- Email: [email protected]
Quantifying consciousness
Reflection and Reaction
might be to define the relative amounts of types 1 and 2 PrPSc in brains of patients with CJD with discriminatory antibodies. Finally, rather than undermining the hypothesis that strain-specific characteristics of prions are determined by the conformation of PrPSc, these apparently discrepant findings probably indicate that invitro protease digestion is an inefficient method with which to study PrPSc conformations. Indeed, approaches that do not rely on protease digestion to investigate PrPSc conformations confirm that there are more strainassociated PrPSc conformations than can be defined by their resistance to in-vitro digestion with proteinase K.10
1 2 3
4
5
6
7
8
Glenn Telling Department of Microbiology, Immunology and Molecular Genetics, Department of Neurology, and the Sanders Brown Center on Aging, University of Kentucky, Lexington, USA [email protected] I have no conflicts of interest.
9
10
Hill AF, Joiner S, Wadsworth JD, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003; 126: 1333–46. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull 2003; 66: 213–39. Polymenidou M, Stoeck K, Glatzel M, Vey M, Aguzzi A. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 2005; 4: 805–14. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859–68. Telling GC, Parchi P, DeArmond SJ, et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 1996; 274: 2079–82. Telling GC, Scott M, Hsiao KK, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric humanmouse prion protein. Proc Natl Acad Sci USA 1994; 91: 9936–40. Wadsworth JDF, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J. Strainspecific prion-protein conformation determined by metal ions. Nat Cell Biol 1999; 1: 55–59. Notari S, Capellari S, Giese A, et al. Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J Biol Chem 2004; 279: 16797–804. Zanusso G, Farinazzo A, Fiorini M, et al. pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377–80. Safar J, Wille H, Itri V, et al. Eight prion strains have PrPSc molecules with different conformations. Nat Med 1998; 4: 1157–65.
Quantifying consciousness In 1974, Teasdale and Jennett’s Glasgow coma scale (GCS) was published in The Lancet.1 This standardised bedside tool to quantify consciousness became a medical classic. Despite its indisputable worldwide success it has also been criticised. Several investigators disagree that scoring eye opening is sufficiently indicative of activity in brainstem arousal systems and have proposed coma scales that include brainstem reflexes, such as the comprehensive level of consciousness scale, the clinical neurologic assessment tool, the Bouzarth coma scale, and the Maryland coma scale.2 None of these scales have known widespread use because they generally are more complex than the Glasgow coma scale. A simpler system, the Glasgow Liège scale,3 combined the Glasgow coma scale with five brainstem reflexes but also failed to convince the medical community outside its country of origin. Another shortcoming of the Glasgow coma scale is that the increasing use of intubation has rendered its verbal component immeasurable in many patients in coma. A Swedish team, therefore, developed the reaction level scale, which does not include a verbal response criterion but combines different responses into an ordinal eightgraded scale.2 Outside of Sweden, however, the use of this scale remains very limited. The Glasgow coma scale http://neurology.thelancet.com Vol 4 December 2005
also lacks reliability when assessing patients progressively recovering from their coma and entering a vegetative or minimally conscious state. For these patients, more sensitive scales are the coma recovery scale-revised, sensory modality assessment and rehabilitation technique, or Wessex head injury matrix.4 These scales, however, are not adapted for use in acute settings. Wijdicks and colleagues5 think it is time for a change and have proposed a new coma scale: the full outline of unresponsiveness (FOUR). This acronym reflects the number of components tested (eye, motor, brainstem, and respiratory functions) and the maximum score assigned to each of these (E4, M4, B4, and R4). The researchers tested 120 patients in intensive care and compared FOUR scores made by neurology residents, neurointensivists, and neuroscience nurses with scores using the Glasgow coma scale. Their scale explicitly tests for eye movements or blinking on command— requesting to open eyes manually if closed. This test facilitates the early detection of locked-in syndrome and is very much welcomed, given that recent studies have shown that medical carers did not recognise signs of consciousness during the first weeks in more than half of patients with locked-in syndrome.6 Unlike the 789
Reflection and Reaction
450 400
Number of papers
350 300 250 200 150 100 50 0 1975
1980
1985
1990
1995
2000
2005
Year
Figure: Ever-increasing number of papers making reference to the Glasgow coma scale MEDLINE search done in October 2005.
