusion around criteria for vascular dementia; instead of criteria, a recommended set of measurements was developed through consensus that is sensitive to research settings, to help to generate a better evidence base for future criteria. These measurements must include all those elements that make up a highquality diagnosis—reasonable evidence for prognosis, treatment, and management relevant to that person— otherwise patients will be given diagnoses with implications, but without meaning. Previous exercises have shown how important such stepping back can be to understand how diagnostic criteria perform. Examples include the criteria for mild cognitive impairment9 and dementia,10 which both show how www.thelancet.com/neurology Vol 13 June 2014
variable criteria can be in the context of real populations, including who is identified and what the prognosis is. It is crucial that new sets of criteria, and the measures that make them up, are defined and tested in a rigorous way. The suggestions made in IWG-2 are an important part of this process. Each measure in the criteria must be tested and validated against some agreed performance standard in appropriate and relevant populations. The Cochrane Dementia and Cognitive Improvement Group’s consultation response11 to the National Institute on Aging–Alzheimer’s Association criteria incorporating biomarkers is still relevant, and includes the following points: research and clinical criteria are not so far apart, and often research criteria are assumed to be best practice (and, by implication, should be subject to similar evidence standards); assessments of reliability and validity to generate a sufficient evidence base must incorporate standardisation and replication, including in settings independent of those developing them. To suggest that this evidence exists remains premature. The IWG-2 authors report results in a narrative review with examples of supporting evidence. This is no substitute for an independent rigorous systematic review on each new measure, with systematic extraction of features for quality evaluation allowing full synthesis of existing evidence. Such a major exercise within the Cochrane Collaboration is under way. Study design, recruitment, implementation, and reporting for each component of the evidence are key to interpretation of value. If this exercise is not incorporated before criteria are created, it is difficult to assess how valuable criteria using such measures will be. The authors of IWG-2 do acknowledge this lack of evidence and the need for further work—let us as a community generate research that creates valuable new insights rather than tautological confirmation of a created reality (a danger for the ‘‘atypical’’ subheading group, which is likely to be welcome, but could also lead to repetition of much circular research). These criteria, like others, have been generated by a small group of internationally renowned researchers from high-income countries in settings with heavy investment in intensive technology (one middleincome country representative, very few women, narrow disciplinary mix, and several potential conflicts of interest regarding diagnostic process). The centres centres from which these authors are drawn are at the 533
Comment
forefront of diagnostic methodology, and are closely followed by national and international experts. The choice of methods adopted in the IWG-2 criteria reflects what is measurable and visible below the lamp in particular settings and on particular patient groups. The lamp’s light is increasing its reach but is still narrow and there is so much below other lamps or in the dark. We have a great deal of evidence that dementia seen around the world in people in their ninth and tenth decades is a good deal more complex than the Alzheimer’s paradigm allows. Use of the IWG-2 and other criteria to collect the range of measures in rigorous ways, wherever possible, will gradually help us to understand the complexity of human brain ageing, but the diagnoses created by these criteria should not be assumed to have an existence beyond the supporting evidence. Carol Brayne Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Forvie Site, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK [email protected]
I declare that I have no competing interests. 1
2 3 4 5 6 7 8
9
10
11
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–629. Brayne C. Clinicopathological studies of the dementias from an epidemiological viewpoint. Br J Psychiatry 1993; 162: 439–46. Morris JC, Blennow K, Froelich L, et al. Harmonized diagnostic criteria for Alzheimer’s disease: recommendations. J Intern Med 2014; 275: 204–13. Lock MM. The Alzheimer conundrum : entanglements of dementia and aging. Princeton: Princeton University Press, 2013. Brayne C, Davis D. Making Alzheimer’s and dementia research fit for populations. Lancet 2012; 380: 1441–43. Richards M, Brayne C. What do we mean by Alzheimer’s disease? BMJ 2010; 341: c4670. Brayne C. The elephant in the room—healthy brains in later life, epidemiology and public health. Nat Rev Neurosci 2007; 8: 233–39. Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37: 2220–41. Matthews FE, Stephan BC, McKeith IG, Bond J, Brayne C. Two-year progression from mild cognitive impairment to dementia: to what extent do different definitions agree? J Am Geriatr Soc 2008; 56: 1424–33. Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. New Engl J Med 1997; 337: 1667–74. Cochrane Dementia and Cognitive Improvement Group. Cochrane Dementia Group Response to Proposal for New Diagnostic Criteria. http://srdta.cochrane.org/ (accessed May 6, 2014).
