**7. Cognitive recovery**

A diagnosis of VS is made if a patient demonstrates no evidence of awareness of self or environment. No evidence of sustained, reproducible, purposeful or voluntary behavioral response to visual, auditory, tactile, or noxious stimuli and critically no evidence of language comprehension or expression. In contrast, the patient in a MCS demonstrates partial preservation of awareness of self and environment, responding intermittently, but reproducibly, to verbal command and therefore demonstrating some degree of basic language comprehension (Coleman et al., 2007).

VS and MCS patients may permanently remain in their clinical condition, or may partly or fully recover consciousness through different stages (Laureys et al., 2004). In this view, it's very important evaluate the residual cognitive across the time. In fact, it allows to make a differential diagnosis between VS and MCS, to monitoring functional changes of the patients, in order to customize the treatment, and, at least, to have a baseline evaluation of the patients in case of consciousness recovery. Nevertheless, the assessment of residual brain functions and the degree of recovery of these patients remain, still today, an opened issue in the medical field. To date, there have been no detailed studies of these patients evaluating cognitive changes and recovery over time through a specific neuropsychological battery (Neumann & Kotchoubey, 2004). This might suggest a new and possible way to further investigate the potential outcome of these challenging patients.

area in 19 patients, few months after severe anoxic brain injury. Eleven patients were in VS, while eight patients were in MCS. The VS patient group differed from the MCS patient group in having a higher threshold, longer duration, and greater irregularity in the form of the response, while the threshold, form, and latency of motor evoked potentials (MEPs) from the MCS group were similar to healthy control subjects. In another study, TMS is used to monitor recovery. The authors examined MEPs from upper and lower limbs in 27 patients in the subacute period and then at 6 and 12 months post – ictus. During the study period, the authors observed an overall trend toward an increase and decrease of latency of MEPs. MEPs from upper and lower limbs progressively normalized in all patients, and at one year after trauma,

only 12% of patients had mild abnormalities in MEP responses (Mazzini et al., 1999).

the recovery period.

(Gosseries et al., 2008).

**7. Cognitive recovery** 

language comprehension (Coleman et al., 2007).

TMS elicited MEP responses in the majority of severely brain damage patients, and a trend toward an increase of amplitude and decrease of latency of MEPs could be observed during

DBS works on reactivating the cortex, aiming to produce a functional recovery. In study of Yamamoto et al. (2010) patients in VS were treated with DBS. Eight of the patients recovered from VS and were able to obey verbal commands at 13 and 10 months in the case of head trauma and a year and a half in the case of vascular disease after comatose brain injury, and no patients without DBS recovered from VS spontaneously within 24 months after brain injury. In the last years the interest in using of neurophysiological investigations (EEG and EPs) in association with fMRI, has grown: the combination of these different neuroimaging techniques allows study of different components of the brain's activity (e.g., neurovascular coupling, electromagnetic activity) with both a high temporal and spatial resolution

Clinical neurophysiology procedures are useful as easily performed, non invasive and repeatable at the bed side. These methods provide irreplaceable data about the degree of neuronal dysfunctions and their evolution, and gave also information to assess the outcome.

A diagnosis of VS is made if a patient demonstrates no evidence of awareness of self or environment. No evidence of sustained, reproducible, purposeful or voluntary behavioral response to visual, auditory, tactile, or noxious stimuli and critically no evidence of language comprehension or expression. In contrast, the patient in a MCS demonstrates partial preservation of awareness of self and environment, responding intermittently, but reproducibly, to verbal command and therefore demonstrating some degree of basic

VS and MCS patients may permanently remain in their clinical condition, or may partly or fully recover consciousness through different stages (Laureys et al., 2004). In this view, it's very important evaluate the residual cognitive across the time. In fact, it allows to make a differential diagnosis between VS and MCS, to monitoring functional changes of the patients, in order to customize the treatment, and, at least, to have a baseline evaluation of the patients in case of consciousness recovery. Nevertheless, the assessment of residual brain functions and the degree of recovery of these patients remain, still today, an opened issue in the medical field. To date, there have been no detailed studies of these patients evaluating cognitive changes and recovery over time through a specific neuropsychological battery (Neumann & Kotchoubey, 2004). This might suggest a new and possible way to

further investigate the potential outcome of these challenging patients.

In this paragraph we try to identify some markers of consciousness with prognostic value, based on literature review. As it has been clearly established in clinical practice, significant spontaneous recovery frequently occurs during the subacute period (Wilson et al., 2002; Giacino & Trott 2004). Two factors can facilitate cognitive recovery of these patients: young age and immediate medical assistance after the injury.

Literature findings demonstrated that no clinical tools strongly predicted good outcome. In contrast, complementary examinations such as electrophysiological and functional neuroimaging studies objectively measure residual brain functions and are indicative of recovery of consciousness.

