V.J.M. Wijnen

The continuing problem of diagnosing unresponsive patients : searching for neurophysiological correlates of consciousness

Objectively diagnosing disorders of consciousness, such as vegetative state (VS) and minimally conscious state (MCS), is a great challenge as well as a very important task. It is becoming more obvious that a diagnosis based only on behavioral assessment does not accurately predict underlying brain functioning after severe brain damage, the state of consciousness, or rehabilitation possibilities. Earlier studies found up to 43% of patients who were erroneously assigned the diagnosis of VS when using behavioral assessment (Andrews et al., 1996; Childs et al., 1993). A recent prospective study revealed that by using observational methods, the rate of misdiagnoses in VS has not changed in the past 15 years: still 41% of VS patients, and also 10% of MCS patients were misdiagnosed (Schnakers et al., 2009). Schnakers et al. therefore recommend to always use a sensitive standardized neurobehavioral assessment scale, e.g., the Coma Recovery Scale-Revised (GRS-R, Giacino et al., 2004), or the Post-Acute Level of Consciousness scale (PALOC-s; Eilander et al., 2009). Doing so might indeed be an important step forward toward accurate diagnoses, with great impact on the treatment plan. However, consciousness and awareness, memory and other higher brain functions are not necessarily characterized by overt behavioral output. Therefore, misdiagnoses are likely to remain persistent in this field, even leading to extreme cases such as described by Schnakers et al. (2009). They reported on a patient with an atypical locked-in syndrome who had been conscious for 24 years, but was left untreated in a nursing home because he was misdiagnosed as vegetative. What is needed to prevent such extreme situations are valid and reliable markers of states of consciousness. In this respect, the latest work of Catherine Fischer and colleagues published in this issue of the journal (Fischer et al., 2010) is of great importance. They describe a study in which they searched for electrophysiological markers of cognition in permanent VS and MCS patients. Fischer and colleagues had conducted numerous earlier studies in comatose, vegetative and minimally conscious patients as a result of acquired brain damage of diverse etiology (e.g., stroke, anoxia or traumatic injuries). In their earlier work, they mainly focused on the prognostic value of sensory and cognitive evoked potentials in the acute comatose phase, immediately after the brain damage. One of the strongest predictors was found to be the Mismatch Negativity (MMN) (Fischer et al., 1999, 2004); a brain wave that detects auditory deviance in a regular sequence of tones (Näätänen et al., 1978). In a more recent study Fischer et al. (2008) introduced a new paradigm, in which they included an infrequent, highly deviant as well as subjectively significant speech stimulus; the subject’s own name (SON) spoken by an unfamiliar female voice. The occurrence of a brain response to SON (a novelty P3) increased the prognostic value of the MMN alone. In the current issue, Fischer et al. (2010) describe a study in which they use their latest paradigm in groups of patients in the permanent VS or MCS. The event-related potentials did not differ between the MCS and VS patients in their study. This finding is in contrast with other studies in which differences in brain activity between VS and MCS patients have already been found using Positron Emission Tomography (PET) while presenting auditory or noxious stimuli (Boly et al., 2004, 2005), functional Magnetic Resonance Imaging (fMRI) while presenting the patient’s name (Di et al., 2007) and a language paradigm (Coleman et al., 2007; Fernandez-Espejo et al., 2008), as well as by using event-related potentials, such as the MMN (Wijnen et al., 2007), and P3 to the patient’s name (Perrin et al., 2006; Schnakers et al., 2008). The discrepancy between Fischer et al.’s (2010) null finding and the other studies might be related to the fact that Fischer et al.’s patients were all in a permanent VS. The Multi-Society Task Force on PVS (1994) defined the VS to be permanent three months after non-traumatic brain injury or 12 months after traumatic brain injury. Importantly, although Fischer et al. (2010) did not find differences between states as others did, they did find differences related to the etiology of the brain damage; patients who suffered traumatic brain damage were more likely to show electrophysiological responses to their own name compared to anoxic patients. This finding causes other studies to be viewed in a better perspective. For instance, in the study of Wijnen et al., four out of five patients who showed an increase in MMN and finally recovered to consciousness had suffered traumatic brain injury (Wijnen et al., 2007), and in the study of Schnakers et al. (2008), four out of five MCS patients who showed a P3 to the active condition (counting own name) were also suffering from traumatic brain injury. Thus, the study of Fischer et al. (2010) suggests that, apart from not relying on behavioral observation alone, etiology (mainly traumatic versus anoxic brain damage) may be another important factor in determining the correct diagnosis of states of consciousness. Diagnosing unresponsive patients by behavioral observation alone has a high chance of resulting in an underestimation of the