Francesco Lombardi1 and Antonio De Tanti2

1Riabilitazione Intensiva Neurologica, Ospedale di Correggio, AUSL Reggio Emilia, Via Mandriolo Superiore Correggio, Reggio, Emilia, Italy and2Responsabile U.O. Gravi Cerebrolesioni e Disturbi Cognitivi, Centro Riabilitativo "Villa Beretta",

Costamasnaga, Lecco, Italy

The main objective in the rehabilitation of the comatose patient is the regaining of consciousness. This is the first step in a life of relationship. After this objective has been achieved, the quality of the rehabilitation project is heightened, and the therapeutic relationship between the therapist and the patient is transformed from a one-way to a two-way relationship. The patient begins to participate, to seek to communicate, to move autonomously, and to take up an independent daily life. Failing to achieve contact with the surroundings, on the other hand, means being doomed to a life of vegetative perceptions and expression, and a negative rehabilitation prognosis.

Due precisely to this aspect of "promotion" or "failure", the definition of the state of consciousness of an individual recovering from a coma is a potential source of conflict between rehabilitation staff and the patient's family. Staff must avoid the formulation of superficial judgments, judgments based on hasty observations, or worst of all, judgments made by inexpert personnel (Zasler, 1997). Currently, a vegetative state (VS) diagnosis is based essentially on clinical observation (Andrews, 1996), and requires the clinical experience of a multidiscipli-nary team that works well together and that places adequate importance on the family's observations (Giacino et al., 2002; Jennet, 2002). In this realm of extremely complex interests, significant errors of misdiagnosis are still made today (Andrews et al., 1996; Cranford, 1996).

The joint work of several authors has allowed the formulation over time of a more precise definition of the evolution of the state of consciousness beginning from the coma. The definitions for coma, VS, Minimally Responsive State or Minimally Conscious State, A kinetic Mutism and Locked-in Syndrome (American Congress of Rehabilitation Medicine, 1995; Giacino et al., 2002) have been more clearly defined in operative terms, and on the basis of behavioral observation (Table 22.1).

A clearer definition has been provided as well for prognostic terms such as Persistent VS, and Irreversible VS. According to some authors, a VS that persists 3 months after an anoxic event or 1 year after a severe cranial trauma can be defined as permanent (The Multi-Society Task Force on persistent vegetative state (PVS), 1994). Other authors suggest using an interval of 6 months for patients with post-anoxic damage (Working group Royal College of Physicians and Conference of Medical Royal Colleges, 1996). The scientific community is also divided over the possibility of considering a post-traumatic VS permanent after 1 year (American Congress of Rehabilitation Medicine, 1995).

22.1 The natural history of the coma

The comatose state is widely perceived as a serious clinical prognosis. The early literature dealing with the comatose prognosis spoke of the risk of severe disability or the VS for 79% of patients who remained in a non-traumatic coma for at least 1 week (Bates et al., 1977). More recent data paints a less disastrous picture. According to the Traumatic Coma Data Bank (TCDB), "good recovery" or

Table 22.1. Behavioral features associated with coma, vegetative state, minimally responsive state, a kinetic mutism and locked-in syndrome.

Coma

Vegetative state

Minimally responsive state

Akinetic mutism

Locked-in syndrome

Consciousness Sleep/awake Motor activity

Sensory activity

Absent

Absent

Reflexive movement Posturing

Absent

Communication Absent

Absent

Present

Spontaneous eyes opening Reflexive movement Posturing Non-purposeful movement

Startle to auditive and visual stimuli

Absent

Partial

Present

Localizes noxious stimuli Can reach, touch and hold objects in a correct way in respect to their size and shape Inconsistent command following

Localizes sound location Sustained visual fixation and tracking Contingent vocalization Inconsistent intelligible verbalization or gesture

Partial Present

Present Present

Minimal degree of Quadriplegia movement and command Vertical eyes following, depending on movement the nature and intensity and blinking of the stimuli

Intact visual tracking

Minimal degree of speech , depending on the nature and the intensity of the stimuli on command

Preserved

Aphonia or anarthria Communication by means of vertical eyes movement and blinking

"moderate disability was observed in 43% of patients 674 days after the event on the average, as compared to 16% that were considered "severely disabled", 5% that were declared to be in "VSs", and 36% that were deceased (Marshall et al., 1991).

The likelihood of recovery varies in relation to the cause that generated the coma. Thirty-three percent of the patients discharged from intensive care in post-traumatic VS achieve contact with the environment 3 months after the trauma. Forty-six percent achieve contact after 6 months, and 52% after a year. Seven percent of these patients achieve the good recovery category described by the Glasgow Outcome Scale (GOS), and 17% reach a state of moderate disability (The Multi-Society Task Force on PVS, 1994). The prognostic picture is considerably less optimistic for post-anoxic encephalopathies, where 11% of patients reach a state of consciousness after 3 months, and 15% achieve consciousness after 6 months. This percentage remains unchanged at follow-up examinations. The prospect for good recovery for these patients is 1%, while 3% of them recover with moderate disability (The Multi-Society Task Force on PVS, 1994; Sazbon et al., 1993).

