Challenges and Opportunities in Brain Injury

Challenges and Opportunities in Brain Injury

Hadanny, A., Maroon, J. C., & Efrati, S. (2023b).


IntroductionThe application of hyperbaric oxygen therapy for patients with both acute and chronic traumatic brain injury has been suggested for over five decades. In the past decade, the design and quality of studies were more detailed and thorough leading to an improved unerstanding of the uses of HBOT and the profiles of the patients who can benefit the most.

ObjectivesPerform a comprehensive literature review of hyperbaric oxygen therapy application for the treatment of patients with both acute, subacute and chronic traumatic brain injury.

MethodsExtensive literature search from 1969 to April 2023 was performed on April 1st 2023 within the following databases: Cochrane Library, PubMed, Google Scholar, and Web of Science, including humans clinical data, in articles providing information on the type of treatment and clinical outcomes. Articles were first categorized into acute-subacute traumatic brain inury and chronic traumatic brain injury and further classified into low, medium or high level quality.

ResultsThere was high level evidence including nine randomized controlled trials, one meta-analysis and two prospective study evaluating the clinical effects of hyperbaric oxygen therapy in patients suffering from traumatic brain injuries in the acute and subacute settings. Mortality was significantly reduced in all studies that used it as an endpoint, while favorable functional outcomes in survivors showed mixed results.

In chronic severe traumatic brain injury, there is low to moderate evidence including two uncontrolled prospective studies, two cohort studies and eight case reports suggesting improved outcomes.

In chronic mild traumatic brain injury, there is high level evidence including seven randomized controlled trials, and six prospective studies suggesting significant improvement in cognitive function, symptoms and quality of life.

Conclusions: Hyperbaric oxygen therapy may be recommended in acute moderate-severe traumatic brain injury patients (Type 2a recommendation, level A evidence). However, further studies are needed to both evaluate outcomes and to determine the optimal treatment protocols for the different types of injuries (Type 1 recommendation, level A evidence).

Hyperbaric oxygen threrapy should be recommended in chronic traumatic brain injury for a selected group of patients suffering from prolonged post-concussion syndrome who have clear evidence of metabolic dysfunctional brain regions as determined by neuroimaging (Type 2a recommendation, level B-R evidence). Patients should be properly evaluated by standardized cognitive tests and functional brain imaging (Type 1 recommendation, level B-R evidence).

Ornstein, T., Pejic, O., O’Hagan, M., Berlingieri, J., & Egeto, P. (2022).


Background. Recovery following brain injury can be significantly impeded by the way in which an individual appraises pain, which in turn, can affect ability to cope with pain, and result in psychological distress. Pain catastrophizing, implicated in the appraisal of pain, can exacerbate the intensity of pain-related distress and impact psychological well-being. However, the concurrent evaluation of these phenomena via functional outcomes has not been examined in mild traumatic brain injury.

Material and methods. The present study evaluated de-identified archival data of 190 patients with mild traumatic brain injury following injury in motor vehicle accidents. Of primary interest was whether pain catastrophizing mediated the relationship among psychological distress (i.e., anxiety, depression) and functional disability outcomes in patients with mild traumatic brain injury.

Results. Pain catastrophizing was found to have a significant mediating effect on the relationship between anxiety and functional disability, as well as for depression and functional disability. Age, gender, time since injury, and/or pain intensity, were not significant predictors of outcome. Although, pain severity was linked to pain catastrophizing. Moreover, the current work also evaluated feigning amongst a subset of patients with mild traumatic brain injury. Interestingly, it appears that the presence of psychological distress, irrespective of the nature of that reporting, is itself predictive of functional well-being. This is an important clinical finding and supports the role of psychological factors on real-life functional compromise in patients with mild traumatic brain injury.

Conclusion. The present study found that psychological distress and functional disability are mediated by pain catastrophizing in patients with mild traumatic brain injury. It also appears that the presence of psychological distress, irrespective of the level of reported complaints (i.e., the over-reporting of symptomatology) itself, is predictive of functional well-being.

Hashim, M. N. M., Awang, M. S., Ramanathan, A., Wahab, M. S. A., Nor, M. M., & Aidid, E. M. (2023).


