Rita Formisano PhD, MD, Eva Azicnuda PsyD, Marianna Contrada, Marta Aloisi, Maria Paola Ciurli PsyD, Andrea Gabrielli, MD, Sheila Catani MD , Umberto Bivona PhD

IRCCS Santa Lucia Foundation, Rome, Italy

Department of Anesthesiology, University of Florida College of Medicine, Philadelphia

Neurorehabilitation and Disorders of Consciousness

Disorders of consciousness (DOC) after severe acquired brain injury (ABI) include coma, vegetative state (VS), and minimally conscious state (MCS). Coma is primarily assessed via the Glasgow Coma Scale (GCS) (Teasdale et al., 1974) in the acute phase, whereas the Disability Rating Scale (DRS) (Rappaport et al., 1982), Levels of Cognitive Function (LCF) (Hagen et al., 1979), Glasgow Outcome Scale (GOS), Glasgow Outcome Scale-Extended (GOS-E) (Jennett and Bond, 1975; Jennett and MacMillan, 1981) and Coma Recovery Scale-Revised (CRS-R) (Giacino et al., 2014) are the most commonly used scales in the post-acute phase.

1.1 Coma

The definition of coma includes the clinical triad of “closed eyes, not obeying simple commands, no comprehensible verbal utterances” (Jennett, 1986). Coma has also been defined as a complete failure of the arousal system, with no spontaneous eye opening in patients who are unable to be awakened by application of vigorous sensory stimulation (Plum and Posner, 1982).

The presence of muscular hypertonia, vegetative dysautonomia - defined as paroxysmal sympathetic hyperactivity (Perkes et al., 2010), and/or psychomotor agitation have to be generally addressed with specific pharmacotherapy, such as muscle relaxant drugs, beta-blockers, anti-epileptic therapy and sedation, which may compromise vigilance and responsiveness.

1.2 Vegetative State

The vegetative state (VS) is a condition that follows coma when the patient recovers vigilance or alertness (eyes opening), but not awareness - the latter defined as the ability to interact with the surroundings in spite of the eyes opening and partial recovery of the sleep-wake circadian cycle. The term “persistent” has been used in the past to indicate a potentially reversible process, whereas the term “permanent” indicated an irreversible condition. The time interval for the recovery potential is presently one year for trauma cases and 3-6 months for all other etiologies. Vegetative state remains a commonly used term, but qualifying the VS with “persistent” or “permanent” has been recently challenged, considering the increasing number of late recoveries reported with this diagnosis (Childs et al., 1993; Andrews et al., 1996; Estraneo et al., 2013). A number of complex neurological syndromes may affect the likelihood of appropriate rehabilitation at this stage. Undiagnosed epileptic activity, as nonconvulsive seizures, has been detected in 6.3% of the cases (Vespa et al., 1999). Parkinsonism is also common (Gerstenbrand, 1967; von Wild et al., 2007), especially as an evolution of diffuse axonal injury (DAI) (Tomaiuolo et al., 2004; Graham et al., 1983; McLellan et al., 1986; Adams, 1990) generally consisting of akinesia, rigidity, hypomimia, parkinsonian posture and hypersalivation (Formisano et al., 2009; 2010; 2011a; Formisano & Zasler, 2014).

The Multi-Society Task Force for the Study of Vegetative State has recommended the utilization of a common terminology for this condition, suggesting that any other term describing this state of DOC, such as “coma vigile” (French literature) and “apallic syndrome” (Austrian and German literature), should be abandoned (Ashwal et al., 1994). The term, “akinetic mutism”, remains an exception to the rule, and is characterized as a condition with severe quadriparesis, mutism, akinesia, visual fixation, and pursuit (Black et al., 1996). More recently, a European task force has introduced the definition of unresponsive wakefulness syndrome (UWS) (Laureys et al., 2010) to replace the term, vegetative state, although it has not been universally accepted (Formisano et al., 2011b).

1.3 Minimally Conscious State (MCS)

The MCS may follow either coma or VS as a transition or a permanent condition (Beaumont et al., 2005), usually between the VS and “severe disability” categories of the GOS (Jennett and Bond, 1975; Jennett and MacMillan, 1981). However, the evaluation of the consciousness level may be affected by sensorial disorders, such as visual and auditory disorders; neuropsychological deficits, such as aphasia, apraxia and apathy; recurrent infections; convulsive and nonconvulsive seizures (Vespa et al., 1999); psychomotor agitation, restlessness, aggressiveness, erratic behaviours (Formisano et al., 2005); normotensive or hypertensive hydrocephalus (Missori et al., 2006); and sedative, antiepileptic and muscle-relaxant drugs.