The anatomical lesions generated in these two conditions are different, and this is the clear reason for the differing prognoses. Severe hypoxia causes multifocal or diffuse extensive laminar cortical necrosis, with constant involvement of the hippocampus. These lesions may be accompanied by small infarcted areas or neuronal loss in the basal ganglia, hypothalamus, or brain stem, with the effect extending to the gray and the white matter (Graham et al., 1993). Diffuse axonal damage, the typical result of traumatic brain injury (TBI), is characterized by extensive subcortical axonal lesions that virtually cut off the cerebral cortex from the other parts of the brain. These lesions are localized in the white matter, and do not greatly affect the gray matter of the cortex (Gennarelli, 1993). In both cases, the lesions in the acute phase are sufficiently widespread to cause the comatose state. However, while anatomical lesions related to axonal damage are theoretically "reparable" since the neuronal bodies are preserved (see Volume I, Chapter 24), the neuronal destruction caused by hypoxia makes the potential for regeneration extremely low. The theory of synaptic plasticity helps provide an explanation for neural repair when axonal damage is involved (Albensi and Janigro, 2003). According to this theory, the central nervous system reacts to external or internal stimuli by modifying its synapses (Hebb, 1949). A high frequency stimulus produces an increase of efficiency in synaptic transmission that continues and lasts in time (Bliss and Lomo, 1973). This phenomenon, which is called long-term potentiation (LTP), is thought to be the normal neurobiological mechanism underlying the learning or memorization processes. The opposite phenomenon was also described, wherein negative stimuli may produce a long-term depression (LTD) that may interfere with stable learning processes (for a detailed discussion of LTP and LTD, see Volume I, Chapter 4). The LTP and LTD responses are manifestations of synaptic plasticity that last in time and which are related to memory consolidation (Bliss and Collingridge, 1993; Izquierdo and Medina, 1997; Holscher, 1999). The LTP and LTD processes are thought to function in the exact opposite way. The factors that modulate the balance between the LTP and LTD responses are the patient's synaptic history, learning, development, age, stress level, type of illness, and brain injury (Stanton, 1996; Foster, 1999). It has been stated that cerebral trauma causes a decrease in LTP responses, while there is no concurring information about LTD responses (Albensi and Janigro, 2003).

In light of physiological learning mechanisms, considering that axonal damage - the anatomical condition underlying the post-traumatic VS - is compatible with the conservation of vitality in the neuronal bodies in the gray matter, it is logical to think of the neurobiological recovery process in these patients as the recovery of the neurophysio-logical mechanisms underlying the normal learning process. The borderline for neurobiological recovery is represented essentially by the degree of axonal degeneration and by the number of neuronal connections that are saved. Patients in irreversible VS are those that have sustained such widespread axonal degeneration as to no longer regenerate axons or re-establish new synapses.

Axonal damage is by definition a primary lesion. It is determined at the moment the trauma takes place. In serious cases, where there is a risk of irreversible VS, the only strategy that will theoretically limit axonal damage is to prevent the process of extensive degeneration that takes place during the first few months after the trauma (Graham et al., 1993).

What has been said about diffuse axonal damage does not apply to diffuse hypoxic cerebral lesions characterized by extensive loss of gray and white matter. The degree of seriousness of the prognosis for this type of diffuse brain injury is proportionate to the degree of seriousness of the anatomical-pathological lesion. Unlike diffuse axonal damage, hypoxia is a secondary lesion. The severity and the extension of the hypoxic lesion can be limited through appropriate, timely cardio-pulmonary resuscitation during the acute phase (Graham et al., 1993).

22.2 Analyses of prognostic factors

The use of prognostic indicators is of fundamental importance in planning the rehabilitation treatments that will be necessary after the acute phase. Scientifically valid prognostic factors will allow us to offer the family correct information about the patient's chance of recovery, and will help foresee the need for long-term care. Most important, these factors will allow choices to be made in terms of programming finances and health care, and in seeking out effective, appropriate treatment in a system where resources are limited. Finally, we must not forget that a strong demand for scientific evidence comes from the world of bio-ethics and jurisprudence, in relation to the ever-increasing request to stop treatment if the VS can be defined as irreversible (American Academy of Neurology, 1989; May and McGivney, 1998; Diamond, 1999; O'Rourke, 1999).