Context: Serum albumin is the major protein of the human plasma, accounting for about 60% of the total plasma protein. Serum albumin levels tend to decline in the plasma due to injury or infection independent of nutritional status. Serum albumin consumption increases in a state of stress. Reduction in serum albumin occurs with intracranial haemorrhages. In a patient with severe head injury, there is a significant decline in serum albumin leading to hypoalbuminemia. Serum albumin can be used as an outcome marker in various critical illnesses, including traumatic brain injury.

Aim: To determine that serum albumin is an independent predictor affecting the outcome of patients with severe traumatic brain injury over a 6-month duration

Settings and design: This was conducted as prospective cohort study in two neurosurgical centres in the East Coast of Malaysia from June 2020 to June 2021

Subjects and methods: A total of fifty-five patients were admitted to our emergency intensive care, or high dependency unit with varying degrees of severe head injuries. Forty patients fulfilled the inclusion criteria of our study and were recruited for data collection and further analysis. Their serum albumin levels were drawn, analysed, and recorded.

Statistical analysis used: Descriptive, univariate and multivariate analyses using Multiple Logistic Regression model were done using SPSS version 26.0.

Results: Average age for patients in this study was 42 years old. 87.5% of patients involved in this study were male, while the remaining 12.5% were female. The ethnicity of the majority of patients were Malays (77.5%) and the other ethnicities involved were Chinese, Indians and Bangladeshi, with a total of 22.5%. Multiple intracranial injuries were suffered by 57.5% of our study population, Subdural Hemorrhage, Extradural Hemorrhage, Contusional bleed, and Diffuse Axonal Injury were seen respectively in 20%, 10% 7.5% and 5% of the study population. At six months, the unfavourable outcome for serial serum albumin in patients with severe head injury patients was 62.5%, while the favourable outcome was 37.5%. Serum albumin of 30 g/L or less than 30g/L at day 1,3 and 5 post-trauma was noted to have unfavourable outcomes compared to serum albumin level of more than 30g/L.

Conclusion: Serum albumin is an independent predictor of outcome in severe TBI patients. However, larger prospective studies are required to verify these findings.

Mamatkulovich, М. А., & Abdukholikovich, A. (2022).


Clinical manifestations were correlated with traumatic brain injury outcomes using electronic computers. Neuroopthalmologic signs, motor and vital disorders had maximal prognostic values. Outcome was highly correlated with consciousness disorders phase scaling and patients’ state scores as well as with coma and consciousness disorders length suggesting that these parameters are of major prognostic importance. A close correlation was found between consciousness states, patients’ state scores and traumatic brain injury variants, brain lesion forms, vital and somatic disorders indicating their role as determinants of traumatic brain injury outcome.

Borghol, A., Jamero, D., Ahmed, F., Hadgu, R. M., Wilson, C., Fabre’-LaCoste, N., Dinh, A., Thompson, J., Castro, M., Paudyal, A., Corvers, E., Iwuchukwu, I., & Onor, I. (2022).


Background: Modafinil is used for improving wakefulness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. The goal of this study is to evaluate alertness and participation in physical therapy and occupational therapy in patients with a first-time diagnosis of traumatic brain injury using modafinil.

Methods: This was a single-center, retrospective, chart review, cohort study of Ochsner Medical Center patients from January 2016 to December 2018. Patients included in the study were 18 years of age or older who were hospitalized due to a traumatic brain injury and received modafinil either by mouth, nasogastric, or enteral feeding tube to help improve alertness. The primary outcome is the change in Glasgow Coma Scale (GCS) score from baseline to 72 hours after initiating modafinil.

Results: One-hundred and Forty patients were included with a mean age of 67.8 years and 59.3% were male. The majority of the patients (52.9 %) were predominantly patients who suffered ischemic stroke. The mean change in GCS score in 72 hours was +0.35 (95% CI [-0.16, 0.88], p=0.177). One of the secondary endpoints was the mean change in course of therapy GCS score which showed significant improvement in neurological function after initiation of modafinil: +1.22 (95% CI [0.64, 1.80], p=0.0001). The percent physical therapy/occupational therapy (PT/OT) session participation at 72-hour post-modafinil initiation was 96.7% compared to 95.7% during the course of therapy. The correlation between increase in GCS score and percent PT/OT therapy session participation was analyzed at 72 hours and throughout the course of therapy, which revealed no significant association (r=0.14 [p=0.0911] and -0.06 [p=0.4881], respectively).