MCS has been recently classified as Minimally Conscious State “Minus”, when the patient recovers the ability of visual fixation and eye tracking, and/or to localize the noxious stimuli; whereas the Minimally Conscious State “Plus” is defined as a condition in which the patient becomes able to use some objects functionally, according to their shape and direction, or to follow simple commands or verbalize, but in inconstant and fluctuating way, while remaining unable to communicate (Giacino et al., 2002; Giacino and Trott, 2004; Bruno et al., 2011).

Many MCS patients may be able to exhibit visual fixation, and eye pursuing and tracking, in addition to being mute and akinetic; therefore, akinetic mutism should be considered a subcategory of MCS.

Psychomotor agitation and aggressiveness are frequent behaviours in individuals with severe ABI who may be unable to follow simple commands. Agitated patients often display intentional aggressive behaviors against themselves or others, and only rarely can they obey simple commands (Formisano et al., 2005). Aggressiveness may be the manifestation of physical or emotional discomfort, or mental confusion that the patient is not able to express otherwise. For these reasons, agitated patients should be also diagnosed with a MCS instead of VS, even if not able to follow commands (Formisano et al., 2011).

2. Prognostic Factors and neurological evaluation of patients with disorders of consciousness

Rare blinking and absent threat reflex, consisting of the lack of blinking at the rapid approach of the hand to the eye, is a common feature demonstrating the lack of responsivity in VS patients, as well as the “eye-doll phenomenon” and may be generally interpreted as confirmation of unconsciousness, although blindness due to bilateral lesion of the optic nerve can also be the cause of the absence of blinking in response to visual stimuli.

In the acute and post-acute phase, endocrine disorders - hypopituitarism being the most common - should be investigated (Kelly et al., 2000; Benvenga et al., 2000). Vigilance disorders, electrolyte imbalance, immunological deficits, dysautonomic symptoms, and cognitive and behavioral disturbances also may be secondary to dysfunction of the hypothalamic-pituitary axis (Masel, 2004; Agha et al., 2004; 2005; 2006; Aimaretti and Ghigo, 2005; Aimaretti et al., 2005; Bondanelli et al., 2005; Leal-Cerro et al., 2005; Popovic et al., 2005; Schneider et al., 2006).

Prediction of recovery of consciousness in patients with prolonged DOC is more difficult, since the severity and duration of coma are similar in all subjects with severe ABI, i.e. GCS≤ 8 and duration of unconsciousness of at least one month in the VS.

The Medical Disability Society (1988) defines severe ABI as all states of coma lasting at least 6 hours. The definition of “prolonged coma” has also been suggested as an indicator of “very severe brain injury” for patients with unconsciousness lasting at least 15 days (Danze, 1993; Formisano et al., 2004a; 2004b). In patients with prolonged DOC, the time interval from coma to the achievement of some rehabilitation goals (Formisano et al., 2004b) seems to be predictive of the final outcome at one year follow up according to the GOS (Jennett and Bond, 1975) and Barthel Index (BI) (Mahoney and Barthel, 1965). The most significant predictive clinical features are the presence of spontaneous motor activity and the time interval to the recovery of sustained visual fixation, eye tracking, and safe oral feeding, the latter tending to be correlated with neuropsychological recovery (Formisano et al., 2004b). Psychomotor agitation and bulimia during recovery from DOC may be considered favourable prognostic indicators of the final prognosis. In fact, the diagnosis of a confused-agitated state upon admission to the rehabilitation ward, evaluated by means of the LCF scale (Hagen et al., 1979), predicted a statistically significant better outcome at discharge compared to patients without any agitation (Formisano et al., 2005).

Post-traumatic psychomotor agitation (PPA) represents, according to some authors (Reyes et al., 1981; Corrigan and Mysiw. 1988; Corrigan and Bogner, 1994) a positive indicator of consciousness recovery, especially if it occurs in the early stages of coma (Formisano et al., 2005). Nevertheless, aggressiveness may be considered a predictive indicator of an unfavourable neuropsychological prognosis when persisting for several months. Post-traumatic psychomotor agitation has been classified as a subtype of delirium, with onset during the period of post-traumatic amnesia (PTA). It is characterized by extreme behaviors, including aggressiveness, akathisia, disinhibition, and emotional lability (Sandel and Mysiw, 1996); PTA is defined as the period after coma when the patient is not able to recall everyday events of the last 24 hours (Russel and Smith, 1961).

