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Future Neurology
Editorial
Neuroimaging of patients with disorders of consciousness: from bench to bedside? “The diagnosis, prognosis and treatment of patients with disorders of consciousness is a medical, societal and ethical challenge.” Laurent Hermoye1, Jean-Jacques Lemaire2 & Steven Laureys*3
Imagilys, Brussels, Belgium Service of Neurosurgery, University Hospital, Clermont-Ferrand, France Coma Science Group, Liège University, Allée du 6 août no.°8, Sart Tilman B30, 4000 Liège, Belgium *Author for correspondence: Tel.: +32 4 366 2316 n
[email protected] 1 2 3
The diagnosis, prognosis and treatment of patients with disorders of consciousness is a medical, societal and ethical challenge. Progress in intensive care has led to an increase in the number of patients who survive severe acute brain damage in which etiology is most often traumatic or ischemic. This can lead to disabilities that, in some cases, can last a lifetime. In the USA, the number of individuals who sustain severe traumatic brain injury with prolonged loss of consciousness each year is estimated to be between 56 and 170 per 1 million [1]. The burden of these disorders is so heavy, for the patients themselves, for their family and for society, that any progress in this field of research can have huge societal impact. The definition of consciousness itself remains debated. In 1966, Plum and Posner defined it as “awareness of self and the environment” [2]. It can be divided into two components: wakefulness, which is related to the level of arousal and can be detected by checking if the patient’s eyes are open or closed; and awareness, which is related to the perception of oneself and the environment. In normal individuals, these two components are generally positively correlated [3]. In patients with disorders of consciousness, these two components can be dissociated [4]. The diagnosis of brain death requires the loss of all brainstem reflexes and the demonstration of continuing apnea in a persistently comatose patient [5]. In coma, both wakefulness and awareness are missing [6]. It is a temporary state: after 2–4 weeks, the patients who survive usually awaken, potentially leading to one of the disorders described here after. Vegetative state, now called ‘unresponsive wakefulness 10.2217/FNL.13.53 © 2013 Future Medicine Ltd
syndrome’ [7], in order to avoid the negative connotation of patients living like ‘vegetables’, describes patients who are awake (i.e., show eye opening), however, remain unresponsive (i.e., show only reflex movements). Since 2002, minimally conscious state defines patients who have more than reflex movements but cannot communicate [1]. Their awareness of themselves and the environment is limited but visible. Locked-in syndrome, also called pseudocoma, is not a disorder of consciousness. Owing to a lesion in the brainstem, these patients are completely paralyzed, except for their eyes, which are their only communication tool. The differential diagnosis between all these disorders can be complex and, if not carefully assessed, patients may be misclassified. The first-line examination is behavioral. Wakefulness is not complex to assess clinically: if the patients have their eyes open, they are awake; if not, they are not awake. Awareness is more complex to assess in these patients, whose motor responses are very limited and can be inconsistent. The assessment of nonreflex behavior (e.g., visual pursuit or orientation to pain) or response to command and other behavioral tests is sufficient in most patients, but their results are sometimes not conclusive or may miss the presence of residual consciousness in the absence of motor signs thereof. New imaging techniques in patients with disorders of consciousness have several purposes: scientifically, understanding the neural correlates of consciousness; clinically, assessing the brain injury in these patients, their degree of awareness and, potentially, making a better prognosis and communicating with them. Future Neurol. (2013) 8(6), 601–603
Keywords coma n consciousness disorders of consciousness n fMRI n locked-in syndrome n minimally conscious state n neuroimaging n unresponsive wakefulness syndrome n n
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ISSN 1479-6708
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Editorial
Hermoye, Lemaire & Laureys
In 2006, our group, in collaboration with Owen’s group at Cambridge University (Cambridge, UK), published a groundbreaking article [8], in which we showed signs of awareness, as detected by functional MRI (fMRI), in a patient who was thought to be in the vegetative/unresponsive state. The patient, who was asked to mentally play tennis and visit her house, exhibited similar activations (in the supplementary motor area and parahippocampal gyrus) than healthy volunteers performing the same mental imagery tasks. This article made headlines around the world, but also triggered doubts and criticisms [9], arguing that the detected activations may be the result of unconscious processes or may be unspecific. However, 4 years later, we published similar results in a larger cohort [10], proving that functional imaging can help assess the state of consciousness of some patients that were clinically misclassified, and we even communicated with one patient that was assessed in our tertiary expert center.
