Functional Locked-in Syndrome Research Articles

Toward Improving Diagnostic Strategies in Chronic Disorders of Consciousness: An Overview on the (Re-)Emergent Role of Neurophysiology.

The differential diagnosis of patients with Disorder of Consciousness (DoC), in particular in the chronic phase, is significantly difficult. Actually, about 40% of patients with unresponsive wakefulness syndrome (UWS) and the minimally conscious state (MCS) are misdiagnosed. Indeed, only advanced paraclinical approaches, including advanced EEG analyses, can allow achieving a more reliable diagnosis, that is, discovering residual traces of awareness in patients with UWS (namely, functional Locked-In Syndrome (fLIS)). These approaches aim at capturing the residual brain network models, at rest or that may be activated in response to relevant stimuli, which may be appropriate for awareness to emerge (despite their insufficiency to generate purposeful motor behaviors). For this, different brain network models have been studied in patients with DoC by using sensory stimuli (i.e., passive tasks), probing response to commands (i.e., active tasks), and during resting-state. Since it can be difficult for patients with DoC to perform even simple active tasks, this scoping review aims at summarizing the current, innovative neurophysiological examination methods in resting state/passive modality to differentiate and prognosticate patients with DoC. We conclude that the electrophysiologically-based diagnostic procedures represent an important resource for diagnosis, prognosis, and, therefore, management of patients with DoC, using advance passive and resting state paradigm analyses for the patients who lie in the “greyzones” between MCS, UWS, and fLIS.

Diagnosis of the phenomenon of cognitive-motor dissociation in patients with chronic consciousness disorders

Locked-in syndrome in basilar artery thrombosis is a classic example of dissociation between preserved consciousness and complete deefferentation as total myoplegia with preserved vertical eye movement. Something similar is observed in post-comatose patients, described under the name “functional locked-in syndrome”, and is also a clinical reflection of the phenomenon of cognitive-motor dissociation (CMD). Diagnosis of this condition in a patient with chronic consciousness disorders indicates that there may be a cognitive imprint, which gives a chance for the maximum realization of the rehabilitation potential of latent consciousness as an exit to the clinical level of small consciousness or creation of a brain-interface. In any case, this patient should be given an extended rehabilitation program.Objective: to search for the optimal set of clinical and instrumental diagnostic methods, allowing the identification of CMD in patients with chronic consciousness disorder.Patients and methods. The 2016–2018 prospective single-center study enrolled patients with unresponsive wakefulness syndrome (UWS) who had received a treatment cycle at the Clinical Brain Institute (Yekaterinburg). The study included 39 patients (22 men, 17 women) aged 19 to 71 years who had sustained various cerebral injuries (traumatic, hypoxic, and acute vascular disease-associated) in different periods (from 32 to 2431 days) before being included in the study. All the patients underwent 5-fold clinical assessments according to the Coma Recovery ScaleRevised (CRS-R) and navigated transcranial magnetic stimulation (nTMS) in order to determine the time course of changes in the activity of the cortical motor centers at the time of presentation of verbal paradigms. Registration of the changes was assessed as the presence of a cognitive imprint and served as a criterion for diagnosing CMD as a positive predictor for the outcome of UWS. The outcome of the state was analyzed using the Glasgow Outcome Scale (GOS) at 180 days.Results and discussion. Positive changes (GOS >3) were noted in 10 (66%) patients with established CMD; the patients who had not diagnosed as having the cognitive potential showed a further increase in the level of cognition in 3 (12.5%) cases. Whether the identified sign could be used in the comprehensive prediction of chronic consciousness disorder was discussed.Conclusion. The use of TMS in diagnosing the phenomenon of CMD optimizes the routing of patients, for whom intensive rehabilitation can contribute to more favorable long-term outcomes.

Unexpected recovery from a vegetative state or misdiagnosis? Lesson learned from a case report.

