Medical comorbidities in patients with prolonged disorder of consciousness: A narrative review.

BACKGROUND: A few studies specifically addressed medical comorbidities (MCs) in patients with severe acquired traumatic or non-traumatic brain injury and prolonged disorders of consciousness (pDoC; i.e., patients in vegetative state/unresponsive wakefulness syndrome, VS/UWS, or in minimally conscious state, MCS). OBJECTIVE: To provide an overview on incidence of MCs in patients with pDoC. METHODS: Narrative review on most impacting MCs in patients with pDoC, both those directly related to brain damage (epilepsy, neurosurgical complications, spasticity, paroxysmal sympathetic hyperactivity, PSH), and those related to severe disability and prolonged immobility (respiratory comorbidities, endocrine disorders, metabolic abnormalities, heterotopic ossifications). RESULTS: Patients with pDoC are at high risk to develop at least one MC. Moderate or severe respiratory and musculoskeletal comorbidities are the most common MCs. Epilepsy and PSH seem to be more frequent in patients in VS/UWS compared to patients in MCS, likely because of higher severity in the brain damage in VS. Endocrine metabolic, PSH and respiratory complications are less frequent in traumatic etiology, whereas neurogenic heterotopic ossifications are more frequent in traumatic etiology. Spasticity did not significantly differ between VS/UWS and MCS and in the three etiologies. MCs are associated with higher mortality rates, worse clinical improvement and can impact accuracy in the clinical diagnosis. CONCLUSIONS: The frequent occurrence of several MCs requires a specialized rehabilitative setting with high level of multidisciplinary medical expertise to prevent, appropriately recognize and treat them. Comprehensive rehabilitation could avoid possible progression to more serious complications that can negatively impact clinical outcomes.

Sleep Disruptions in Hospitalized Adults Sustaining a Traumatic Brain Injury: A Scoping Review.

OBJECTIVE: Adults sustaining a traumatic brain injury (TBI) are at risk of sleep disturbances during their recovery, including when such an injury requires hospitalization. However, the sleep-wake profile, and internal and external factors that may interfere with sleep initiation/maintenance in hospitalized TBI patients are poorly understood. This review aimed to: (1) identify/summarize the existing evidence regarding sleep and sleep measurements in TBI adults receiving around-the-clock care in a hospital or during inpatient rehabilitation, and (2) identify internal/external factors linked to poor sleep in this context. METHODS: A scoping review was conducted in accordance with the PRISMA Scoping Review Extension guidelines. A search was conducted in MEDLINE, PsycINFO, CINAHL, and Web of Science databases. RESULTS: Thirty relevant studies were identified. The most common sleep variables that were put forth in the studies to characterize sleep during hospitalization were nighttime sleep time (mean = 6.5 hours; range: 5.2-8.9 hours), wake after sleep onset (87.1 minutes; range: 30.4-180 minutes), and sleep efficiency (mean = 72.9%; range: 33%-96%) using mainly actigraphy, polysomnography, and questionnaires (eg, the sleep-wake disturbance item of the Delirium Rating Scale or the Pittsburgh Sleep Quality Index). Twenty-four studies (80%) suggested that hospitalized TBI patients do not get sufficient nighttime sleep, based on the general recommendations for adults (7-9 hours per night). Sleep disruptions during hospitalization were found to be associated to several internal factors including TBI severity, cognitive status, and analgesia intake. External and modifiable factors, such as noise, light, and patient care, were consistently associated with sleep disruptions in this context. CONCLUSION: Although the literature on sleep disturbances in hospitalized TBI patients has been increasing in recent years, many gaps in knowledge remain, including phenotypes and risk factors. Identifying these factors could help clinicians better understand the multiple sources of TBI patients' sleep difficulties and intervene accordingly.

Validation of a New Tool to Detect and Characterize Spinal Cord Injury in the Acute Trauma Patient: The Montreal Acute Classification of Spinal Cord Injury.