Glasgow coma scale, FOUR also tests for eye tracking of a moving object. Most commonly, this is the first sign heralding the transition from a vegetative to a minimally conscious state.4 The rest of the FOUR’s E-score is identical to that of the Glasgow coma scale. Most innovative is the hand-position test, in which patients are asked to make thumbs-up, fist, or peace signs. This is a smart alternative to the V-score of the Glasgow coma scale and remains testable in intubated patients. The rest of the M-score is taken from the Glasgow coma scale, with the exception that no difference is made between abnormal stereotyped flexion and normal flexion to pain (similar to the early version of the Glasgow coma scale1). This difference may be difficult for inexperienced observers to appreciate but might lead to lower prognostic power of the FOUR scale. Generalised myoclonic status epilepticus, which is a sign of poor prognosis in anoxic coma, is scored the same as absent motor response to pain. Amending the Glasgow coma scale’s lack of brainstem-reflexes assessment, FOUR tests pupil, cornea, and cough reflexes and separately scores respiration. For untrained users, evaluation of the brainstem component is probably the most complex because it proposes different combinations of the presence or absence of each of its three reflexes. Unilateral fixed midriasis, alerting uncal herniation, has a separate score. To avoid corneal trauma by repeated testing, it is cleverly proposed to instil some drops of saline on the cornea. The last category of FOUR scores 790
respiration as spontaneous regular, irregular, CheyneStokes, ventilator-assessed patient-generated breaths, or absent. Whether pulmonary disease and respiratory settings will bias the assessment and how reliably inexperienced users can separate Cheyne-Stokes from irregular respiration are unknown. With all FOUR categories graded zero, the scale alerts to consider brain death or standard apnoea (oxygen-diffusion) testing. In the past 30 years, many coma scales have been proposed as an alternative to the Glasgow coma scale, but none with success. Not all change is an improvement, but there can be no improvement without change. Do we need another coma scale? The answer depends on who uses it, where it is used, and why it is used. Is it used for clinical diagnosis, assessment of neurological change, prognosis, guiding interventional decisions, or research purposes? The validity of this new scale first needs to be corroborated when used in a general hospital setting by examiners other than neuroscience professionals. By virtue of its simplicity, and despite its drawbacks, the Glasgow coma scale became the most universally used and validated consciousness scale worldwide. More than 4500 publications make reference to its use (figure) and it is part of many other scoring systems including the acute physiology and chronic health evaluation II score. Albeit convinced of the utility of FOUR, the Glasgow coma scale will not be dethroned effortlessly. Steven Laureys, Sonia Piret,Didier Ledoux Fonds National de Recherche Scientifique, Cyclotron Research Centre and Neurology Dept, Université de Liège, (SL), and General Intensive Care Department, Centre Hospitalier Universitaire, Liège, Belgium (SP, DL) [email protected] We have no conflicts of interest. 1 2
3
4
5
6
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2: 81–4. Laureys S, Majerus S, Moonen G. Assessing consciousness in critically ill patients. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Heidelberg: Springer-Verlag, 2002: 715–27. Born JD, Albert A, Hans P, Bonnal J. Relative prognostic value of best motor response and brain stem reflexes in patients with severe head injury. Neurosurgery 1985; 16: 595–601. Majerus S, Gill-Thwaites H, Andrews K, Laureys S. Behavioral evaluation of consciousness in severe brain damage. In: Laureys S, ed. The boundaries of consciousness: neurobiology and neuropathology. Amsterdam: Elsevier, 2005: 397–413. Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: the FOUR score. Ann Neurol 2005; 58: 585–93. Laureys S, Pellas F, Van Eeckhout P, et al. The locked-in syndrome: what is it like to be conscious but paralyzed and voiceless? Prog Brain Res 2005; 150: 495–511.
http://neurology.thelancet.com Vol 4 December 2005
might be to define the relative amounts of types 1 and 2 PrPSc in brains of patients with CJD with discriminatory antibodies. Finally, rather than undermining the hypothesis that strain-specific characteristics of prions are determined by the conformation of PrPSc, these apparently discrepant findings probably indicate that invitro protease digestion is an inefficient method with which to study PrPSc conformations. Indeed, approaches that do not rely on protease digestion to investigate PrPSc conformations confirm that there are more strainassociated PrPSc conformations than can be defined by their resistance to in-vitro digestion with proteinase K.10
1 2 3
4
5
6
7
8
Glenn Telling Department of Microbiology, Immunology and Molecular Genetics, Department of Neurology, and the Sanders Brown Center on Aging, University of Kentucky, Lexington, USA [email protected] I have no conflicts of interest.
9
10
Hill AF, Joiner S, Wadsworth JD, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003; 126: 1333–46. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull 2003; 66: 213–39. Polymenidou M, Stoeck K, Glatzel M, Vey M, Aguzzi A. Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 2005; 4: 805–14. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859–68. Telling GC, Parchi P, DeArmond SJ, et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 1996; 274: 2079–82. Telling GC, Scott M, Hsiao KK, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric humanmouse prion protein. Proc Natl Acad Sci USA 1994; 91: 9936–40. Wadsworth JDF, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J. Strainspecific prion-protein conformation determined by metal ions. Nat Cell Biol 1999; 1: 55–59. Notari S, Capellari S, Giese A, et al. Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J Biol Chem 2004; 279: 16797–804. Zanusso G, Farinazzo A, Fiorini M, et al. pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377–80. Safar J, Wille H, Itri V, et al. Eight prion strains have PrPSc molecules with different conformations. Nat Med 1998; 4: 1157–65.
Quantifying consciousness In 1974, Teasdale and Jennett’s Glasgow coma scale (GCS) was published in The Lancet.1 This standardised bedside tool to quantify consciousness became a medical classic. Despite its indisputable worldwide success it has also been criticised. Several investigators disagree that scoring eye opening is sufficiently indicative of activity in brainstem arousal systems and have proposed coma scales that include brainstem reflexes, such as the comprehensive level of consciousness scale, the clinical neurologic assessment tool, the Bouzarth coma scale, and the Maryland coma scale.2 None of these scales have known widespread use because they generally are more complex than the Glasgow coma scale. A simpler system, the Glasgow Liège scale,3 combined the Glasgow coma scale with five brainstem reflexes but also failed to convince the medical community outside its country of origin. Another shortcoming of the Glasgow coma scale is that the increasing use of intubation has rendered its verbal component immeasurable in many patients in coma. A Swedish team, therefore, developed the reaction level scale, which does not include a verbal response criterion but combines different responses into an ordinal eightgraded scale.2 Outside of Sweden, however, the use of this scale remains very limited. The Glasgow coma scale http://neurology.thelancet.com Vol 4 December 2005
also lacks reliability when assessing patients progressively recovering from their coma and entering a vegetative or minimally conscious state. For these patients, more sensitive scales are the coma recovery scale-revised, sensory modality assessment and rehabilitation technique, or Wessex head injury matrix.4 These scales, however, are not adapted for use in acute settings. Wijdicks and colleagues5 think it is time for a change and have proposed a new coma scale: the full outline of unresponsiveness (FOUR). This acronym reflects the number of components tested (eye, motor, brainstem, and respiratory functions) and the maximum score assigned to each of these (E4, M4, B4, and R4). The researchers tested 120 patients in intensive care and compared FOUR scores made by neurology residents, neurointensivists, and neuroscience nurses with scores using the Glasgow coma scale. Their scale explicitly tests for eye movements or blinking on command— requesting to open eyes manually if closed. This test facilitates the early detection of locked-in syndrome and is very much welcomed, given that recent studies have shown that medical carers did not recognise signs of consciousness during the first weeks in more than half of patients with locked-in syndrome.6 Unlike the 789
Reflection and Reaction
450 400
Number of papers
350 300 250 200 150 100 50 0 1975
1980
1985
1990
1995
2000
2005
Year
Figure: Ever-increasing number of papers making reference to the Glasgow coma scale MEDLINE search done in October 2005.