Conclusion: Our study did not find a significant increase in the mean change of GCS score at 72 hours of modafinil use. Although, there were high percentage of patients participated in PT/OT in 72 hours and course of therapy (96.7% and 95.7%), there was no significant statistical correlation between increase in GCS score and PT/OT participation. Randomized studies are needed to further assess the impact of modafinil for treating traumatic brain injury associated sleep-wake disturbances while considering factors such as medication initiation time, appropriate dosage, GCS score, and long-term outcomes.

Sigurjonsson, P., Jonasdottir, A., Ólafsson, I. H., Kárason, S., Sigthorsson, G., & Sigurjónsdóttir, H. (2022).


Background and aims of the study: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) can cause death and long-term morbidity. Studies indicate that both TBI and SAH may affect pituitary function in both the acute and the chronic phase. The aims of this study were firstly to evaluate the nature of neuroendocrine changes in the acute phase of moderate and severe TBI and all SAH, to evaluate association between neuroendocrine disturbance and indicators of severity of insult as well as hypotension, desaturation and anemia and to evaluated the incidence of neuroendocrine changes after moderate and severe TBI and SAH in the acute phase. Purpose: To explore neuroendocrine disturbances in moderate traumatic brain injury (mTBI), severe TBI (sTBI) and subarachnoid hemorrhage (SAH) in the acute phase.

Methods: The study was a prospective single-center study. Anterior hypothalamic-pituitary (HP) hormone axis were assessed on admission (day 0) with baseline hormone levels and on day 6 post insult with baseline hormone levels and a Synacthen test. From patient charts we recorded for all patients GCS, APACHEII score, length of ICU stay, pupil dilatation, documented hypotension, desaturation and hemoglobin value <80 g/dL. Hunt and Hess grade for SAH group and Injury severity score for TBI group. S100b was measured in all patients on admission. We included 21 TBI patient, 6 moderate TBI and 15 severe TBI, and 19 SAH patients. Anterior hypothalamic-pituitary (HP) hormone axis were assessed on day 0 and 6 post insult in Twenty-one TBI patient and 19 SAH patients.

Results: HP-adrenal axis: The TBI group had significantly lower mean cortisol than the SAH group on day 0, 23.8% of TBI patients had low cortisol and 0% of SAH patients. On day 6, one patient in each group had low cortisol, 6.7% of TBI and 9.1% of SAH. HP-gonadal axis: In males on day 0, 52.9% of TBI patients and 57.1% of SAH patients had suppressed HP-gonadal axis and on day 6, 84.6% of TBI patients and 90% of SAH patients. There was a greater suppression of LH/FSH in the TBI group. HP-thyroid axis: Only one TBI patient (5.9%) had secondary hypothyroidism on day 6. HP-somatotroph axis: On day 0, 52.4% of TBI patients and 35.7% of SAH patients had low IGF-1. On day 6 all but one TBI patient (5.9%) had normalized their IGF-1 but 25% of SAH patients still had low IGF-1. In general, when evaluating association there seemed to more suppression of the hypothalamic-pituitary (HP) gonadal and thyroid axis with more severe insult and adequately more activation of the hypothalamic-pituitary adrenal axis.

Conclusion: Neuroendocrine disturbances in the acute phase of TBI and SAH are common and seem to differ between the two groups. The clinical significance of these disturbances is uncertain.

Azurmendi, L., Cancelliere N., Sempere L., Schena A., Chocano E., Diez Naz A., Chinchilla Palomares E., Perez Torres I., Cancelliere N., Quintana Diaz M., Menendez B., Garcia Armengol R., Laguna Carrero L., Placer López de Alda A., Perea M., Montaner j., & Sanchez J-C (n.d.).