Neuropathological processes in sepsis See Personal View page 630
534
Sepsis is a life-threatening condition that is often revealed or complicated by an encephalopathy but is not related to a primary brain infection. Sepsis-associated encephalopathy is defined by changes in consciousness, ranging from confusion (ie, delirium) to coma, and is characterised by various electrophysiological changes that have been associated with poor prognosis.1 Diagnosis of sepsis-associated encephalopathy is crucial for avoiding potentially devastating effects and is based on neurological examination that guides further investigations. Neuroimaging is needed if there are focal signs, persistent clinical symptoms, or severe changes in electroencephalogram (EEG) readings;1,2 analysis of CSF is needed if meningitis is suspected. Physicians should also assess whether sepsis is controlled and due to new infections or whether other causes of confusion are present. Sepsis-associated encephalopathy is associated with increased mortality and long-term cognitive impairment.1,3,4 Results from observational studies show
that cognitive impairment is accelerated by admission to hospital for sepsis or critical illness.1,3,4 Attention, memory, and executive functions are preferentially affected, and the intensity of cognitive impairment after sepsis is similar to that of mild Alzheimer’s disease,3 which suggests that sepsis-associated encephalopathy causes dementia with particular involvement of the frontal lobe and hippocampus. However, two points put this association into perspective. First, cognitive impairment after sepsis seems partially reversible, and might not follow a chronic progressive and irreversible course. Second, it is not known whether sepsis induces or worsens a pre-existing neurodegenerative process; pre-existing cognitive status is difficult to assess at admission in intensive care units, and predementia probably accounts substantially for the relation between sepsis and cognitive impairment, especially in elderly patients. The bidirectional relation between pneumonia and cognitive impairment4 might be attributable to undiagnosed or misdiagnosed bulbar dysfunctions that are common in neurodegenerative www.thelancet.com/neurology Vol 13 June 2014
immunotherapies, and by a presumptive role of neuralcell adhesion molecules in the modulation of REM-sleep in animals.10 The presence of unique HLA alleles in four of four patients tested suggests their necessity for presentation of peptides to T cells and for the triggering of immune responses via activation of T-cell receptors. The identity of this presumptive antigen and its relation to IgLON5 needs further delineation. Alternatively, the pathophysiological basis of symptoms of the patients described by Sabater and colleagues might have as much to do with the widespread deposition of hyperphosphorylated tau in brainstem and subcortical neurons that the authors report in post-mortem samples from two patients. If accumulation of hyperphosphorylated tau in neurons is ultimately established as the primary as opposed to a secondary pathological feature, this tauopathy will be unique from that of Alzheimer’s disease, frontotemporal dementia, corticobasal degeneration, or progressive supranuclear palsy, in which parasomnias, especially RBD, are rarely encountered. In either instance, this seminal work from Sabater and colleagues will enhance appreciation for sleep and sleepiness as windows for assessment of brain health, and will advance understanding of the diversity in molecular pathways leading to neurodegeneration.
David Rye Department of Neurology, Emory University, Atlanta, GA 30322, USA [email protected] I have served as a consultant and advisor to Jazz Pharmaceuticals, UCB Pharma, and Xenoport. I am listed as inventor on a patent application about the use of GABA receptor antagonists for excessive sleepiness and related disorders. 1
2 3
4 5
6
7
8
9
10
Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol 2014; published online April 3. http://dx.doi.org/10.1016/ S1474-4422(14)70051-1. Peever J, Luppi PH, Montplaisir J. Breakdown in REM sleep circuitry underlies REM sleep behavior disorder. Trends Neurosci 2014; 37: 279–88. De la Herran-Arita AK, Kornum BR, Mahlios J, et al. CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med 2013; 5: 216ra176. Lancaster E, Dalmau J. Neuronal autoantigens–pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 2012; 8: 380–90. Compta Y, Iranzo A, Santamaria J, Casamitjana R, Graus F. REM sleep behavior disorder and narcoleptic features in anti-Ma2-associated encephalitis. Sleep 2007; 30: 767–69. Adams C, McKeon A, Silber MH, Kumar R. Narcolepsy, REM sleep behavior disorder, and supranuclear gaze palsy associated with Ma1 and Ma2 antibodies and tonsillar carcinoma. Arch Neurol 2011; 68: 521–24. Iranzo A, Graus F, Clover L, et al. Rapid eye movement sleep behavior disorder and potassium channel antibody-associated limbic encephalitis. Ann Neurol 2006; 59: 178–81. Cornelius JR, Pittock SJ, McKeon A, et al. Sleep manifestations of voltage-gated potassium channel complex autoimmunity. Arch Neurol 2011; 68: 733–38. Stamelou M, Plazzi G, Lugaresi E, Edwards MJ, Bhatia KP. The distinct movement disorder in anti-NMDA receptor encephalitis may be related to Status Dissociatus: a hypothesis. Mov Disord 2012; 27: 1360–63. Black MA, Deurveilher S, Seki T, et al. Role of polysialylated neural cell adhesion molecule in rapid eye movement sleep regulation in rats. Eur J Neurosci 2009; 30: 2190–204.