Glasgow coma scale, FOUR also tests for eye tracking of a moving object. Most commonly, this is the first sign heralding the transition from a vegetative to a minimally conscious state.4 The rest of the FOUR’s E-score is identical to that of the Glasgow coma scale. Most innovative is the hand-position test, in which patients are asked to make thumbs-up, fist, or peace signs. This is a smart alternative to the V-score of the Glasgow coma scale and remains testable in intubated patients. The rest of the M-score is taken from the Glasgow coma scale, with the exception that no difference is made between abnormal stereotyped flexion and normal flexion to pain (similar to the early version of the Glasgow coma scale1). This difference may be difficult for inexperienced observers to appreciate but might lead to lower prognostic power of the FOUR scale. Generalised myoclonic status epilepticus, which is a sign of poor prognosis in anoxic coma, is scored the same as absent motor response to pain. Amending the Glasgow coma scale’s lack of brainstem-reflexes assessment, FOUR tests pupil, cornea, and cough reflexes and separately scores respiration. For untrained users, evaluation of the brainstem component is probably the most complex because it proposes different combinations of the presence or absence of each of its three reflexes. Unilateral fixed midriasis, alerting uncal herniation, has a separate score. To avoid corneal trauma by repeated testing, it is cleverly proposed to instil some drops of saline on the cornea. The last category of FOUR scores 790
respiration as spontaneous regular, irregular, CheyneStokes, ventilator-assessed patient-generated breaths, or absent. Whether pulmonary disease and respiratory settings will bias the assessment and how reliably inexperienced users can separate Cheyne-Stokes from irregular respiration are unknown. With all FOUR categories graded zero, the scale alerts to consider brain death or standard apnoea (oxygen-diffusion) testing. In the past 30 years, many coma scales have been proposed as an alternative to the Glasgow coma scale, but none with success. Not all change is an improvement, but there can be no improvement without change. Do we need another coma scale? The answer depends on who uses it, where it is used, and why it is used. Is it used for clinical diagnosis, assessment of neurological change, prognosis, guiding interventional decisions, or research purposes? The validity of this new scale first needs to be corroborated when used in a general hospital setting by examiners other than neuroscience professionals. By virtue of its simplicity, and despite its drawbacks, the Glasgow coma scale became the most universally used and validated consciousness scale worldwide. More than 4500 publications make reference to its use (figure) and it is part of many other scoring systems including the acute physiology and chronic health evaluation II score. Albeit convinced of the utility of FOUR, the Glasgow coma scale will not be dethroned effortlessly. Steven Laureys, Sonia Piret,Didier Ledoux Fonds National de Recherche Scientifique, Cyclotron Research Centre and Neurology Dept, Université de Liège, (SL), and General Intensive Care Department, Centre Hospitalier Universitaire, Liège, Belgium (SP, DL) [email protected] We have no conflicts of interest. 1 2
3
4
5
6
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2: 81–4. Laureys S, Majerus S, Moonen G. Assessing consciousness in critically ill patients. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Heidelberg: Springer-Verlag, 2002: 715–27. Born JD, Albert A, Hans P, Bonnal J. Relative prognostic value of best motor response and brain stem reflexes in patients with severe head injury. Neurosurgery 1985; 16: 595–601. Majerus S, Gill-Thwaites H, Andrews K, Laureys S. Behavioral evaluation of consciousness in severe brain damage. In: Laureys S, ed. The boundaries of consciousness: neurobiology and neuropathology. Amsterdam: Elsevier, 2005: 397–413. Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: the FOUR score. Ann Neurol 2005; 58: 585–93. Laureys S, Pellas F, Van Eeckhout P, et al. The locked-in syndrome: what is it like to be conscious but paralyzed and voiceless? Prog Brain Res 2005; 150: 495–511.
http://neurology.thelancet.com Vol 4 December 2005