STUDY DESIGN: Retrospective validation protocol. OBJECTIVE: The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) is the most comprehensive tool for classifying spinal cord injuries (SCI), but it is not adapted for the evaluation of trauma patients. The objective is to develop and validate a streamlined tool, the Montreal Acute Classification of Spinal Cord Injury (MAC-SCI) that can be integrated in the evaluation of trauma patients to detect and characterize traumatic SCI (tSCI). METHODS: The completion rate of the ISCNSCI during initial evaluation after tSCI was estimated at a Level-1 trauma center specialized in SCI care. Using a modified Delphi technique, we designed the MAC-SCI, a new tool to detect and characterize the severity grade and level of SCI in the polytrauma patient. A cohort consisting of 35 consecutive tSCI patients with complete ISNCSCI documentation was used to validate the MAC-SCI. The severity grade and neurological level of injury (NLI) were assessed using the MAC-SCI, and compared to those obtained with the ISNCSCI. RESULTS: Only 33% of 148 patients admitted after a tSCI had a complete ISNCSCI performed at initial presentation. The MAC-SCI retains 53 of the 134 elements from the ISNCSCI. There was a 100% concordance in severity grade between the MAC-SCI and ISNCSCI. The NLI were within 2 levels between the MAC-SCI and ISNCSI for 100% of patients. CONCLUSION: The MAC-SCI is a streamlined tool that accurately detects and characterizes tSCI in the acute trauma setting. It could be implemented in trauma protocols to guide the management of SCI patients. LEVEL OF EVIDENCE: Level III Diagnostic criteria.

How do early perioperative changes in AIS grade correlate with long-term neurological recovery? A retrospective cohort study.

CONTEXT/OBJECTIVE: Providing accurate counseling on neurological recovery is crucial after traumatic spinal cord injury (TSCI). The early neurological changes that occur in the subacute phase of the injury (i.e. within 14 days of early decompressive surgery) have never been documented. The objective of this study was to assess peri-operative neurological improvements after acute TSCI and determine their relationship with long-term neurological outcomes, measured 6-12 months following the injury. METHODS: A retrospective cohort study of 142 adult TSCI patients was conducted. Early peri-operative improvement was defined as improvement of at least 1 AIS grade between the pre-operative and follow-up (6-12 months post-TSCI) assessment. neurological improvement of at least 1 AIS grade. RESULTS: Out of the 142 patients, 18 achieved a peri-operative improvement of at least 1 AIS grade. Presenting a pre-operative AIS grade B and having shorter surgical delays were the main factors associated with stronger odds of achieving this outcome. Out of the 140 patients who still had potential for improvement at the time of the post-operative assessment, 44 achieved late neurological recovery (improvement of at least 1 AIS grade between the post-operative assessment and follow-up). Patients who presented a perioperative improvement seemed more likely to achieve later neurological improvement as well, although this was not statistically significant. CONCLUSION: Our results suggest that it is important to assess early perioperative neurological changes within 14 days of surgery because it can provide beneficial insight on long-term neurological outcomes for some patients. In addition, earlier surgery may promote early neurological recovery.

Scoping Review on the Diagnosis, Prognosis, and Treatment of Pediatric Disorders of Consciousness.