BACKGROUND:Growing research is focusing on the identification of markers predicting recovery and demonstrating covert awareness in patients with chronic disorders of consciousness (DOC). Herein, we describe the case of a woman who emerged from unresponsive wakefulness syndrome (UWS) after four years, in whom an experimental protocol assessing brain connectivity predicted her awareness recovery, indicating a functional locked-in syndrome (FLIS) diagnosis.CASE DESCRIPTION:A 68-year-old woman was admitted to our institute in 2012 in a UWS secondary to a severe brain hemorrhage, with a Coma Recovery Scale-Revised score of five. Her clinical conditions were stable for about two years, despite the intensive neurorehabilitation treatment. During hospitalization, she underwent a neurophysiological protocol demonstrating an extensive nociceptive processing within the pain matrix. After 3 years, our subject emerged from UWS, and then from minimally conscious state, being able to communicate properly.DISCUSSION:Approaches investigating brain connectivity may be useful in DOC diagnosis and prognosis, highlighting residual brain networks subtending covert awareness. Hence, our case supports the necessity of taking into account FLIS diagnosis in DOC differential diagnosis and implementing paraclinical follow-up to intercept cases of possible, late recovery of consciousness, thus optimizing the most appropriate management and rehabilitative setting.

Pain perception in patients with chronic disorders of consciousness: What can limbic system tell us?

Although it is believed that patients with Unresponsive Wakefulness Syndrome (UWS) do not feel pain, recent neuroimaging and neurophysiologic studies have demonstrated some residual traces of nociceptive processing. To confirm this growing evidence, we evaluated 21 patients suffering from chronic disorders of consciousness (DOC) (both UWS, n=11, and Minimally Conscious State - MCS -, n=10), using an Event-Related Potential (ERP) Low-Resolution Brain Electromagnetic Tomography (LORETA) approach, based on nociceptive repeated laser stimulation (RLS). We delivered laser stimuli to the dorsum of both hands and analysed the γ-band LORETA activations and the ERP γ-power magnitude induced by laser stimulation, as well as the heart rate variability (HRV). We found partially preserved cortical activations and ERP γ-power magnitude in all MCS and two UWS individuals. These effects were paralleled by a purposeful behaviour, and a reduced HRV concerning nociceptive stimulation, whereas the two UWS individuals showed no more than reflex behaviours, besides a strong limbic activation. Some UWS patients may somehow perceive the affective components of nociceptive stimulation. The diagnosis of functional locked-in syndrome should be taken into account when dealing with DOC differential diagnosis.

Do you see me? The role of visual fixation in chronic disorders of consciousness differential diagnosis

Visual fixation (VF) of a target is a possible, although atypical, feature of the Unresponsive Wakefulness Syndrome (UWS). Whether VF may indicate residual awareness in these patients is debatable, since it may simply subtend a series of reflex processes. Objective tools should therefore be used to identify aware VF, which depends on the integrity of visuomotor networks encompassing frontal-parietal-occipital areas. The aim of our study was to detect residual visuomotor network functionality potentially sustaining aware VF. To this end, we evaluated the visuomotor integration (VMI) and visual P300 patterns in a chronic Disorder of Consciousness (DOC) sample and a control group of healthy individuals (HC), using an associative stimulation protocol combining transcranial magnetic stimulation (TMS) with visual stimulation through transorbital alternating current stimulation. The Minimally Conscious State (MCS) patients showed preserved patterns of VMI and P300, whereas nearly all the UWS patients showed no significant VMI. Notably, the electrophysiological findings were correlated with the visual domain of the Coma Recovery Scale-Revised. Nonetheless, two fixating UWS individuals had a VMI similar to MCS patients. Our data suggest that some UWS patients showing VF could be aware, but unable to manifest it clearly, probably because of a severe motor output impairment, which is a condition compatible with the Functional Locked-In Syndrome.