Introduction: The TBICheckTM Rapid test is an immunochromatographic rapid test capable of assisting in the triage of patients with mild Traumatic Brain Injury suspected of brain lesions. It quantitatively determines heart-type Fatty Acid Binding Protein (H-FABP) levels in whole blood, serum, or plasma. The aim of the present study was to evaluate its technical performance and test it in two different cohorts of mTBI patients as a potential diagnostic tool for detecting brain lesions in patients with mTBI.

Material and methods: Description of the assay: Linearity and low limit of quantification of TBICheckTM lateral flow assay were determined using serial dilution of standardized samples. Results were read using the TBICheckTM Reader, a mobile photometric immunoassay analyzer based on reflectance measurements to capture the optical density. Obtained results were compared to classical ELISA assays, Meso Scale Diagnostics. Patient cohorts: Two different cohorts of adult mTBI patients were included: a retrospective one including 82 patients and a prospective one including 65 patients. Values of H-FABP area under the curve, specificity, sensitivity were calculated.

Results: The H-FABP dose response fitted a linear regression within the range of 0.5-25 ng/mL. LLOQ in blood was 0.5 ng/mL. High Spearman correlation was found (ρ=0.933, p<0.001) when MSD ELISA and TBICheckTM concentrations were compared.

In the retrospective cohort, when the clinical sensitivity was set at 100%, a specificity value of 32.9% was obtained. In the prospective cohort, the SP value raised to 66.1% with 100% SE, meaning that 6 out of 10 patients might be discharged on the basis of their serum H-FABP concentration at hospital admission.

Conclusions: The quantification of H-FABP by using the TBICheckTM Rapid test on adult mTBI patients may allow to rule out the need of a CT-scan reducing the radiation exposure and avoiding the long waiting times in emergency units. It may lead to savings in hospital resources and assists medical doctors to provide the most appropriate treatment to the patients.

Al-Nisr, M., & Alguacil, N. (2022). 


The objective of the present study was to evaluate the effectiveness and tolerability of incobotulinumtoxinA, at doses according to individual needs, in 10 patients with acquired brain injury and severe upper and lower limb spasticity. Patients received a multipattern periodic treatment with ultrasound-guided injections of incobotulinumtoxinA at doses of 800-900 U in the upper and lower limbs. The mean number of injection cycles per patient was 4.2. The 0-10 visual analogue scale for pain score decreased significantly from pre-injection (mean: 4.7) to four-week post-injection (mean: 0.7). Similarly, the mean Ashworth Scale score (muscular tone assessment) at four-week post-injection (mean: 1.4) was significantly lower than at injection (mean: 2.5). Except for two patients in one pattern, all cases showed an improvement in passive range of motion assessments using goniometry. All patients reported maximum satisfaction with the treatment, all reporting “much improved” after the treatment. No treatment-related adverse effects were observed during the study. Individualized doses of incobotulinumtoxinA are effective and well-tolerated for this type of patients and allow better management of their severe spasticity. Therefore, individualization of doses should be taken into account for optimizing clinical outcomes and improving the patients’ treatment satisfaction.

Johnson, L. E., & Weinberg, A. (2023). 


Cognitive rehabilitation is a critical component of intervention for many individuals with both short- and long-term impairments associated with traumatic brain injury (TBI). By focusing on major cognitive domains, emotional processing, and behavioral strategies, clinicians use cognitive rehabilitation to improve cognitive related functional outcomes, quality of life, and social relationships. Cognitive rehabilitation is traditionally divided into restorative and compensatory approaches, though increasingly combined approaches within the larger medical, multidisciplinary team are being incorporated and explored. Literature related to cognitive rehabilitation within the TBI population continues to be needed in order to assist clinicians in developing evidence-based intervention protocols and therapy plans. This paper details current approaches to cognitive rehabilitation and provides an updated review of the literature associated with the efficacy of cognitive rehabilitation. Reviewed evidence supports the use of cognitive rehabilitation to improve multiple cognitive domains, including attention, memory, executive function, and metacognitive skills. The long-term outcomes of continued cognitive rehabilitation services post-TBI are not as comprehensively documented as the relative short-term outcomes. The efficacy of cognitive rehabilitation is impacted by patient-specific variables, timing and intensity of treatment. This paper concludes with noted information related to the limitations of the current evidence of cognitive rehabilitation, including study design concerns, and reduced generalizability of the relevant research. 