BACKGROUND AND OBJECTIVES: Comprehensive guidelines for the diagnosis, prognosis, and treatment of disorders of consciousness (DoC) in pediatric patients have not yet been released. We aimed to summarize available evidence for DoC with >14 days duration to support the future development of guidelines for children, adolescents and young adults aged 6 months-18 years. METHODS: This scoping review was reported based on Preferred Reporting Items for Systematic reviews and Meta-Analyses-extension for Scoping Reviews guidelines. A systematic search identified records from 4 databases: PubMed, Embase, Cochrane Library, and Web of Science. Abstracts received 3 blind reviews. Corresponding full-text articles rated as "in-scope" and reporting data not published in any other retained article (i.e., no double reporting) were identified and assigned to 5 thematic evaluating teams. Full-text articles were reviewed using a double-blind standardized form. Level of evidence was graded, and summative statements were generated. RESULTS: On November 9, 2022, 2,167 documents had been identified; 132 articles were retained, of which 33 (25%) were published over the past 5 years. Overall, 2,161 individuals met the inclusion criteria; female patients were 527 of 1,554 (33.9%) cases included, whose sex was identifiable. Of 132 articles, 57 (43.2%) were single case reports and only 5 (3.8%) clinical trials; the level of evidence was prevalently low (80/132; 60.6%). Most studies included neurobehavioral measures (84/127; 66.1%) and neuroimaging (81/127; 63.8%); 59 (46.5%) were mainly related to diagnosis, 56 (44.1%) to prognosis, and 44 (34.6%) to treatment. Most frequently used neurobehavioral tools included the Coma Recovery Scale-Revised, Coma/Near-Coma Scale, Level of Cognitive Functioning Assessment Scale, and Post-Acute Level of Consciousness scale. EEG, event-related potentials, structural CT, and MRI were the most frequently used instrumental techniques. In 29/53 (54.7%) cases, DoC improvement was observed, which was associated with treatment with amantadine. DISCUSSION: The literature on pediatric DoCs is mainly observational, and clinical details are either inconsistently presented or absent. Conclusions drawn from many studies convey insubstantial evidence and have limited validity and low potential for translation in clinical practice. Despite these limitations, our work summarizes the extant literature and constitutes a base for future guidelines related to the diagnosis, prognosis, and treatment of pediatric DoC.

Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial

Background: Patients with disorders of consciousness (DoC) are a challenging population prone to misdiagnosis with limited effective treatment options. Among neuromodulation techniques, transcutaneous auricular vagal nerve stimulation (taVNS) may act through a bottom-up manner to modulate thalamo-cortical connectivity and promote patients’ recovery. In this clinical trial, we aim to (1) assess the therapeutic clinical effects of taVNS in patients with DoC; (2) investigate the neural mechanisms underlying the effects of its action; (3) assess the feasibility and safety of the procedure in this challenging population; (4) define the phenotype of clinical responders; and (5) assess the long-term efficacy of taVNS in terms of functional outcomes. Methods: We will conduct a prospective parallel randomized controlled double-blind clinical trial investigating the effects of taVNS as a treatment in DoC patients. Forty-four patients in the early period post-injury (7 to 90 days following the injury) will randomly receive 5 days of either active bilateral vagal stimulation (45 min duration with 30s alternative episodes of active/rest periods; 3mA; 200-300μs current width, 25Hz.) or sham stimulation. Behavioural (i.e., Coma Recovery Scale-Revised, CRS-R) and neurophysiological (i.e., high-density electroencephalography, hd-EEG) measures will be collected at baseline and at the end of the 5-day treatment. Analyses will seek for changes in the CRS-R and the EEG metrics (e.g., alpha band power spectrum, functional connectivity) at the group and individual (i.e., responders) levels. Discussion: These results will allow us to investigate the vagal afferent network and will contribute towards a definition of the role of taVNS for the treatment of patients with DoC. We aim to identify the neural correlates of its action and pave the way to novel targeted therapeutic strategies. (AU)

Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial.

Background: Patients with disorders of consciousness (DoC) are a challenging population prone to misdiagnosis with limited effective treatment options. Among neuromodulation techniques, transcutaneous auricular vagal nerve stimulation (taVNS) may act through a bottom-up manner to modulate thalamo-cortical connectivity and promote patients' recovery. In this clinical trial, we aim to (1) assess the therapeutic clinical effects of taVNS in patients with DoC; (2) investigate the neural mechanisms underlying the effects of its action; (3) assess the feasibility and safety of the procedure in this challenging population; (4) define the phenotype of clinical responders; and (5) assess the long-term efficacy of taVNS in terms of functional outcomes. Methods: We will conduct a prospective parallel randomized controlled double-blind clinical trial investigating the effects of taVNS as a treatment in DoC patients. Forty-four patients in the early period post-injury (7 to 90 days following the injury) will randomly receive 5 days of either active bilateral vagal stimulation (45 min duration with 30s alternative episodes of active/rest periods; 3mA; 200-300µs current width, 25Hz.) or sham stimulation. Behavioural (i.e., Coma Recovery Scale-Revised, CRS-R) and neurophysiological (i.e., high-density electroencephalography, hd-EEG) measures will be collected at baseline and at the end of the 5-day treatment. Analyses will seek for changes in the CRS-R and the EEG metrics (e.g., alpha band power spectrum, functional connectivity) at the group and individual (i.e., responders) levels. Discussion: These results will allow us to investigate the vagal afferent network and will contribute towards a definition of the role of taVNS for the treatment of patients with DoC. We aim to identify the neural correlates of its action and pave the way to novel targeted therapeutic strategies. Clinical trial registration: Clinicaltrials.gov n° NCT04065386.

Effectiveness of transcranial alternating current stimulation for controlling chronic pain: a systematic review.

Background: Chronic pain is common, disruptive, and often treatment-resistant. Hence, researchers and clinicians seek alternative therapies for chronic pain. Transcranial alternating current stimulation (tACS) is an emerging neuromodulation technique that non-invasively modulates neural oscillations in the human brain. tACS induces pain relief by allowing the neural network to restore adequate synchronization. We reviewed studies on the effectiveness of tACS in controlling chronic pain. Methods: The PubMed, SCOPUS, Embase, and Cochrane Library databases were systematically searched for relevant studies published until December 6, 2023. The key search phrase for identifying potentially relevant articles was [(Transcranial Alternating Current Stimulation OR tACS) AND pain]. The following inclusion criteria were applied for article selection: (1) studies involving patients with chronic pain; (2) tACS was applied for controlling pain; and (3) follow-up evaluations were performed to assess the degree of pain reduction after the application of tACS. Results: We identified 2,330 potentially relevant articles. After reading the titles and abstracts and assessing eligibility based on the full-text articles, we included four articles in our review. Among the included studies, tACS was used for fibromyalgia in one study, low back pain (LBP) in two studies, and migraine in one study. In the study on fibromyalgia, it did not show a better pain-reducing effect of tACS compared with sham stimulation. Two studies on LBP showed conflicting results. In migraine, tACS showed a positive pain-reducing effect 24-48 h after its application. Conclusion: There is insufficient research to draw a conclusive judgment on the effectiveness of tACS in controlling chronic pain. More studies across various chronic pain-related diseases are required for a definitive conclusion.

Preservation of Brain Activity in Unresponsive Patients Identifies MCS Star.

OBJECTIVE: Brain-injured patients who are unresponsive at the bedside (ie, vegetative state/unresponsive wakefulness syndrome - VS/UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed "non-behavioural MCS" or "MCS*". In the present study we aimed to investigate the proportion and underlying brain characteristics of patients in MCS*. METHODS: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged VS/UWS (n = 48) or MCS (n = 87). From an existing database, relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was visually inspected by three experts. Patients with hypometabolism of the fronto-parietal network were labelled "VS/UWS", while its (partial) preservation either confirmed the behavioural diagnosis of "MCS" or, in absence of behavioural signs of consciousness, suggested a diagnosis of "MCS*". Clinical outcome at 1-year follow-up, functional connectivity, grey matter atrophy, and regional brain metabolic patterns were investigated in the three groups (VS/UWS, MCS* and MCS). RESULTS: 67% of behavioural VS/UWS presented a partial preservation of brain metabolism (ie, MCS*). Compared to VS/UWS patients, MCS* patients demonstrated a better outcome, global functional connectivity and grey matter preservation more compatible with the diagnosis of MCS. MCS* patients presented lower brain metabolism mostly in the posterior brain regions compared to MCS patients. INTERPRETATION: MCS* is a frequent phenomenon that is associated with better outcome and better brain preservation than the diagnosis of VS/UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. ANN NEUROL 2021;90:89-100.