An analysis of the literature relating to this subject unfortunately leaves us partially unsatisfied. Several authors found that the signs of hypothalamic damage (e.g. generalized sweating) and flaccid motor response most clearly differentiated the recovered from non-recovered patients (Sazbon and Grosswasser, 1990). Others reported that age, pupillary reactivity to light and the best motor response were the most useful prognostic factors for death or continued VS (Braakman et al., 1988). Data from the TCDB unfortunately has not confirmed the existence of any useful prognostic indicator for recovery from VS (Levin et al., 1991).

Other studies have concentrated on the possibility of cerebral magnetic resonance imaging (MRI) being used to help define prognostic indicators. A series of 80 consecutive severe cranial trauma patients in VS was subjected to cerebral MRI within 6-8 weeks from the outset (Kampfl et al., 1998). From an analysis of the results, it was evident that lesions located on the posterior part of the corpus callosum, in the dorsal-lateral cranial areas of the brain stem, and in the corona radiata are strongly indicative of a risk of prolonged VS to 1 year from the trauma (The risk was respectively 132 times greater for lesions on the corpus callosum, 7 times greater for the brain stem, and 4 times greater for the corona radiata). These lesions are typical of diffuse axonal damage. The same authors however, warn us not to consider this pattern to be a sure prediction of irreversible VS in the separate patients we examine. Twenty-four percent of the patients with lesions on the corpus callosum and 26% of those with dorsallateral lesions on the brain stem were not in VS 1 year after the trauma, even if none of them reached the "good recovery" stage on the GOS.

Neurophysiological exams have proven so far to be rather unreliable in making predictions concerning traumatic etiology, while they are a powerful tool in the precocious prognosis of anoxic encephalopathies and ischemia. A systematic review of the literature analyzed 33 studies with a total of 4500 patients examined (Zandbergen et al., 1998). Four variables were found to predict an unfavorable outcome (death or VS), with a specificity of 100%. These four factors are: mydriatic pupils that do not react to light, the absence of motor reflexes as a reaction to pain, a flat electroencephalogram with burst-suppression, and bilateral absence of somatosen-sory evoked potential (SSEP). The first two factors are reliable within 3 days from the beginning of the coma, and the last two factors within 7 days from the outset. The absence of SSEP is the variable that yields the most accurate prognosis.

Following these results, the authors propose a step-by-step procedure for coming to a decision, which calls for suspending treatment at the end of the first week when the four factors all indicate an unfavorable prognosis. The authors also analyze the predictive value of the SSEP separately, and conclude that the bilateral absence of cortical SSEP 1 month from the beginning of a post-anoxic coma constitutes a sure prognosis for severe and irreversible brain damage (Krieger, 1998; Zandbergen et al., 1998).

Studies of functional imaging, such as single photon emission computed tomography imaging (SPECT) and positron emission tomography (PET) scanning, have not provided sure prognostic elements for predicting the probability of regaining consciousness (Oder et al., 1996). As we have previously pointed out, the duration of the VS is a negative prognostic factor, and criteria for defining a VS as permanent have been recorded in literature (The Multi-Society Task Force on PVS, 1994; Working group Royal College of Physicians and Conference of Medical Royal Colleges, 1996). The currently available data allow us to define a post-anoxic VS as irreversible 6 months after the trauma (Zandbergen et al., 1998; Latronico et al., 2000), while the scientific community is still divided over the possibility of considering a post-traumatic VS permanent after 1 year (American Congress of Rehabilitation Medicine, 1995). Statistics have confirmed the possibility of regaining consciousness after more than 1 year from the trauma, with seven individuals out of

434 (1.6%) regaining consciousness after 1 year in the figures reported by the Task Force. According to other authors, the percentage of late awakenings is about 14% (Childs and Mercer, 1996).

Many projects have been carried out to study the relationship between the length of the period in which the patient does not respond and the quality of the functional recovery after a long period of time. In all cases, a longer duration of the coma/VS is related to worse outcome (The Multi-Society Task Force on PVS, 1994). This is probably due both to the fact that protraction of the coma indicates more severe brain damage, and that the longer the patient is in a coma, the greater the risk of secondary damage.

A retrospective analysis of 134 patients that remained in a coma for more than 30 days showed that 54% regained consciousness within a year of the trauma. Seventy-two percent of these went home, and 48% regained their independence in daily life (Sazbon and Grosswasser, 1990). But in a previous paper, in 1985, Sazbon yet outlined that most of the patients, who recovered from a period of coma of more than 1 month, regained consciousness by 6 months; by 1 year only 4% more of traumatic patients and none of non-traumatic had recovered (Sazbon, 1985). According to the Task Force, progressive protraction of the VS leads to a more serious prognosis, to the extent that after 6 months from the trauma, one finds only patients that are severely disabled according to the GOS (The Multi-Society Task Force on PVS 1994).

