Reflection and Reaction http://neurology.thelancet.com Vol 4 December 2005 789 might be to define the relative amounts of types 1 and 2 PrP Sc 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 PrP Sc , these apparently discrepant findings probably indicate that in- vitro protease digestion is an inefficient method with which to study PrP Sc conformations. Indeed, approaches that do not rely on protease digestion to investigate PrP Sc conformations confirm that there are more strain- associated PrP Sc conformations than can be defined by their resistance to in-vitro digestion with proteinase K. 10 Glenn Telling Department of Microbiology, Immunology and Molecular Genetics, Department of Neurology, and the Sanders Brown Center on Aging, University of Kentucky, Lexington, USA gtell2@email.uky.edu I have no conflicts of interest. 1 Hill AF, Joiner S, Wadsworth JD, et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003; 126: 1333–46. 2 Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterisation. Br Med Bull 2003; 66: 213–39. 3 Polymenidou M, Stoeck K, Glatzel M, Vey M, Aguzzi A. Coexistence of multiple PrP Sc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 2005; 4: 805–14. 4 Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 1994; 68: 7859–68. 5 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. 6 Telling GC, Scott M, Hsiao KK, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human- mouse prion protein. Proc Natl Acad Sci USA 1994; 91: 9936–40. 7 Wadsworth JDF, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J. Strain- specific prion-protein conformation determined by metal ions. Nat Cell Biol 1999; 1: 55–59. 8 Notari S, Capellari S, Giese A, et al. Effects of different experimental conditions on the PrP Sc core generated by protease digestion: implications for strain typing and molecular classification of CJD. J Biol Chem 2004; 279: 16797–804. 9 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. 10 Safar J, Wille H, Itri V, et al. Eight prion strains have PrP Sc molecules with different conformations. Nat Med 1998; 4: 1157–65. 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 eight- graded scale. 2 Outside of Sweden, however, the use of this scale remains very limited. The Glasgow coma scale 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 colleagues 5 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 Quantifying consciousness