Management of Epileptic Seizures in Disorders of Consciousness: An International Survey.

Epileptic seizures/post-traumatic epilepsy (ES/PTE) are frequent in persons with brain injuries, particularly for patients with more severe injuries including ones that result in disorders of consciousness (DoC). Surprisingly, there are currently no best practice guidelines for assessment or management of ES in persons with DoC. This study aimed to identify clinician attitudes toward epilepsy prophylaxis, diagnosis and treatment in patients with DoC as well as current practice in regards to the use of amantadine in these individuals. A cross-sectional online survey was sent to members of the International Brain Injury Association (IBIA). Fifty physician responses were included in the final analysis. Withdrawal of antiepileptic drug/anti-seizure medications (AED/ASM) therapy was guided by the absence of evidence of clinical seizure whether or not the AED/ASM was given prophylactically or for actual seizure/epilepsy treatment. Standard EEG was the most frequent diagnostic method utilized. The majority of respondents ordered an EEG if there were concerns regarding lack of neurological progress. AED/ASM prescription was reported to be triggered by the first clinically evident seizure with levetiracetam being the AED/ASM of choice. Amantadine was frequently prescribed although less so in patients with epilepsy and/or EEG based epileptic abnormalities. A minority of respondents reported an association between amantadine and seizure. Longitudinal studies on epilepsy management, epilepsy impact on neurologic prognosis, as well as potential drug effects on seizure risk in persons with DoC appear warranted with the goal of pushing guideline development forward and improving clinical assessment and management of seizures in this unique, albeit challenging, population.

Transcutaneous Auricular Vagal Nerve Stimulation and Disorders of Consciousness: A Hypothesis for Mechanisms of Action.

Disorders of consciousness (DoC) are the hallmark of severe acquired brain injuries characterized by abnormal activity in important brain areas and disruption within and between brain networks. As DoC's therapeutic arsenal is limited, new potential therapies such as transcutaneous auricular vagal nerve stimulation (taVNS) have recently been explored. The potential of taVNS in the process of consciousness recovery has been highlighted in recent studies with DoC patients. However, it is not clear how taVNS plays a role in the recovery of consciousness. In this article, we first describe the neural correlates of consciousness, the vagus nerve anatomy and functions, along with the results of functional magnetic resonance imaging studies using taVNS. Based on consciousness recovery and taVNS mechanisms, we propose the Vagal Cortical Pathways model. This model highlights four consecutive pathways (A. Lower brainstem activation, B. Upper brainstem activation, C. Norepinephrine pathway, and D. Serotonin pathway) likely to have an impact on patients with a brain injury and DoC. Additionally, we suggest six different mechanisms of action: (1) Activation of the ascending reticular activating system; (2) Activation of the thalamus; (3) Re-establishment of the cortico-striatal-thalamic-cortical loop; (4) Promotion of negative connectivity between external and default mode networks by the activation of the salience network; (5) Increase in activity and connectivity within the external network through the norepinephrine pathway; and (6) Increase in activity within the default mode network through the serotonin pathway. This model aims to explain the potential therapeutic effects that taVNS has on brain activity in the process of consciousness recovery.

A Moving Residual Limb: Botulinum Toxin to the Rescue.

Movement disorders post-amputation are a rare complication and can manifest as the jumping stump phenomenon, a form of peripheral myoclonus. The pathophysiology remains unknown and there is currently no standardized treatment. We describe the case of a 57-year-old male with unremitting stump myoclonus, starting one month after transtibial amputation, in his residual limb without associated phantom or neurological pain. The consequence of the myoclonus was a reduction in prosthetic wearing time. Failure to respond to oral medication led us to attempt the use of botulinum neurotoxin Type A injections in the involved muscles of the residual limb. Injection trials, over a two-year period, resulted in an improvement of movement disorder, an increased prosthetic wearing time and a higher satisfaction level of the patient. Injection of botulinum toxin type A should be considered as an alternative treatment for stump myoclonus to improve prosthetic wearing time and comfort.