In conclusion, at the moment there is no single prognostic factor or model of prediction that will allow us to make an early-on forecast for individual patients in post-traumatic VS. In most cases, no reliable elements are available for formulating a negative recovery prognosis that would justify denying access to rehabilitation facilities (Italian Consensus Conference, 2002). Limiting access to rehabilitation facilities on the basis of uncertain prognostic indicators carries a risk of losing a certain number of patients with neurobiological recovery potential, even though that recovery is delayed. The risk that an unfavorable prognosis may turn into a self-fulfilling prophecy is a real one. Patients will move towards a negative outcome precisely because the prematurely formulated negative prognosis has prohibited access to treatment that could have improved their outcome. The one and the most important exception is that of severe anoxic cerebral lesions where it is possible to formulate a shared, reliable negative prognosis even several weeks after the patient has gone into a coma (Zandbergen et al., 1998).

22.3 Effectiveness of multisensory stimulation programs

In order to facilitate regaining contact with the environment for patients in a coma or VS, many authors have maintained that rehabilitation programs including multisensory stimulation are useful. Such a rehabilitation approach is supported both by a demonstration that sensory deprivation produces loss of neurological functions in animals - as the first authors who proposed this theory believed (Le Winn and Dimancescu, 1978) - and by the theory involving synaptic plasticity and LTP and linguistic data processing (LDP) phenomena (Albensi and Janigro, 2003). It is necessary to point out however, that according to the theory of neuronal plasticity, not all sensory stimuli by nature have a positive effect on the production of stable synaptic bonds. In fact, negative stimuli may produce synaptic depression that will influence learning negatively (Izquierdo and Medina, 1997; Holscher, 1999). To summarize, part of the criticism about multisensory stimulation programs - meaning intensive (15-20 min, repeated every hour for 12-14 h per day, 6 days a week), simultaneous administration of maximum intensity stimuli (all five senses), applied in succession to sensory receptors (Doman et al., 1993) - regards the risk that intense, prolonged and indiscriminate stimulation may produce a temporary increase in the level of arousal during the initial phase, which is not sufficient to lead to or to increase the possibility of full awakening. Prolonging such stimulation rapidly leads to a phenomenon known as psychological "noise habituation", where the patient is psychologically accustomed to background noise, with a corresponding decrease

in the ability to elaborate information (Wood, 1991; see Volume I, Chapters 2 and 5). In light of these considerations, an opposite approach to multisen-sory stimulation has been proposed, called a "Sensory Regulation Program". It is characterized by single brief sessions of stimulation in a quiet environment completely free of noise (Wood et al., 1993).

Studies dealing with the administration of D-amphetamine to facilitate neurological recovery in animals (see below) have shown that the experience the animal has while under the effect of the drug is essential to producing the desired effect (Feeney et al., 1993). If the rat is confined to a small cage to prevent more energetic movements, the positive effect on neurological recovery is canceled (Feeney et al., 1982). The same thing happens if the major motor-sensory experience is carried out before administering the drug (Hovda and Feeney, 1984). This underlines the fact that the drug is a sort of fuel for rehabilitative exercise (see Volume I, Chapter 15 for more details).

These results have been confirmed by a second experiment, in which the effects of bilateral ablation of cortical areas 17 and 18 on the stereoscopic vision of a cat were studied. The produced impairment regresses completely and definitively after the administration of D-amphetamine, provided the animal's sight is preserved. If the animal is placed in a completely dark place with a total deafferentation, the positive effect on recovery will be completely canceled (Feeney and Hovda, 1985). Unfortunately, the effectiveness of sensory-motor exercise on neurological recovery has not yet been demonstrated in studies carried out on humans. No studies have even been conducted on the combined effect of neuro-transmitter therapy and sensory-motor exercise.

A systematic review of the literature on the effectiveness of multisensory stimulation for facilitating awakening from a coma has led to the selection of 25 studies in which the rehabilitation methods used and the system for checking for clinical effectiveness were described in sufficient detail (Lombardi, 2002a,b). Out of these studies, 22 have been excluded from our review for various reasons: fourteen of them were series of cases without a control group (Rosadini and Sannita, 1982; Boyle and Greer, 1983; Weber, 1984; De Young and Grass, 1987; Johnson et al., 1989; Rader et al., 1989; Sisson, 1990; Wilson et al., 1991; 1993; 1996a, b; Hall et al., 1992; Doman et al., 1993; Schinner et al., 1995), five were studies with a historical control group (Cooper et al., 1999; Le Winn and Dimancescu, 1978; Pierce et al., 1990; Wood et al., 1992; 1993), two were case reports (Jones et al., 1994; Guina et al., 1997), and one was a comparative cervical test (CCT) study, and included in the experimental group other types of intervention in addition to multisensory stimulation (Mackay et al., 1992). The remaining three studies, which were considered valid from a methodological point of view, unfortunately did not provide valid results confirming the effectiveness of

Figure 22.3. Arousal of patients by oral stimulation. Although patients can be aroused by oral stimulation when they are in a sitting position, the same patient as in Figure 22.1 fails to be aroused when orally stimulated in a supine, relaxed position.