Some recovery phases from DOC may be characterized not only by psychomotor agitation, but also by the Klüver-Bucy syndrome, defined as a transient phase with behavioral disinhibition, as well as increased primitive oral automatisms and hypersexuality, described as a possible recovery phase of prolonged DOC (Gerstenbrand et al., 1983; Goscinski et al., 1997). Undergoing the Klüver-Bucy syndrome after DOC has been previously reported as a favourable predictive indicator of the final prognosis (Formisano et al., 1995). During this remission phase, patients may have extreme attention lability (hypermetamorphosis) and restlessness, and, therefore they are only rarely able to follow commands. This condition, generally transient, should be also diagnosed as MCS and, in some cases, may evolve to bulimia lasting also several months.

Pathological postures in decortication (flexion and intrarotation of the upper limbs along with intrarotation and hyperextension of the lower limbs) and decerebration (intrarotation and hyperextension of the upper and lower limbs) are rarely described in the literature in DOC patients (Gerstenbrand, 1967; Dolce and Sazbon, 2002). In general, they represent a negative indicator of long-term functional outcome (Dolce and Sazbon, 2002), in comparison with patients without these postures, who conversely present with earlier recovery of spontaneous motility of the upper and/or lower limbs. Pathological postures are also frequently associated with severe spasticity, akinesia, rigidity, parkinsonian posture, and dysautonomic symptoms. Baguley et al. (1999) found dysautonomic syndrome in about 30% of individuals in the VS, with a simultaneous and paroxysmal increase in at least five of the following seven autonomic parameters: heart rate (tachycardia), respiratory rate (tachypnea), muscle tone (increased), posture (decerebrate or decorticate), blood pressure (arterial hypertension), sweating (profuse), and temperature (increased or decreased). Dysautonomia or paroxysmal sympathetic hyperactivity (PSH) has been reported as a negative prognostic indicator of the final outcome of severe ABI patients (Perkes et al., 2010; Dolce and Sazbon, 2002; Baguley et al., 2008). Passive range of motion may be also limited by muscle contractures and ankylosis at the level of the major joints, frequently due to peri-articular ossification (PAO) and tendon retractions or shortenings (Sazbon et al., 1981; Ippolito et al., 1999a; 1999b; 1999c).

Sensorial deficits of central or peripheral origin, such as blindness or deafness, may be due to cerebral lesions or cranial nerve paralysis, and may often cause diagnostic errors when evaluating the consciousness disorder. Similarly, patients with language disorders (aphasia) or gesture execution deficit (apraxia) may be not able to obey simple commands because of comprehension deficits or difficulty in executing gestures, respectively. A right hemiparesis or quadriparesis with right prevalence may be factors for aphasia and apraxia to be suspected, while a left hemiplegia or quadriparesis with left prevalence may be associated with neglect or hemi-inattention.

In individuals with VS, the presence of primitive oral automatisms, such as chewing, sucking, and yawning, may also predict a worse prognosis in patients with DOC (Dolce and Sazbon, 2002).

Among cranial nerve deficits, the optic nerve is the most commonly involved, followed by involvement of one of the ocular muscle nerves (Jennet and MacMillarn, 1981). Deficits of the oculomotor, trochlear, or abducens nerves may be responsible of monolateral or bilateral ptosis, strabismus, and diplopia, all of which can complicate the evaluation of visual fixation and eye tracking movements. In some cases, after eye opening, the patients may voluntary close one eye during visual fixation or pursuing, most likely due to diplopia. Monolateral or bilateral blepharospasm may also impair the patient’s attempts at communication via eyelid closure.

Locked-in syndrome (LIS) is a neurological condition, due to a ventral pontine lesion, in which patients are quadriplegic, mute, conscious and aware. Unlike patients with VS, they are able to communicate by means of vertical gaze, and/or upper eyelid movements (Plum and Posner, 1966) and their electroencephalographic (EEG) activity is generally normal. However, some LIS patients are unable to communicate by eyelid movements because of palsy that extends to ocular motility (Smith and Delargy, 2005; Laureys et al., 2005; Formisano et al., 2008; Schnakers et al., 2009). In such cases, clinical differentiation between VS and LIS may be very difficult (Formisano et al., 2011a).

It has been reported that some VS patients may pass through a locked-in-like syndrome during recovery of consciousness (Formisano et al., 2011b; Formisano et al., 2013).

Functional LIS has been defined as a condition of severe disorder of consciousness, where the patient is able to communicate only by means of eyelids closure or blinking, because of a dissociation between extreme motor deficit output and some preserved consciousness and residual cognitive abilities (Bruno et al., 2011).

This process does not necessarily occur in the presence of structural brainstem lesions, given that diffuse axonal injury (DAI), too, can cause a functional disconnection syndrome (Formisano et al., 2008; Trojano et al., 2009). This possible evolution of the clinical picture may not be recognized, especially if the first attempts at functional communication by means of blinking occur several months after the onset of coma, evolving into VS.