Several studies explore the prognostic validity of behavioural assessment scales (i.e. GOS, Coma Recovery Scale, Wessex Head Injury Matrix, Western Neuro Sensory Stimulation Profile, DRS, Functional Independence Measure), electrophysiological measures (ERPs), and functional neuroimaging (PET, fMRI), to predict outcome in patients with low levels of consciousness. Particular progress towards addressing this objective has been made using brain imaging techniques such as PET and fMRI. Schiff et al. (2002) suggested that rather than a complete loss of cortical function some patients retain "island" of preserved cognitive functions. PET and fMRI studies suggest that a higher-level associative cortical activation seems to predict recovery of consciousness with a 93% specificity and 69% sensitivity (Di et al., 2008). PET work has identified preserved responses to a variety of sensory stimuli, including photographs of familiar people, noxious, tactile (Laureys et al. 2000; Owen et al., 2002; Boly et al., 2004) in some vegetative and minimally conscious patients. Some studies underline the importance of the cognitive ERPs in the assessment of residual functions in comatose, VS, or MCS patients. As a general rule, early ERPs (such as the absence of cortical response on somatosensory evoked-potentials) predict bad outcome, while cognitive ERPs are indicative of recovery of consciousness (Vanhaudenhuyse et al., 2007). Moreover, auditory cognitive ERPs are useful to investigate residual cognitive functions, such as echoic memory (Mismatch Negativity), acoustical and semantic discrimination (P300), and incongruent language detection (N400). In VS patients, cognitive potential are more frequently obtained when using stimuli that are more ecologic or have an emotional content (such as the patients' own name) than when using classical sine tones.

Electrophysiological and functional neuroimaging studies may provide useful and objective information to the outcome and possibly cognition of patients with low levels of consciousness (Di et al., 2007). To date, there have been no detailed studies of these patients combining and correlating specific neuropsychological tools and functional imaging, in order to evaluate the cognitive changes and recovery over time (Bekinschtein et al, 2005). In spite of the important findings, functional neuroimaging cannot, and should not replace, clinical and behavioural evaluation as the criterion standard for assessment of patients with DOC. It offers an objective method of differentiating brain activity measured at rest and during external stimulation, but further studies are needed to assess the temporal evolution of individual patients' somatosensory and cognitive processing (Giacino et al., 2006). Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible (Owen et al., 2002). There are no standards of care to guide the selection of rehabilitation assessment and treatment

Neuroimaging and Outcome Assessment in Vegetative and Minimally Conscious State 195

MCS (e.g. patients in MCS from TBI) have been more reliable (Bernat et al.,2010). The appropriate level of treatment of patients with chronic DOC depends on their diagnosis, prognosis and prior stated treatment values and preferences. Specialized neurorehabilitation units are the optimal treatment for patients with chronic DOC , at least until they are no longer improving. Patients have better functional out comes when treated by skilled personnel who have been trained in neurorehabilitation. The difference between patients in VS and patients in MCS in their response to stimulatory treatment is noteworthy: patients in VS rarely improve as a consequence of stimulation but patients in MCS may improve to some extent. Treatment modalities that have been studied include environmental and sensory stimuli such as sounds, smells, touch, images and music. Pharmacologic stimuli include treatment with stimulants, levodopa, and dopamine agonists (by stimulating intact dopaminergic thalamic neurons), and selective serotonin reuptake inhibitor antidepressants. Electrical stimuli include deep brain stimulation of medical thalamic nuclei. Each of these modalities has been reported to improve functional responsiveness in some patients in MCS though there are few controlled studies. These therapies are also widely tried in patients in VS but a meta-analysis of their outcomes

The use of unimodal and multimodal sensory stimulation for the treatment of comatose patient, both in the acute and prolonged states, has been advocated (Johnson et al., 1988). The rationale behind the use of these techniques is that all aspects of the patient must be treated; it is insufficient to attend to the maintenance of bodily well being alone. Sensory stimulation should at the least not have any ill-effects on the patient and could enhance the processes of recovery. S.L. Wilson et al. (1991) have observed patients diagnosed as being in prolonged coma, routinely treated according to a sensory stimulation protocol. They reported an evaluation of the efficacy of this procedure using the comparison of behavioral measures taken immediately prior and post-stimulation. Sensory stimulation treatment appears to be widely used with patients who are in VS arising from traumatic causes, but the term has to be regarded as generic rather than specific since sensory stimulation procedures appear to differ widely in content (Wilson et al., 1993). A number of studies have been published evaluating the effects of these treatment; some have methodological flaws, but the major difficulty in evaluating any treatment with this group of patients is getting sufficient subjects, so most of the published studies use relatively small numbers. Ideally, a large-scale matched control study would be looked for, which examined rate of recovery and long-term outcome. If sensory stimulation is rejected on the basis of lack of empirical evidence, then logically many other treatments used with medical settings should also be rejected. In real life, however, where definitive empirical evidence is not yet available, then clinicians can reasonably make decisions on treatment by combining clinical experience with inferences from scientific knowledge concerning related populations. For example, stimulation treatments which involve the use of some constant background stimulation within the patient's environment, such as TV or radio, have been justifiably criticized. As Wood points out, it is likely to be damaged within the brain that mediate selective attention are highly likely to be damaged within these patients; therefore it is unlikely they are going to be able to differentiate between stimuli in a situation where they are being bombarded

with sensory input. In addition, habituation may exacerbate the problem.

showed no consistent benefits (Bernat, 2006).