Figure 22.2. Arousal of patients by verbal stimulation. With the patient of figure 1 in the sitting position, which is best for stimulating her to obey simple commands, the therapist asks the patient to look toward her.

Figure 22.3. Arousal of patients by oral stimulation. Although patients can be aroused by oral stimulation when they are in a sitting position, the same patient as in Figure 22.1 fails to be aroused when orally stimulated in a supine, relaxed position.

multisensory stimulation techniques on patients in a coma (Kater, 1989; Mitchell, 1990; Johnson et al., 1993). The review concludes that there is no reliable evidence to support the effectiveness of multisensory stimulation programs in patients in coma or VS, and that - in order to improve our knowledge of this field -the effectiveness of multisensory stimulation programs should be evaluated through adequately dimensioned randomized, controlled studies (Lombardi, 2002a,b). Given the lack of evidence, the authors suggest that any delivery of treatment interventions based on the concept of "sensory stimulation" should be provided only in the context of properly designed and adequately sized Randomized Controlled Trials, in rehabilitation environments specialized in the care of this type of patient. The precocious, formalized rehabilitation program aimed at facilitating interaction with the environment should be conducted by a multidisciplinary team of experts made up of nurses, physiotherapists and speech therapists, who are able to carry out structured monitoring of patients' responsiveness (Figs 22.1-22.3).

22.4 The influence of drugs on awakening from a coma

Various authors claim that correct use of drugs facilitates regaining contact with the environment (Haig and Ruess, 1990; Wroblewski et al., 1993; Wroblewski

1996; Plenger et al., 1996; Reinhard et al., 1996; Matsuda et al., 1999; Passler and Riggs, 2001; Meythaler et al., 2002). The most widely shared opinion is that some drugs produce an inhibiting effect, while others facilitate neurological recovery (Feeney et al., 1993; Goldstein, 1999). To summarize very briefly, pro-monoaminergic drugs have been credited with a "favorable effect", while anti-monoaminergic drugs cause "inhibition". This opinion has been fairly widely spread in literature and clinical practice in spite of the fact that no concrete evidence of this positive or negative effect has ever been found in studies on humans (Forsyth and Jayamoni, 2003). The only evidence we have is the opinion of experts.

Although there is no scientific evidence from randomized, controlled clinical studies on humans, the neurophysiological knowledge of neuronal plasticity (Goldstein, 1999; Albensi and Janigro, 2003) and of the importance of neurotransmitters in physiology and pathology has grown in time, and the body of doctrine has become more and more substantial and precise, with extremely promising realms of research like the one on the possibility that neurotransmitter drugs may provide neuronal protection or that they may stimulate neuronal plasticity. As we await more substantial scientific evidence, drugs for rehabilitation are prescribed mainly on the basis of neuro-physiological knowledge and upon demonstration of reduced cerebral concentration of aminergic neurotransmitters in severe TBI (Gualtieri, 1988). The administration of drugs to speed up neurological recovery has produced and is producing surprising results in selected cases, with clear acceleration of contextual functional recovery upon administration of the drug, as has also been demonstrated in anecdotal studies and experiments by the authors of this review (Haigand Ruess, 1990; Matsuda et al., 1999).

This type of experience is in some ways similar to what has been observed in laboratory animals by the authors who were the first to study the effectiveness of D-amphetamine for facilitating neurological recovery (Feeney et al., 1982). The administration of D-amphetamine, combined for a short period with significant sensory-motor experience, facilitates functional recovery measured by a particular ability called beam-walking (BW), even when the experience is begun days or weeks after a unilateral ablation has been practiced on the rat's sensory-motor cortex. The animals are able to spontaneously regain BW, but only over a long period of time. The effect of the drug plus the significant experience is so rapid that it would seem that the animal's difficulty in walking is not caused by a neuro-anatomical impairment, but by remote functional depression (RFD) (Feeney et al., 1993). Clinical cases of rapid and contextual clinical and functional improvement in patients in VS or minimally responsive patients treated with activator drugs shows the same results as those described in the animals, and may be explained as a condition of functional inhibition (Haig and Ruess, 1990; Matsuda et al., 1999).

In other cases reported in the literature, the results are modest from a functional point of view, but they have been received positively by health care personnel, therapists, and/or family members, who are able to interact better when they see that the patient is more aware or responsive (Wolf and Gleckman, 1995). In clinical practice however, there are patients that do not receive any benefit from pharmacological manipulation with neurotransmitter drugs. Obviously, these cases have not been published, but they can be perceived through an analysis of the results from observational studies (Passler and Riggs, 2001; Wolf and Gleckman, 1995).

In studies carried out on animals as well, neurological conditions have been found that cannot be modified and that are not consistently affected by multisensory-motor manipulation and drug therapy. This is the case with the placing reflex, which disappears totally in a cat with a unilateral ablation of the sensory-motor cortex (Feeney et al., 1993). It is important not to forget that neurobiological recovery is not possible where there is considerable anatomical brain injury, without transplanting new cerebral tissue. There are also patients in VS who -due to extensive degeneration of the white matter because of severe, diffuse axonal damage or extensive degeneration of the gray and white matter because of diffuse hypoxic lesions - have injuries that will not allow the recovery of neurobiological functions. These patients are defined as being insensitive to both neurotransmitter drugs and to multisensory-motor exercise.

During a rehabilitation project, it is necessary to ask oneself if the individual patient in VS is affected by functional inhibition, or if the patient has an extensive and irreversible neurobiological lesion. It is an integral part of the project to make clear whether the individual patient still has neurobiolog-ical potential for recovery through the manipulation of the variables at our disposal: multisensory-motor exercise and available drugs. In the absence of scientific evidence, the clinical experience of those who use neurotransmitter drugs to facilitate awakening carries the risk of remaining in the superficial realm of anecdotal trial and error, without contributing to the necessary evolution of scientific knowledge in this field. It is necessary for reliable models of experimentation to be created in this field too, in spite of all the real methodological difficulties that are often encountered in rehabilitation (Phipps et al., 1997; White et al., 1999).

22.5 Catabolism and neurotransmitter imbalance in severe TBI

Studies that have been conducted to analyze the concentration of neurotransmitters and their metabolites in the fluid after traumatic brain damage have revealed a reduction in these levels as compared to the norm (Minderhoud et al., 1976; van Woerkom et al., 1977; 1982; Vecht et al., 1975a, b; 1976). In particular, the levels of catecholamine in the fluid increase during the first few hours after the traumatic lesion, while their production is chronically reduced during the following phases, with consequent reduction in the concentration in the fluid (Bakay et al., 1986).

The cause of depauperation of neurotransmitters can be traced initially to the massive, acute release of neurotransmitters from neuronal cells in the so-called excitotoxicity phase. Following this, depauperation is maintained by the condition of hyper-catabolism to which the traumatized organism is subject (Aquilani, 2000; 2003). This process characterized by an initial excess of neurotransmit-ters followed by a deficiency in neurotransmitters, has been pointed out in literature and has even been thought to be a possible cause of failure for clinical trials with antagonists to N-Methyl-D-Asperate (NMDA) receptors (Ikonomidou and Turski, 2003). According to this hypothesis, while the blockage of receptors is initially oriented to preventing the excitotoxicity cascade, this later works as a negative factor for the survival of neurons.

Severe encephalic cranial trauma causes hyperca-tabolism that is manifested by an increased loss of nitrogen in the urine and destruction of muscle proteins, which are used as the groundwork for producing energy, repairing proteins, cytokines, hormones, and cells. In spite of nutritional efforts to obtain a stable condition, in most patients a balanced level of nitrogen is not reached until 2 or 3 weeks after the trauma (Clifton et al., 1984; Young et al., 1985; Bivins et al., 1986; Bruder et al., 1991). A hypercatabolic condition and failure to reach a positive balance of nitrogen has been demonstrated even 60 days after a severe encephalic cranial trauma (Fugazza et al., 1998). Consuming a larger amount of proteins in the diet produces greater nitrogen balance, but the difference is not statistically significant (Clifton et al., 1985). Since over-feeding is damaging, it is not correct to continue increasing the protein in-take in order to balance the nitrogen level (Roberts, 1995). Administering supplementary ramificated amino acids and arginine has been shown in two different studies to improve the nitrogen balance (Rowlands et al., 1986; Ott et al., 1988), even if the influence on the outcome has not been established.

Studies conducted with patients in the rehabilitation phase have shown considerable reduction in the plasmatic aminogram even 60 days after a severe cranial trauma. In particular, the concentration of essential amino acids was found to be reduced by 60%, and non-essential amino acids were found reduced by more than 50% (Aquilani, 2000). The authors observed the persistence of the hyper-catabolic state even in patients in rehabilitation, along with an increase in plasmatic carnitine (which indicates muscular destruction) and reduced concentration of essential amino acids - in particular ramificated chain amino acids - which suggests selective use of the latter. According to various authors, the depauperation of amino acids (in particular, arginine and glutamine) has an effect on immunocompetence (Ziegler et al., 1993; Jensen et al., 1996; Griffiths, 1997; Houdijk et al., 1998) as well as on the balance of neu-rotransmitters in the central nervous system. In particular, this regards glutamate, aspartate, tyrosine, and tryptophan, the precursors of monoaminergic neurotransmitters (Aquilani, 2000; 2003).

For this reason, it is important that future studies on humans concentrate on a real "nutritional therapy" approach, in the hopes that nutritional manipulation might facilitate and stimulate neurobiological recovery in trauma patients (Aquilani, 2003). It is interesting to point out here that both the nutritional therapy approach and pharmacological manipulation using neurotransmitter drugs work in the same direction. The former approach constitutes the underlying activity for the therapeutic strategy, while the pharmacological approach serves as a temporary support until the patient regains autonomous metabolism. The combined action of these two approaches might constitute a reasonable treatment for facilitating neu-robiological recovery in patients in the VS, provided the anatomical potential for recovery exists, or in other words that there is not diffuse axonal or neuronal degeneration (Graham et al., 1993).

22.6 Neurobiological recovery may be interrupted by interfering factors

The outcome of a patient in the VS actually often depends on a combination of various factors. It is possible for these factors to intervene in sequential order, producing situations that inhibit neurobio-logical recovery. The axonal or hypoxic lesion is the pathognomonic pathological element causing the VS, but these lesions may be accompanied by other lesions that overlap later on. In the following paragraphs, we will discuss a couple of potential secondary causes for the primary rehabilitation prognosis becoming progressively more negative.

Post-traumatic hydrocephalus

It is practically impossible to clinically detect the onset of post-traumatic hydrocephalus in a patient in the VS, since it is impossible for the usual signs of hydrocephalus-cognitive disturbance, gait apraxia, or bladder incontinence-to be manifested (Zasler and Marmarou, 1992; Narayan et al., 1990). One way to make an alteration in fluid circulation visible is to carry out a series of CT brain scans, that will show over a month's time the progressive increase in the dimensions of the cerebral ventricles (Narayan et al., 1990; Chesnut et al., 1992).

Unfortunately, simply noting ventricular enlargement is not sufficient for detecting hydrocephalus, since progressive cerebral atrophy is also characterized by an increase in the dimensions of the ventricles (Zasler and Marmarou, 1992; Marmarou et al., 1996). As we know, both severe diffuse axonal damage and severe hypoxic encephalopathy cause cerebral atrophy and chronic VS (The Multi-Society Task Force on PVS, 1994). Supplementary methods have been defined to allow for the different diagnoses of the two conditions: cerebral spinal fluid (CSF) dynamics studies (Marmarou et al., 1996) and SPECT imaging (Mazzini et al., 2003). However, the use of these diagnostic instruments has not become widespread, and they are not easy to procure in many hospital settings.

The uncertainty in terms of diagnosis, whether clinical or instrumental, is probably one of the reasons the results of ventricular peritoneal shunt operations have been unsatisfactory so far (Chesnut et al., 1993; Cardosa and Galbright, 1985). Data from the TCDB shows that 27 patients were found to have post-traumatic ventricular Enlargement (PTVE) 1 month after the acute event, or 5.4% of the total number of 498 in a sample group of patients with severe cranial trauma. All of the patients in the group were assessed by computerized axial tomography (CAT) scan at 3 days, 7-10 days, 3 months and 6 months from the event, and none of them had shown ventriculomegaly when admitted (Chesnut et al., 1993). This incidence is fairly near to the 3.9% observed by Grosswasser out of a sampling of 335 patients affected with severe cranial trauma, for whom hydrocephalus had been

Table 22.2. Outcome of patients with post traumatic ventricular enlargement in the TCDB.

Outcome number (%)

Status of Number of % Total Moderate or Vegetative ventricles patients patients Good severe or dead

Total cases 498 100 28 40 32

PTVE 27 5 4 70 26

No PTVE 471 95 29 38 33

Reproduced with permission from Chesnut et al. (1993).

Table 22.3. Outcome of patients with post traumatic ventricular enlargement in the TCDB. A comparison between shunted and not shunted patients.

Outcome number (%)

Presence of Number of % Total Moderate or Vegetative shunt patients patients Good severe or dead

PTVE 27 100 4 70 26

Shunted 17 63 6 65 29

Not shunted 10 37 0 80 20

Reproduced with permission from Chesnut et al. (1993).

diagnosed through serial CAT scans and radionuclide cisternographies (Grosswasser et al., 1988). Other authors have found very different rates of occurrence of post-traumatic hydrocephalus, ranging from 20% in a sampling of 237 patients with severe cranial trauma - of which 44% showed ventriculomegaly (Marmarou et al., 1996) - to 45% in a series of 240 individuals (Mazzini et al., 2003). From the TCDB data, we know that the prognosis for patients that show PTVE as assessed by the GOS is clearly more serious than that of the total cases in the sample group (see Table

22.2): Chi2 = 13.04; P = 0.0015 (Chesnut et al., 1993). Of the 27 patients that showed ventricular enlargement, only 17 were given a CSF shunt. The treatment did not generate a statistically significant difference in outcome in GOS points (see Table

22.3): Chi2 = 0.338; P = 0.561 (Chesnut et al., 1993). The small number of patients studied, the insufficient number of subjects in several of the boxes in the table, and the obvious lack of randomization oblige us to maintain a certain amount of caution in assuming that this study really did not produce statistically significant results. One aspect is interesting however, and provides food for thought: the authors themselves have underlined the following sentence twice in the article. "In various individual patients, the shunt treatment produced considerable and contextual clinical improvement" (Chesnut et al., 1993). This emphasis corresponds to the experience we have had as well.

Ifwe consider that patients affected by ventricular dilation are in any case subject to a negative prognosis (see Table 22.1), and that the "good recovery" category in the table has only one individual (estimated number based on the percentages reported) treated with CSF shunt, we may conclude that for the 27 subjects of the study, the only chance to enter the good recovery category was through surgery. The clinical observation of clear-cut benefit following a

CSF shunt operation was observed in 52.1% of a group of 48 severely traumatized patients that were all treated surgically (Tribl and Oder, 2000).

There are various ways to discuss the usefulness of a CSF shunt in post-traumatic ventricular enlargement. We could speak about the complications the patients are subject to, of the cost-benefit ratio, or of the low degree of effectiveness of the operation. However, from a point of view considering the individual patient in the VS, it is highly likely that "non-treatment" corresponds to a standstill in neu-robiological recovery, while "treatment" is the only chance for the individual to express his full neurobiological recovery potential on the basis of the primary neurological lesions alone.

Generalized spasticity

The risk of misdiagnosis among disorders of consciousness in severe brain injuries is well known (Childs et al., 1993). In most cases, the possible diagnostic mistake is usually associated with the presence of significant sensory impairment. For instance, in Andrew's reported cases, 65% of misdiagnosed subjects were either blind or severely visually impaired (Andrews et al., 1996).

In one published case report regarding spasticity which did not respond to treatment by oral drugs (Palumbo, 2004, in press), spasticity was found to be a factor leading to a mistaken diagnosis of the VS. For this individual, treatment by intrathecal baclofen therapy (IBT) 258 days after the trauma brought a rapid change in the patient's response level, going from a minimal response level that continued from the third month after the trauma, to a state of full response, although conditioned by evident cognitive impairment and severe motor disability. The patient, who had episodes of autonomic disorder, showed rapid improvement 7 days after surgery. This result had already been observed by previous authors (Becker et al., 2000; Cuny et al., 2001). In the case described by Palumbo, solving the severe spasticity problem led to an improvement in nutritional methods and the capacity to respond to environmental stimuli, improving the level of participation in the rehabilitation program, with further improvement - albeit slow - in the outcome at check-ups that were carried out 385 and 453 days after the acute event.

22.7 Conclusions

Although there is no substantial scientific evidence, rehabilitation of the comatose patient, and in particular of the patient in a VS, is a process that is geared towards assessing the individual patient's neurobiological potential for recovery. This assessment should be based on a series of different behaviors that make up a step-by-step procedure on which to base the rehabilitation process.

1 In order to conduct the process correctly, it is necessary that it be carried out by a team of experts who are able to sensitively and effectively evaluate every change in the patient's state of response, however small.

2 In order to draw out the patient's residual neurobiological recovery potential, it is necessary to carry out an active assessment process to detect the presence or absence of every possible negative or mistakable factor (sedative drugs, hydrocephalus, spasticity, malnutrition) and to follow up with specific treatment to manage or correct the factor.

3 Standstills in neurobiological recovery come in addition to the primary lesions. They differ by nature, severity, and the time at which they arise, and it is possible for an individual patient to demonstrate more than one inhibiting factor at a time.

4 Once the negative factors that are interfering have been eliminated or put under control, it is necessary to check to see if the introduction of facilita-tive factors will produce real improvement in the patient's response level:

- stimulating drugs,

- nutrients to foster amino acid metabolism,

- postural variations,

- changes in the environmental context,

- stimulating sensory experiences.

5 The improvement in the patient's response level is the basic element on which a prognosis is made at a suitable amount of time after the acute event.

Although there is agreement on the idea that regaining contact with the environment is a multi-factorial problem, many studies carried out up until now on single therapeutic approaches may have failed to be in any way effective due to the lack of a holistic vision of the problem, in addition to other reasons. Many of the factors involved are difficult to diagnose, both because of the patient's clinical condition, and because of unsatisfactory instruments. Until more precise diagnostic instruments are available, the only approach that will allow us to raise the number of patients that regain contact with the environment is to operate "by exclusion".

It is important that the clinical attitude of the rehabilitation team be self-determined, and not geared to the patient's clinical progress. This will prevent the risk of considering negative progress predetermined or unavoidable. The clinical behavior of the team must also be analytical and periodically concentrated on checking for possible interfering factors and on the impact of possible favorable factors. Given the uncertainty in detecting interfering factors, it is reasonable to act as though the factor were present, and to carry out the correct treatment, considering the advantages and the risks the patient will be subject to in each particular situation as it arises.

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