A population perspective on the IWG-2 research diagnostic criteria for Alzheimer’s disease See Position Paper page 614
532
The International Working Group (IWG) for New Research Criteria for the Diagnosis of Alzheimer’s Disease has produced a revision of its earlier 2007 criteria, updating the diagnostic algorithm with novel measurement methods.1 The IWG-2 criteria, which join other new diagnostic criteria in the dementia field, cover clinical aspects of Alzheimer’s disease and new biological and imaging methods, including preclinical, clinical, and atypical presentations. The IWG-2 criteria, along with other new criteria, at last acknowledge the much reported fact that the component features of criteria exist along continua when measured in older populations.2 The new criteria also explicitly note that clinical expression of dementia, particularly in individuals in their ninth decade and above, does not
always reflect underlying neurobiology. The stated intention of these IWG-2 criteria is for use within research settings. How are researchers and clinicians to cope with several sets of criteria from highly respected leaders in the field? Certainly, they should not be implemented in the research or clinical setting without careful consideration. A helpful harmonisation exercise done by many of these leaders suggested basic principles: Alzheimer’s disease should be defined as a brain disorder, regardless of clinical status; the clinically expressed disorder, including its prodromal stages, should be referred to as symptomatic Alzheimer’s disease; after the successful completion of standardisation efforts, incorporation of biomarkers into diagnostic algorithms www.thelancet.com/neurology Vol 13 June 2014
Comment
for Alzheimer’s disease should be considered; and nonamnestic, atypical presentations should be included as symptomatic Alzheimer’s disease, especially when there is supportive biomarker evidence.3 This last statement segues to this IWG-2 update. However, the implicit message remains that if Alzheimer’s disease pathology could be detected early enough and effectively treated, the assumed appearance of a later dementia syndrome would be averted. Through these efforts, most dementia cases worldwide (assuming that Alzheimer’s-type pathology is the cause) would be prevented and a global catastrophe averted. Is this simply wishful thinking? The wider implications of the adoption of a biological Alzheimer’s disease diagnosis have been emphasised by many researchers.4 In view of the known propensity for new diagnostic criteria to be adopted in clinical settings, are the IWG-2 criteria ready for roll out? For now, they will be applied to those selected individuals—relatively young and fit—attending highly specialised clinics.5 Will the use of these criteria in such settings generate relevant evidence for dementia as a whole? These and other criteria still rely on the dominant Alzheimer’s paradigm, despite ample evidence that this paradigm does not survive well outside highly selective specialist environments.6 Thus, comorbidity and the relation with ageing of the brain are mentioned only briefly in the new criteria, but remain elephants in the room for societally relevant outcomes from dementia research.7 Taking this, and the responses to earlier sets of criteria, into account, a key recommendation could be that researchers should welcome the new criteria, but also follow, as a community, the approach suggested by Hachinski and colleagues8 in recognition of the confusion around criteria for vascular dementia; instead of criteria, a recommended set of measurements was developed through consensus that is sensitive to research settings, to help to generate a better evidence base for future criteria. These measurements must include all those elements that make up a highquality diagnosis—reasonable evidence for prognosis, treatment, and management relevant to that person— otherwise patients will be given diagnoses with implications, but without meaning. Previous exercises have shown how important such stepping back can be to understand how diagnostic criteria perform. Examples include the criteria for mild cognitive impairment9 and dementia,10 which both show how www.thelancet.com/neurology Vol 13 June 2014
variable criteria can be in the context of real populations, including who is identified and what the prognosis is. It is crucial that new sets of criteria, and the measures that make them up, are defined and tested in a rigorous way. The suggestions made in IWG-2 are an important part of this process. Each measure in the criteria must be tested and validated against some agreed performance standard in appropriate and relevant populations. The Cochrane Dementia and Cognitive Improvement Group’s consultation response11 to the National Institute on Aging–Alzheimer’s Association criteria incorporating biomarkers is still relevant, and includes the following points: research and clinical criteria are not so far apart, and often research criteria are assumed to be best practice (and, by implication, should be subject to similar evidence standards); assessments of reliability and validity to generate a sufficient evidence base must incorporate standardisation and replication, including in settings independent of those developing them. To suggest that this evidence exists remains premature. The IWG-2 authors report results in a narrative review with examples of supporting evidence. This is no substitute for an independent rigorous systematic review on each new measure, with systematic extraction of features for quality evaluation allowing full synthesis of existing evidence. Such a major exercise within the Cochrane Collaboration is under way. Study design, recruitment, implementation, and