Patients with disorders of consciousness (DOC) represent an important proportion of the disabled population worldwide. Severe brain injury can lead to coma where patients remain unaware with their eyes closed and do not respond to external stimulation (Plum and Posner 1983). When patients open their eyes but remain unconscious, they are diagnosed with vegetative state (VS) (The Multi-Society Task Force on PVS 1994; Laureys and Schiff 2012). The European Task Force on Disorders of Consciousness, recognizing that part of the health care, media, and lay public feels uncomfortable using the unintended denigrating “vegetable-like” connotation (seemingly intrinsic to the term VS), proposed the alternative name “unresponsive wakefulness syndrome” (UWS) (Laureys et al. 2010). UWS is a more neutral and descriptive term, pertaining to patients showing a number of clinical signs (i.e., syndrome) of unresponsiveness (i.e., without response to commands or oriented voluntary movements) in the presence of wakefulness (i.e., eye opening).

Patients who evolve from the UWS/VS condition show nonreflexive, goal-directed behaviors (e.g., visual pursuit, reproducible responses to commands or localisation to pain) and hence are considered to be in a minimally conscious state (MCS) (Giacino et al. 2002). Patients with MCS demonstrate partially preserved fluctuating levels of awareness, but they remain unable to functionally communicate. Depending on the complexity of the demonstrated behaviors, it was recently proposed to subcategorize the MCS condition into MCS- (i.e., when only showing simple nonreflex movements, such as visual pursuit, orientation to pain, or non-contingent behaviors) and MCS + (i.e., when patients recover the ability to respond to simple commands) (Bruno et al. 2011). Compared to the patients with MCS+, patients with MCS- may suffer from a significant general decrease in brain metabolism in the dominant hemisphere and particularly in regions that are functionally linked to speech comprehension and production, in motor and pre-motor areas and in sensory-motor areas (Bruno et al. 2012). Differential diagnosis for patients with MCS would therefore be mainly due to the functional recovery (or not) of speech-processing areas (Thibaut et al. 2012). Once these patients can communicate in a functional manner and/or show functional object use, they are diagnosed as having emerged from MCS (Giacino et al. 2002). These states lie between unconsciousness and awareness; the distinction between them has important therapeutic and ethical implications (Hirschberg and Giacino 2011). Patients in MCS are more likely to feel pain (Boly et al. 2008; Chatelle et al. 2014a, b) and might benefit from analgesic treatment or other interventions aimed to improve their interaction with the environment (Cruse et al. 2011; Lule et al. 2013; Thibaut et al. 2014). Patients in an MCS are also more likely to recover higher levels of consciousness than are patients with UWS/VS (Luaute et al. 2010; Hirschberg and Giacino 2011). Several countries have established the legal right of physicians to withdraw artificial life support from patients with UWS/VS (Gevers 2005; Perry et al. 2005; Ferreira 2007), but not from patients in a MCS (Manning 2012).

The detection of unambiguous signs of consciousness in severely brain-damaged patients is challenging and relies on disentangling automatic responses from nonreflex-oriented movements or command following. Motor responses may be ambiguous and inconsistent, potentially leading to diagnostic errors (Monti et al. 2009). A prospective study on coma survivors showed that the clinical consensus diagnosis of UWS/VS, attributed to 44 patients, was incorrect in 18 cases. Such a high rate of diagnostic error (i.e., 41 %) should prompt clinicians to use validated behavioral scales of consciousness before making the diagnosis of UWS/VS (Schnakers et al. 2009). While consensus-based diagnostic guidelines for DOC have been established (Giacino et al. 2002), there are no procedural guidelines regarding bedside assessment. Many different scales have been developed to assess patients in the chronic phase, and this last decade has particularly been focusing on the differential diagnosis between UWS/VS and MCS. Table 8.1 gives a non-exhaustive overview of the behavioral scales used in the chronic setting.

The American Congress of Rehabilitation Medicine conducted a systematic, evidence-based review of these behavioral assessment scales and provided evidence-based recommendations for clinical use (Seel et al. 2010). It was suggested to use the Coma Recovery Scale-Revised (CRS-R; Giacino et al. 2004; Schnakers et al. 2008a – summarized in Table 8.2). CRS-R has excellent content validity, and it is the only scale to address all Aspen Workgroup criteria (i.e., items used to differentiate MCS from UWS/VS). The CRS-R also offers the advantage to systematically search for signs of nonreflex behavior (e.g., visual pursuit or oriented response to noxious stimulation) and command following, in a well-defined manner. Visual pursuit, for example, should be assessed by using a moving mirror, as it has been shown that a substantial number of patients will not show eye tracking of a moving object or person but will do so when using an auto-referential stimulus such as the own face (Vanhaudenhuyse et al. 2008). Conversely, signs such as visual blinking to threat (Vanhaudenhuyse and Giacino 2008) and visual fixation (Bruno et al. 2010) were shown not to necessarily reflect conscious awareness and could hence be compatible with the diagnosis of UWS/VS. It is important that the evaluations are repeated over time and performed by trained experienced assessors (Lovstad et al. 2010). Confounding factors such as drugs with sedative side effects (e.g., against spasticity or epilepsy) or the presence of infection or other medical complications should be accounted for. This situation is even more problematical when patients have underlying deficits with communication functions, such as aphasia, agnosia, or apraxia (Majerus et al. 2005, 2009). Hence, some behaviorally unresponsive patients could, despite the best clinical assessment, be underestimated in terms of residual cognition or conscious awareness (Giacino et al. 2014). Since the venue of functional neuroimaging, this challenging issue can be addressed by measuring brain activity at rest and during sensory stimulation in these patients (Di Perri et al. 2014; Gosseries et al. 2014a)