“The burden of these disorders is so heavy, for the patients themselves, for their family and for society, that any progress in this field of research can have huge societal impact.” Nevertheless, several years later, has fMRI become a real clinical tool for the diagnosis of patients with disorders of consciousness? In our center, yes, among a whole range of other clinical and imaging examinations that help our multidisciplinary team to make a better documented diagnosis for each patient. Since 2010, we have used MRI to examine over 150 patients with disorders of consciousness. Over 50 of those examinations included active fMRI paradigms. Globally, approximately a quarter of the patients performed at least one of the two tasks, indicating a capacity to understand and carry out instructions, which suggested a preserved consciousness. However, practical aspects specific to these patients (e.g., movements, which sometimes requires anesthesia) can make the examination complex, and the development of user-friendly tools is necessary for a wide dissemination of the technique. All of the MRI examinations we performed included resting-state fMRI sequences. This neuroimaging method, based on correlations of spontaneous variations of the blood oxygen leveldependent signal in various places of the brain, can identify functional networks, without requiring the active cooperation of the patient. We have 602
Future Neurol. (2013) 8(6)
shown that the connectivity of one of them, the default mode network, is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment [11]. Other advanced neuroimaging techniques, such as diffusion tensor imaging [12], magnetic resonance spectroscopy [13] and PET scans [6], have also shown their utility in the diagnosis and p rognosis of patients with disorders of consciousness. Severe long-lasting disorders of consciousness cover a wide range of clinical conditions related to intricate dysfunctions of neural correlates of consciousness, of the sensorimotor system, and of behavior and cognition. New imaging techniques should certainly help to decipher the complexity of such disorders, allowing personalized treatments and helping patients’ families and surrogate decision-makers to participate actively, in order to determine an appropriate healthcare pathway in order to reach a long-term perspective [14]. Treatments of disorders of consciousness rely mainly on rehabilitation techniques, although their effectiveness is debated [15]. In most cases, caregivers stimulate remaining brain functions, in order to preserve them, and stimulate spontaneous recovery, via the mechanisms of neuronal plasticity [16]. In seldom cases, drugs, such as zolpidem, can induce a paradoxical response leading to recovery of arousal and cognitive abilities [17]. Invasive techniques, such as deep brain stimulation [18], which are for the moment limited to research studies, should benefit from imaging techniques, which reveal specific dysfunctions of brain networks correlated with clinical symptoms [19]. Targeting pertinent areas within such networks, in order to modulate specific circuits, such as the thalamo–cortico–thalamic loop as suggested by observational studies, could be proposed to alleviate consciousness impairments [18]. Finally, in patients who show activations when stimulated with fMRI, this method could be used to establish a simple binary communication [10]; imagine playing tennis to answer ‘yes’, imagine visiting your house to answer ‘no’. In the future, not only will it allow these patients to partially escape the mental jail in which they reside, and establish a basic communication with their family, but also could it allow the medical team to ask basic questions, regarding feelings and pain, among others. Each patient’s living will could be one of these questions, especially in countries where euthanasia is permitted. Surprisingly, locked-in patients report, in majority, that they feel happy [20]. However, the results of this study should not hide the huge distress that some experience. The cases of Schiavo future science group
Neuroimaging of patients with disorders of consciousness: from bench to bedside?
in the USA, and Humbert in France, largely reported by the media, are the most eloquent examples [101,102]. Financial & competing interests disclosure
L Hermoye is the Chief Executive Officer and a shareholder of Imagilys. The authors have no other relevant References 1.
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Editorial
a ffiliations or financial involvement with any organization or entity with a financial interest in or or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Science 315(5816), 1221; author reply 1221 (2007).
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MR et al. Willful modulation of brain activity in disorders of consciousness. N. Engl. J. Med. 362(7), 579–589 (2010). 11. Vanhaudenhuyse A, Noirhomme Q,
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Neural plasticity lessons from disorders of consciousness. Front. Psychol. 1, 245 (2010). 17. Whyte J, Myers R. Incidence of clinically
significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am. J. Phys. Med. Rehabil. 88(5), 410–418 (2009). 18. Schiff ND, Giacino JT, Kalmar K et al.
Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448(7153), 600–603 (2007). 19. Laureys S, Schiff ND. Coma and
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Demertzi A, Laureys S. A survey on self-assessed well-being in a cohort of chronic locked-in syndrome patients: happy majority, miserable minority. BMJ Open 1(1), e000039 (2011).
Websites 101. Schiavo dies, ending bitter case over
feeding tube. www.nytimes.com/2005/04/01/ national/01schiavo.html?_r=1& 102. Son’s wish to die, and mother’s help, stir
French debate. www.nytimes.com/2003/09/27/world/ son-s-wish-to-die-and-mother-s-help-stirfrench-debate.html
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