reporting for each component of the evidence are key to interpretation of value. If this exercise is not incorporated before criteria are created, it is difficult to assess how valuable criteria using such measures will be. The authors of IWG-2 do acknowledge this lack of evidence and the need for further work—let us as a community generate research that creates valuable new insights rather than tautological confirmation of a created reality (a danger for the ‘‘atypical’’ subheading group, which is likely to be welcome, but could also lead to repetition of much circular research). These criteria, like others, have been generated by a small group of internationally renowned researchers from high-income countries in settings with heavy investment in intensive technology (one middleincome country representative, very few women, narrow disciplinary mix, and several potential conflicts of interest regarding diagnostic process). The centres centres from which these authors are drawn are at the 533
Comment
forefront of diagnostic methodology, and are closely followed by national and international experts. The choice of methods adopted in the IWG-2 criteria reflects what is measurable and visible below the lamp in particular settings and on particular patient groups. The lamp’s light is increasing its reach but is still narrow and there is so much below other lamps or in the dark. We have a great deal of evidence that dementia seen around the world in people in their ninth and tenth decades is a good deal more complex than the Alzheimer’s paradigm allows. Use of the IWG-2 and other criteria to collect the range of measures in rigorous ways, wherever possible, will gradually help us to understand the complexity of human brain ageing, but the diagnoses created by these criteria should not be assumed to have an existence beyond the supporting evidence. Carol Brayne Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Forvie Site, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK [email protected]
I declare that I have no competing interests. 1
2 3 4 5 6 7 8
9
10
11
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–629. Brayne C. Clinicopathological studies of the dementias from an epidemiological viewpoint. Br J Psychiatry 1993; 162: 439–46. Morris JC, Blennow K, Froelich L, et al. Harmonized diagnostic criteria for Alzheimer’s disease: recommendations. J Intern Med 2014; 275: 204–13. Lock MM. The Alzheimer conundrum : entanglements of dementia and aging. Princeton: Princeton University Press, 2013. Brayne C, Davis D. Making Alzheimer’s and dementia research fit for populations. Lancet 2012; 380: 1441–43. Richards M, Brayne C. What do we mean by Alzheimer’s disease? BMJ 2010; 341: c4670. Brayne C. The elephant in the room—healthy brains in later life, epidemiology and public health. Nat Rev Neurosci 2007; 8: 233–39. Hachinski V, Iadecola C, Petersen RC, et al. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 2006; 37: 2220–41. Matthews FE, Stephan BC, McKeith IG, Bond J, Brayne C. Two-year progression from mild cognitive impairment to dementia: to what extent do different definitions agree? J Am Geriatr Soc 2008; 56: 1424–33. Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V. The effect of different diagnostic criteria on the prevalence of dementia. New Engl J Med 1997; 337: 1667–74. Cochrane Dementia and Cognitive Improvement Group. Cochrane Dementia Group Response to Proposal for New Diagnostic Criteria. http://srdta.cochrane.org/ (accessed May 6, 2014).
Neuropathological processes in sepsis See Personal View page 630
534
Sepsis is a life-threatening condition that is often revealed or complicated by an encephalopathy but is not related to a primary brain infection. Sepsis-associated encephalopathy is defined by changes in consciousness, ranging from confusion (ie, delirium) to coma, and is characterised by various electrophysiological changes that have been associated with poor prognosis.1 Diagnosis of sepsis-associated encephalopathy is crucial for avoiding potentially devastating effects and is based on neurological examination that guides further investigations. Neuroimaging is needed if there are focal signs, persistent clinical symptoms, or severe changes in electroencephalogram (EEG) readings;1,2 analysis of CSF is needed if meningitis is suspected. Physicians should also assess whether sepsis is controlled and due to new infections or whether other causes of confusion are present. Sepsis-associated encephalopathy is associated with increased mortality and long-term cognitive impairment.1,3,4 Results from observational studies show
that cognitive impairment is accelerated by admission to hospital for sepsis or critical illness.1,3,4 Attention, memory, and executive functions are preferentially affected, and the intensity of cognitive impairment after sepsis is similar to that of mild Alzheimer’s disease,3 which suggests that sepsis-associated encephalopathy causes dementia with particular involvement of the frontal lobe and hippocampus. However, two points put this association into perspective. First, cognitive impairment after sepsis seems partially reversible, and might not follow a chronic progressive and irreversible course. Second, it is not known whether sepsis induces or worsens a pre-existing neurodegenerative process; pre-existing cognitive status is difficult to assess at admission in intensive care units, and predementia probably accounts substantially for the relation between sepsis and cognitive impairment, especially in elderly patients. The bidirectional relation between pneumonia and cognitive impairment4 might be attributable to undiagnosed or misdiagnosed bulbar dysfunctions that are common in neurodegenerative www.thelancet.com/neurology Vol 13 June 2014