Motor recovery generally starts with distal to proximal limb motility, likely due to the relative sparing of the cerebral cortex, where the cortical representation of the hand and foot is more extended, and there is more involvement of the muscles of the major joints, especially shoulder and hip contractures.

Asymmetric motor recovery between the upper and lower limbs is a possible clinical indicator of either spinal cord injury, critical illness polyneuropathy (CIP) or critical illness myo-neuropathy (CRIMYNE) (Latronico et al., 2005), or hydrocephalus (Missori et al., 2006). The most significant clinical features of hydrocephalus are regression or arrest of previous consciousness improvement, fever, epileptic seizures, and cognitive and behavioural disorders poorly responsive to pharmacologic and rehabilitative treatment (Missori et al., 2006).

Diffuse muscle atrophy, recurrent sepsis, and PAO, especially at the level of the hips, elbows, and knees, should suggest the diagnosis of CIP (Latronico et al., 2005) or compressive neuropathies, often secondary to entrapment by PAO, fibrous retractions by muscle hemorrhagic contusions, or prolonged pathological postures.

Parkinsonian (Jellinger, 2004) and cerebellar symptoms (Formisano at al., 1987) may be both associated with pyramidal paralysis, with mixed features and frequent lateralization (pyramidal-cerebellar syndrome). Occasionally, the improvement of rigidity or spasticity, or of mixed features of rigidity and spasticity, may exacerbate the intentional cerebellar tremor because of the reduction in muscular tone. The main parkinsonian symptoms are rigidity, akinesia, trunk flexion, and hypomimia, whereas tremor is only rarely present. Hypersalivation (sialorrhea), rare blinking, and seborrhoea of the face are common adjunctive extrapyramidal symptoms (Formisano et al., 1996; 2009; 2010; 2011a; Di Russo et al., 2005).

A transient period of post-traumatic mutism (PTM) is commonly associated with parkinsonian symptoms. These patients may recover alternative forms of communication through gestures, or sometimes by writing, but they do not demonstrate any verbal communication or the intention to vocalize. This condition may last several weeks and sometimes a few months, but only rarely persists as permanent unless associated with verbal inertia or severe dysarthria. Post-traumatic mutism has been reported with a frequency of 3% in individuals with severe TBI(Levin et al., 1983), but in our database, its incidence in survivors with DOC seems much higher, up to 30% of the cases, especially when associated with severe frontal damage to brainstem lesions or disconnection syndrome. Recovery of verbal communication during the period of PTM has been widely described in the literature (Vogel and von Cramon, 1983).

Trismus secondary to bilateral masseter contraction or focal dystonia should be dealt with early because of the high risk of muscle contracture and temporomandibular ankylosis, especially after maxillary and jaw fractures.

Myoclonic jerks may be secondary to cortical or brainstem lesions or cerebral hypoxic damage; they are, in general, early predictive indicators of poor prognosis for long-lasting disability (Dolce and Sazbon, 2002).

3. Misdiagnosis

High misdiagnosis rate in individuals with DoC has been reported (Schnakers et al., 2009).

The term ‘functional LIS has been proposed to describe patients with a dissociation between extreme motor dysfunction and preserved higher cortical functions identified only by functional imaging techniques (Bruno et al., 2011). Moreover, Cruse at al. (2012) demonstrated that it is also possible to detect the hidden awareness of patients in behavioural VS, using an EEG technique. Nevertheless, patients clinically diagnosed in the VS who are able to perform mental imagery tasks (Owen et al., 2006; Monti et al., 2010) are still considered to be in the VS with preserved islands of consciousness, not as having functional LIS (Formisano et al., 2011a,b; 2013). Indeed, patients with residual cognitive functions, who are able to perform complex mental imagery tasks or show intentional communication ability with functional neuroimaging techniques, should be diagnosed with functional LIS and not VS with hidden consciousness (Laureys et al., 2010; Formisano et al., 2011b; 2013). Interestingly, Chennu et al. (2014) applied graph theory by means of high-density EEG investigation in a series of patients with chronic DOC. The metric of alpha network efficiency correlated with the degree of behavioral awareness. In particular, some patients in behaviorally unresponsive VS who demonstrated evidence of covert awareness with functional neuroimaging, had alpha networks that were preserved and similar to those of the controls. These findings parallel the alpha rhythm commonly found in patients with LIS and supports our hypothesis that behaviorally unresponsive patients who follow commands based on functional neuroimaging or neurophysiological tests are not, in fact, in a VS (von Wild et al., 2012), but instead in a complete LIS or functional LIS (Formisano and Zasler, 2015).


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