Behavioral scales make inferences about patients’ awareness based on (the prensence/absence of) motor responsiveness. Functional neuroimaging (e.g., positron emission tomography (PET) and functional magnetic resonance imaging – fMRI) and cognitive evoked potential studies allow quantifying and noninvasively DOC patients brain activity at rest and during external activation (see Chaps. 9 and 12). fMRI activation studies in UWS/VS (Bekinschtein et al. 2005; Di et al. 2007; Fernandez-Espejo et al. 2008; Coleman et al. 2009) have confirmed previous PET studies showing preserved activation of “lower level” primary sensory cortices which are disconnected from “higher-order” associative cortical networks (i.e., frontoparietal associative cortices, cingulate gyrus, precuneus, and thalamus) (Laureys et al. 2004; Vanhaudenhuyse et al. 2010, 2011; Langsjo et al. 2012; Demertzi et al. 2013) employing auditory (Laureys et al. 2000; Boly et al. 2005), somatosensory (Boly et al. 2008), visual (Owen et al. 2002), or even emotional stimulations (Bekinschtein et al. 2004; Schiff et al. 2005).

These neuroimaging techniques have also been developed in order to detect “neural” (motor-independent) command following. Clinically unresponsive patients could perform mental imagery tasks, as shown by fMRI (Monti et al. 2010). Since this case report, similar “active” or “command following” paradigms have been tested in severe brain-damaged patients with different technologies such as event related potentials or electromyography (Bekinschtein et al. 2008; Schnakers et al. 2008b; Cruse et al. 2011; Habbal et al. 2014). Recently, it has been demonstrated that ¹⁸F-fluorodeoxyglucose-PET showed the highest sensitivity in identifying MCS having a good overall congruence with repeated CRS-R diagnosis, when compared to mental imagery task in fMRI (Stender et al. 2014). Complementary to these approaches, methods are developed to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways. Transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while bypassing subcortical afferent and efferent pathways and without requiring active participation of subjects or language comprehension (see Chap. 10). Hence, this complementary techinique could also permit an effective way to detect and track recovery of consciousness in patients with DOC who are unable to exchange information with the external environment (Rosanova et al. 2012, Casali AG et al. 2013 and Sarasso S et al.2014). The validation of new promising neuroimaging-based differential diagnostic markers, such as quantified metabolic markers or resting state fMRI, is of primary importance to complement the differential diagnosis.

Although our understanding of the neural correlates of consciousness has greatly evolved over the past years, daily care has not yielded specific, evidence-based medical treatments for patients with DOC. Pharmacological treatment to promote the emergence of consciousness can be administered in the subacute and the chronic (more than 1 month) phases. Frequently prescribed pharmacological treatments include dopaminergic (e.g., amantadine, apomorphine, methylphenidate, levodopa, bromocriptine) and GABAergic agents (e.g., zolpidem, baclofen) (Chew and Zafonte 2009; Gosseries and Charland-Verville, 2014; Thonnard et al. 2014). Next, there is a long history of brain stimulation in medical science, and research has long been focused on some cortical areas and deep brain structures like the prefrontal cortex and the thalamus. Only few techniques were studied scientifically in this population of patients. Deep brain stimulation showed behavioral improvement after the implantation of an electrical stimulator in the intralaminar nuclei (Schiff et al. 2009). However, and the number of patients who can benefit from this intervention is still limited. Recently, noninvasive transcranial direct current stimulation (tDCS) studies showed encouraging results, with improvements in the behavioral signs of consciousness of severely brain-injured patients (Thibaut et al. 2014). Short-duration anodal (i.e., excitatory) tDCS of left dorsolateral prefrontal cortex induced short-term improvement in patients with MCS of acute and chronic etiologies measured by behavioral CRS-R total scores. The long-term noninvasive neuromodulatory tDCS outcome clinical improvement remains to be shown. In the years to follow, interventions should multiply, and therapeutic measures need to be more accessible, controlled, and effective.