**9. Sensory stimulation procedure** 

procedures for patients with DOC (Neumann & Kotchoubey, 2004). Cognition abilities with theory of mind tasks, decision-making tasks, social performance tests and expanded cognitive assessment, to further characterize post-traumatic or hypoxic-ischemic brain damaged vegetative patients after recovery remain under evaluation at this time. The cognitive recovery in patients with DOC is a continual process rather than a step-by-step phenomenon and confirms that a good recovery assessment should include objective measures of behavioural, cognitive and functional domains, and neurophysiological data to support diagnosis. Survivors from a coma frequently suffer from long-lasting disability, which is mainly related to cognitive deficits. Such deficits include slowed information processing, deficits of learning and memory, of attention, of working memory, and of executive functions, associated with behavioral and personality modifications (Azouvi et al., 2009). An accurate cognitive assessment during the very first phase of the convalescence, when it is possible, is the first step for the management and the implementation of an individual and effective treatment.

Appropriate management requires an experienced inter-disciplinary as opposed to multidisciplinary team working style, whose skill repertoire equips them to recognize oftensubtle improvements in cognitive function and act to maximize individual patient's quality of life. The current paucity of service provision for this vulnerable group of patients is highlighted. In fact, predicting the chances of recovery of consciousness and communication in patients who survive their coma, but transit in a VS or MCS remains a major challenge for their medical caregivers. Very few studies have examined the slow neuronal changes underlying functional recovery of consciousness from severe chronic brain damage.

### **8. Prognosis and rehabilitation**

Determining the accurate prognosis of VS and MCS is a critical step in counseling families and determining appropriate treatment. Previous studies of prognosis in VS were limited by several factors: 1) because there were no accepted diagnostic criteria for MCS prior to 2002, some patients in MCS in those studies may have been diagnosed with VS; 2) it is more accurate to determine prognosis by the etiology of brain damage than merely by categorization in a clinical syndrome; and 3) retrospective experiential analysis of outcomes, such us that by the Multi-Society Task Force, committed the fallacy of the self-fulfilling prophecy because they included patients in their survival data who died primarily because their life-sustaining therapy was discontinued (Bernat et al., 2010). Nevertheless, the prognostic guidelines published in 1994 by Multi-Society Task Force on PVS have been generally accepted, showing a very low probability of recovering awareness once VS has been present for a year following TBI or for 3 months following hypoxic-ischemic neuronal injury (Bernat et al., 2009).Two recently published studies of prognosis in VS add useful data. Luautè and colleagues (Luautè et al., 2010), confirmed the prognostic guidelines of the Multi- Society Task Force in all the patients in VS. They studied and showed that age greater than 39 years and absence of the middle-latency auditory evoked potentials were independent early predictors of poor outcome irrespective of pathogenesis. Estraneo and colleagues (Estraneo et al., 2010), found that 88% of patients in VS in their serious conformed to the Multi- Society Task Force prognostic guidelines but 12% made late recoveries of awareness but only to the point of severe disability with MCS, most of whom had TBI. Because of varying pathophysiologies, prognostic indicators for MCS as a group have been difficult to establish whereas prognostic indicators in individual pathophysiologic subsets of MCS (e.g. patients in MCS from TBI) have been more reliable (Bernat et al.,2010). The appropriate level of treatment of patients with chronic DOC depends on their diagnosis, prognosis and prior stated treatment values and preferences. Specialized neurorehabilitation units are the optimal treatment for patients with chronic DOC , at least until they are no longer improving. Patients have better functional out comes when treated by skilled personnel who have been trained in neurorehabilitation. The difference between patients in VS and patients in MCS in their response to stimulatory treatment is noteworthy: patients in VS rarely improve as a consequence of stimulation but patients in MCS may improve to some extent. Treatment modalities that have been studied include environmental and sensory stimuli such as sounds, smells, touch, images and music. Pharmacologic stimuli include treatment with stimulants, levodopa, and dopamine agonists (by stimulating intact dopaminergic thalamic neurons), and selective serotonin reuptake inhibitor antidepressants. Electrical stimuli include deep brain stimulation of medical thalamic nuclei. Each of these modalities has been reported to improve functional responsiveness in some patients in MCS though there are few controlled studies. These therapies are also widely tried in patients in VS but a meta-analysis of their outcomes showed no consistent benefits (Bernat, 2006).