Unravelling motor networks in patients with chronic disorders of consciousness: A promising minimally invasive approach

Behavioral responsiveness and awareness levels correlate with the degree of functional connectivity within cortical-thalamocortical networks, whose breakdown accounts for chronic disorders of consciousness (DOC). Our study was aimed at assessing the role of the primary motor area (M1) and premotor-M1 circuitry dysfunction in motor output deterioration in minimally conscious state (MCS) and unresponsive wakefulness syndrome (UWS) patients. As a control group, we included a healthy subject (HC) sample in the study. We evaluated the effects of different types of transcranial magnetic stimuli over M1 by recording post-stimulus time histogram (PSTH), which includes a series of peaks of unit firing activity that match with D and I-waves, characterizing the descending corticospinal volleys evoked by transcranial magnetic stimuli. As compared to HC, DOC patients showed a dysfunction of intra-M1 and premotor-M1 circuits, which correlated with the Coma Recovery Scale-Revised scorings. Nonetheless, one UWS patient showed a partially preserved premotor-M1 circuitry, paralleled by a severe intra-M1 circuitry dysfunction. Our data suggest that motor unresponsiveness in some DOC patients may be due to a pure motor output failure, as in the functional locked-in syndrome (fLIS), rather than to a premotor-motor connectivity impairment, which instead characterizes MCS and UWS.

Transcranial Alternating Current Stimulation in Patients with Chronic Disorder of Consciousness: A Possible Way to Cut the Diagnostic Gordian Knot?

Unresponsive wakefulness syndrome (UWS) is a chronic disorder of consciousness (DOC) characterized by a lack of awareness and purposeful motor behaviors, owing to an extensive brain connectivity impairment. Nevertheless, some UWS patients may retain residual brain connectivity patterns, which may sustain a covert awareness, namely functional locked-in syndrome (fLIS). We evaluated the possibility of bringing to light such residual neural networks using a non-invasive neurostimulation protocol. To this end, we enrolled 15 healthy individuals and 26 DOC patients (minimally conscious state-MCS- and UWS), who underwent a γ-band transcranial alternating current stimulation (tACS) over the right dorsolateral prefrontal cortex. We measured the effects of tACS on power and partial-directed coherence within local and long-range cortical networks, before and after the protocol application. tACS was able to specifically modulate large-scale cortical effective connectivity and excitability in all the MCS participants and some UWS patients, who could be, therefore, considered as suffering from fLIS. Hence, tACS could be a useful approach in supporting a DOC differential diagnosis, depending on the level of preservation of the cortical large-scale effective connectivity.

A Short Commentary on Non-invasive Brain Stimulation in Chronic Disorder of Consciousness Differential Diagnosis

The diagnosis and awareness assessments in chronic disorders of consciousness (DOC) are biased, owing to their reliance on clinical behavioral measures. Indeed, objective tools should be employed with the goal of more precise awareness detection in these patients. To this end, brain stimulation techniques have been developed to demonstrate residual cortical-thalamocortical connectivity patterns sustaining fragment of awareness. This short commentary aims at illustrating the Non-Invasive Brain Stimulation (NIBS) techniques applied to DOC patients. NIBS are promising in helping clinicians to differentiate among DOC patients and to identify residual fragments of awareness within Vegetative State individuals, namely Functional Locked-In Syndrome.

Islands of consciousness in vegetative state or functional locked-in syndrome?

Islands of consciousness in vegetative state or functional locked-in syndrome?

Coma and Disorders of Consciousness: Scientific Advances and Practical Considerations for Clinicians

Recently, neuroscientists and clinicians have seen the rapid evolution of diagnoses in disorders of consciousness. The unresponsive wakefulness syndrome-vegetative state, the minimally conscious state plus and minus, and the functional locked-in syndrome have been defined using new neuroimaging techniques. Diffusion tensor imaging, positron emission tomography, functional magnetic resonance imaging, electroencephalography, and transcranial magnetic stimulation techniques have all promoted important discoveries in the field of disorders of consciousness. This has led to a better understanding of these patients' condition and to the development of new prognosis, therapeutic, and communication tools. However, low sensitivity and artifacts problems need to be solved to bring these new technologies to the single-patient level; they also need to be studied in larger scale and randomized control trials. In addition, new ethics questions have arisen and need to be investigated.

From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness

Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients' behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS- describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness.