Vegetative State, Minimally Conscious State and Parkinson-like syndrome as a recovery continuum

By: R. Formisano, R. Zafonte, R. Hayes

Owen et al. (Owen 2006) recently described the case of a young woman who sustained a severe head injury in a traffic accident with clinical evolution towards a vegetative state (VS). Although the patient was still unresponsive and unable to communicate five months after the accident, fMRI scans showed that she retained some ability to process language. Moreover, when asked to imagine playing tennis or moving around her home, the patient activated the same cortical areas as healthy people. In the Supporting Online Material (SOM, 2006) the authors report the recovery of minimal interaction with the environment 11.5 months post-injury, when the patient recovered the ability to turn her eyes very slowly to the right, after stimulation on that side, and fixate for more than five seconds. They also report that electroencephalography showed some slow alpha frequencies, as may occur in locked-in syndrome (LIS).

In fact, LIS is a neurological condition secondary to a pontine lesion in which patients are conscious, aware, and behaviourally and neurophysiologically distinguished from VS patients because they are able to communicate by means of vertical gaze, and/or upper eyelid movements (Plum and Posner, 1966) and their EEG activity is normal. However, it is also reported that some LIS patients are unable to communicate by eyelid movements because of palsy that extends also to ocular motility (Smith, Delargy, 2005). In such cases, a clinical differentiation between VS and LIS may be very difficult. Indeed, this could be the case in the Science study cited above.

Moreover, in our clinical experience some VS patients pass through LIS during recovery of consciousness. This process does not always occur in the presence of structural brain stem lesions, but is often associated with diffuse axonal injury with a functional disconnection syndrome.

We had a case similar to the one in the Science report (Owen, 2006). Our patient had a large bifrontal craniectomy (as reported in SOM 2006), that evolved to VS after cranioplasty due to hydrocephalus (Missori et al., 2006). After ventriculo-peritoneal shunting, the patient recovered consciousness and motor function of upper and lower limbs. The authors of the Science report should, therefore, provide more information on a cerebral MRI control of the young TBI patient at 11.5 months post-injury and on any surgical procedures during the chronic phase.

Since fMRI has been demonstrated to be useful in the early diagnosis of Alzheimer’s disease (Greicius, PNAS, 2004), fMRI tests may also be able to predict the recovery of consciousness in VS patients who will later evolve towards a minimally conscious state (MCS) (Giacino, 2004) or full awareness. In fact, after 5-month VS it is still possible to achieve minimal or complete recovery of consciousness. Such recoveries are often gradual (Multi-Society Task Force, 1994; Royal College of Physicians, 2003); therefore, it is not surprising that fMRI may reveal the conscious awareness that will become clinically apparent only later.

Importantly, a number of observations in the literature highlight the complexity of this area.

Previous studies on VS patients demonstrated a massive reduction of cerebral metabolism (Beuthien-Bauman, 2003), whereas recent PET studies indicate altered activity in a critical frontoparietal cortical network and abolished functional connections within this network. It has been shown that recovery of consciousness is paralleled by restoration of this cortico-thalamo-cortical interaction (Laureys, 2004). In the patients studied by Laureys external stimulation of VS patients still induced neuronal activation, as shown by both auditory and noxious stimuli, although this activation was limited to primary cortices. Also, N400 event-related evoked potentials were able to differentiate among VS, near VS, and patients not in VS (Schoenle, 2004).

SPECT studies have demonstrated that changes in regional cerebral blood flow, induced by auditory stimulation, consist of stronger functional connectivity between the secondary auditory cortex and the temporal and prefrontal cortices in MCS compared to VS patients (Boly, 2004).

Other authors have reported brain responses (by means of auditory-evoked potentials) to one’s own name in VS, MCS and LIS. A P3 component, which is a cognitive response, was observed in all patients with LIS and MCS and in 3 out of 5 patients in VS. P3 latency was significantly delayed for MCS and VS patients compared to LIS and healthy volunteers (Perrin, 2006).

All of the recent studies on cerebral blood flow (PET/SPECT) and those based on the use of advanced techniques of neuroimaging (fMRI/DTI) and clinical neurophysiology (event-related evoked potentials) make even more elusive the boundary between VS and MCS (Beuthien-Baumann, 2003; Boly, 2004; Laureys, 2004; Owen, 2006; Perrin, 2006; Schoenle, 2004).

Also, the addition of “persistent” and “permanent”, currently abandoned according to the International Working Party on the VS (Royal College of Physicians, 1996), is certainly discredited by several clinical reports describing the possibility of consciousness recovery more than 1 year after severe brain injury in more than 10% of traumatic VS and more than 5% of non traumatic VS, in the case of cure prosecution (Borthwick, 1996).

Another surprising clinical report is that of a chronic traumatic MCS patient who recovered comprehensive language abilities after 19 years, with associated reorganization of the cerebral white matter, revealed by MRI advanced techniques such as DTI (Voss, 2006). The case described by Voss (2006) can also be interpreted as an associated post-traumatic psychiatric condition, such as catatonia or severe depression of mood, with oppositive behaviour lasting several years as the common neuropsychological sequelae.

Similarly, an unexpected improvement of responsiveness after administration of the minor tranquilizer, zolpidem, was reported in 3 VS patients (2 traumatic and 1 hypoxic) of three years’ duration (Clauss and Nel, 2006). A comment is needed on the “miraculous” efficacy of zolpidem in these chronic VS patients. Zolpidem is a drug with hypnogenic effects used successfully for insomnia. It exerts a specific but indirect GABA agonist action on the omega 1 receptors. In the chronic VS cases described by Clauss and Nel (2006), the drug demonstrated an opposite “awakening” effect, where spontaneous recovery could be excluded because the VS condition had lasted for 3 years. Based on the clinical description of the 3 cases, it is possible to interpret the results as secondary to the anti-convulsant effect of the drug. In fact, the authors do not report any electroencephalographic data of the 3 VS cases, but they report unilateral muscle spasms in the first and third case, and paroxystic aggressive behaviours in the second case. However, both unilateral muscle spasms and aggressive behaviours can be interpreted as partial complex epileptic seizures, which may also explain the chronic alteration of consciousness. The efficacy of zolpidem may, therefore, be interpreted as an anti-convulsant effect, on undiagnosed epileptic activity (Vespa 1999). It is, in fact, well known that some patients with severe brain injury in ICU have an undiagnosed chronic epileptic state, which in some cases may be the cause of coma persistence (Vespa 2005). In the same cases (Clauss and Nel, 2006) the recovery of verbal communication after zolpidem may be explained by the drug’s muscle relaxant effect, which may counteract the oppositive behaviour or the spasticity of the phono-articular apparatus, or both.

It can, therefore, be concluded that behavioural lack of interaction with the environment does not always lead to the exclusion of all awareness content, even in some chronic VS or MCS patients.

Based on previous reports, the efficacy of advanced techniques of neuroimaging and clinical neurophysiology in increasing our knowledge of VS, MCS and LIS must be acknowledged. Moreover, the definition of VS as “persistent” or “permanent” should be abandoned, not only for the anecdotic descriptions of VS cases that recovered consciousness later than the temporal interval decided by the scientific community for the definition of permanent VS, but also because of the possibility of a significant change in responsiveness even after 19 years of chronic MCS (Voss, 2006).

Other neuroimaging studies have shown intact language networks in some patients with MCS who have not yet recovered reliable communication or functional movements (Shiff 2005). More recently, the use of central thalamic deep brain stimulation (DBS) was able to improve the arousal regulation of functionally connected, but inconsistently active, cerebral networks, which might be present in some patients in a MCS but absent in others with VS (Shiff, 2007). In the patient described by Schiff and coll., who remained in MCS for 6 years following TBI, bilateral thalamic DBS obtained improvements in intelligible verbalization and functional limb control. The observed improvements in arousal level, motor control, and response initiation might reflect direct activation of frontal cortical and basal ganglia systems.

In summary, all of these cases with very late recovery of consciousness challenge the definition of permanent VS and MCS, because the scientific community considers as permanent only those irreversible pathological conditions without any possible recovery, whether spontaneous or following pharmacological or surgical therapy.

In conclusion, the differential diagnosis among VS, MCS and LIS is not simple as reported in the International Literature (Giacino 2004, Jennett 1972). In fact, the recovery of optical fixation and pursuing, which is not universally considered equivalent to obeying commands, is, nevertheless, an interactive behaviour with the environment. Likewise, psychomotor agitation and aggressiveness are frequent behaviours in patients with severe brain injury who are still not able to follow simple orders. Agitated patients often show intentional aggressive behaviours against themselves or others; however, also in these cases the extreme attentive exhaustibility or oppositive behaviours rarely make these patients able to obey simple commands (Formisano, 2005). According to the definition of VS as the “lack of any understandable behaviour in response to external stimulus or inner need” (Jennett and Plum, 1972; Danze, 1993), aggressiveness may also be interpreted as the manifestation of physical or emotional discomfort or of mental confusion the patient is unable to express otherwise.