Expanding the clinical description of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

BACKGROUND AND PURPOSE: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) diagnosis is based on the presence of three main clinical features: 1) ataxia, 2) pyramidal involvement, and 3) axonal neuropathy. This study aimed to explore, among a cohort of adults with ARSACS, the prevalence of other signs and symptoms than those commonly describe in this disease and compare their prevalence between younger (<40 years) and older (≥40 years) participants. METHODS: A clinical interview based on a standardized questionnaire was conducted. It included the following items: memory and concentration problems, hearing impairment, epilepsy, spasms, choreathetosis, neuropathic pain, cramps and fecal incontinence. RESULTS: A total of 43 participants were interviewed, with a mean age of 38.9 years and 51.2% were men. Spasms (55.8%), cramps (53.5%), and concentration problems (39.5%) were the most frequent manifestations. Except for choreathetosis, which was present in only one participant, all other signs and symptoms were present in 9.3% to 29.3% of participants. CONCLUSIONS: People with ARSACS may experience many other clinical manifestations than the most commonly described. This study is a preliminary step toward the development of a comprehensive evidence-based clinical care guideline for this population.

Substantial asymmetry in paraspinal muscle cross-sectional area in healthy adults questions its value as a marker of low back pain and pathology.

STUDY DESIGN: A cross-sectional population-based study of paraspinal muscle asymmetry. OBJECTIVE: To examine level- and side-to-side differences in paraspinal muscle areas on magnetic resonance images in a population-based sample of middle aged men without low back pain (LBP). SUMMARY OF BACKGROUND DATA: Level- and side-specific multifidus muscle atrophy and fat infiltration have been suggested as possible markers for localized spinal pathology and LBP, but prior studies have limited generalizability due to small sample sizes, young age of samples and measurement issues. METHODS: From a general population sample of 600 twin men, those reporting no LBP during the prior year, no previous spinal fractures, and no bed rest for at least 1 week in the last 12 months were included in the study. All subjects had T2-weighted axial images available for the three lowest lumbar levels. Both total and fat-free cross-sectional areas (CSAs) of the multifidus and erector spinae muscles at the mid-disc level were measured. Intrarater reliability ranged between 0.90 and 0.98 for area measurements and 0.86 and 0.92 for measurements of side-to-side differences. Data were analyzed using descriptive statistics and paired t tests. RESULTS: Subjects consisted of 126 men whose mean multifidus total CSA measurements varied between 7.3 and 11.1 cm and between 6.9 and 10.8 cm for right and left sides, respectively, depending on the level. The corresponding mean areas for erector spinae were 9.4 to 19.6 cm2 for right side and 10.4 to 19.7 cm2 for left side. The multifidus was larger on the right side than on the left side in 65% to 68% of subjects, depending on spinal level (P < 0.001). The mean asymmetry at the three lowest lumbar levels was 10% to 13.2% and was smallest at L4-L5. Multifidus side-to-side asymmetry ranged from 0.1% to 44.3%. For erector spinae, the left-side measurements tended to be larger, reaching statistical significance (P < 0.0001) for the two lowest levels. The mean side-to-side asymmetry increased caudally for erector spinae, from 8.2% to 18.8% and was significantly different between adjacent levels (P < 0.01). The amount of intramuscular fat significantly increased caudally for both muscles. CONCLUSION: Paraspinal muscle asymmetry greater than 10% was commonly found in men without a history of LBP. This suggests caution in using level- and side-specific paraspinal muscle asymmetry to identify subjects with LBP and spinal pathology.