Therefore, rather than a syndrome “in search of a name”, as reported by Jennett (Jennett and Plum, 1972), VS can be defined as a name in search of a universally accepted definition.

With regard to the above mentioned DBS report (Shiff, 2007), parkinsonian symptoms during recovery from prolonged post-traumatic coma (Formisano, 2004 a,b; 2005) or VS after severe traumatic brain injury (TBI) are very common but are rarely reported in literature. The main features are hypokinesia and rigidity, associated with amimia, non extinguishable naso-glabellar reflex, seborrhoea of the face, hypersalivation (syalorrhea), and extrapyramidal dysarthria (Gerstenbrand, 1967). These parkinsonian features may improve after levodopa treatment together with different degrees of consciousness recovery, especially if used early in the first remission phases (Haig & Ruess, 1990). Amantadine and dopaminergic drugs have also demonstrated some efficacy in treating parkinsonian features and in consciousness recovery (Kraus et al., 1997; Lopez et al., 2002; Krimchansky et al., 2004; Orient Hughes et al., 2005). Very recently, we also published a paper (Di Russo et al., 2005) on the motor slowness of some severe TBI patients with clinical and neurophysiological features resembling post-traumatic parkinsonism, which was confirmed by specific anticipatory-evoked potentials (“Bereistshaft Potentials”). Most of these patients generally show neuroradiological features of diffuse axonal injury (Tomaiuolo et al., 2004), which do not necessarily involve the rostral brainstem; moreover, not all patients respond to levodopa treatment.
Especially in the first phase of coma recovery, survivors of severe TBI with MR features of DAI may show extrapyramidal signs similar to those present in vascular parkinsonism secondary to multi-infarct encephalopathy (Fujimoto et al., 2006). In particular, akinesia and rigidity after severe TBI (Lindenberg, 1964) are common symptoms and may be secondary to multiple lesions either in the substantia nigra or the caudate-putamen area (Morsier, 1960; Nayernouri, 1985). It should be noted that motor disabilities in this population are the consequence of traumatic lesions at the level of the extrapyramidal pathway and not the effect of systemic dopaminergic degeneration (Peppe et al. 1998).

Matsuda et al. (2003) also reported three patients with VS (PVS) after severe head injury who showed parkinsonian features (mainly rigidity and hypokinesia) that improved following levodopa treatment after recovery from prolonged disturbance of consciousness. Jellinger (2004) commented later that the clinical phenotype of post-traumatic parkinsonism often resembles that in postencephalitic parkinsonism, in that both show akinesia, rigidity, hypomimia, rare tremor, and optomotor and vegetative disorders. Both the lesion pattern and the therapeutic efficacy of long-term levodopa treatment suggest dysfunction of the striato-nigral dopaminergic system.

A severe brain injury (VS and MCS) and post-traumatic/post-hypoxic parkinsonism may share a common midbrain (substantia nigra)–striatal-thalamic frontal network dysfunction, VS, MCS and the parkinsonian syndrome might represent a recovery continuum from prolonged disturbances of consciousness. Responsiveness to L-Dopa in some cases and to DBS in others might depend respectively on the integrity of the dopaminergic post-synaptic receptors. 
In light of the diagnostic controversies reported above, a long-term follow up of VS, MCS and LIS should be undertaken, also using the most advanced neuroimaging and neurophysiological techniques, to acquire clinical information on the evolution of these conditions.

Moreover, multi-centre controlled studies on the efficacy of the most common nootropic, dopaminergic, and psychotropic agents utilized in VS and MCS as well as DBS are needed to evaluate the real efficacy of pharmacotherapy or surgical procedures in improving chronic alteration of consciousness.

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Authors

R. Formisano, Post –Coma Unit, Rehabilitation Hospital Santa Lucia Foundation, Rome, Italy

R. Zafonte, D.O., Physical Medicine & Rehabilitation, University of Pittsburgh Medical Center

R. Hayes, Center of Innovative Research Clinical Programs, Director Banyan Biomarkers, Alachua, USA