Belen, P., & Irene, D. (2022). 


Case: Acquired brain damage is one of the most complex pathologies that affect the central nervous system, there is great variability in its pathophysiology, from traumatic focal injuries to diffuse axonal injuries, including spasticity. It supposes a great comorbidity and functional repercussion in patients, hindering their subsequent recovery. We report a case of a young patient with a history of quadriplegia due to acquired brain damage secondary to thrombosis of the dural sinus. The patient presented sensorimotor deficit, restricted function, and a great situation of dependency. He required three cycles of high doses of incobotulinumtoxinA (IncoBoNT) according to his specific need, the first infiltration was 800 U, the second 800 U, and the last 500 U over a period of 14 weeks. Thanks to the previous objectives agreement with the patient the results were satisfactory and relevant for him, presenting a great functional improvement of spasticity and associated pain, as assessed by the visual analog scale score.

Conclusion: IncoBoNT at high doses and short intervals has been shown to be an effective and valuable tool for personalized treatment adapted to the needs of severely affected neurological patients.

Shoemaker, R., Heyman, A., & David, L. (2023b). 


Problems with executive cognitive function, including recent memory, concentration, word finding, confusion, decreased assimilation, and disorientation, can have a variety of sources of disease, including inflammation, metabolic disturbances, and degenerative processes that are typically found in diseases where chronic fatigue is present. The problems presented by multiple coexisting cognitive symptoms are finding: 1) a single diagnostic test that has a history of use by clinicians working with brain-injured patients, such as NeuroQuant (NQ); 2) that is affordable, accurate, and reliable to use as a measure of benefits, or lack of same; and 3) screening, causation, and sequential features of therapy. Furthermore, the complexity of brain injury shows us the limitations of human versus machine-based testing, with advances in transcriptomics leading the way in a new world of diagnostics and therapies that follow gene activation studies.

The objective of this report was to retrospectively look at results of the transcriptomic testing of white blood cells, combined with a brain volumetric imaging study, in an observational study to provide a basis to identify the specific causation of brain injury caused by exposure to the interior environment of water-damaged buildings (WDB). By comparing transcriptomic abnormalities with known volumetric patterns of injury to cortical grey matter, enlargement of superior lateral ventricles and atrophy of grey matter nuclei, we demonstrate the feasibility of treatment of brain injury employing noninvasive methods in preparation for novel treatments previously shown to be effective. We intend to use these tests sequentially in a before-and-after fashion to show correction of metabolic and inflammatory conditions found in chronic inflammatory response syndrome (CIRS) in a subsequent study.

Kukurin, G. W., & Audren, C. (2023). 


The number of literature reports suggesting that various types of electrical, optokinetic, caloric, and mechanical vestibular stimulation may enhance recovery of function in patients suffering from traumatic and degenerative brain disorders is growing. This case report describes the integration of vestibular stimulation techniques into a rehabilitation treatment plan of a traumatically brain injured 16-year-old patient who had failed to sustain recovery after a course of standard care. His intractable signs and symptoms included headache, brain fog/mild cognitive impairment and disequilibrium which made participation in his chosen sport, hockey, virtually impossible.   His symptoms developed following a concussion while playing hockey.  He was treated by the team’s designated sports specialist and eventually cleared to return to play, however he was rapidly re-concussed. At the time he presented for evaluation, a battery of tests was conducted and clearly supported the reoccurrence of his symptoms. His baseline scores were Graded Symptom Checklist symptom severity 46, Standard Assessment of Concussion 25/30, BESS Balance Score 14, Trails Test A 15.0, Trails Test B 27.4, Processing Speed Task 63, Reaction time simple 255 and Reaction time choice 469. Standard methods of rehabilitation including Gaze Stabilization Exercises and Progressive Balance Exercises were augmented with vestibular stimulation through the use of skull vibrations and optokinetic stimulation. After 18 treatments over approximately six weeks of rehabilitation augmented with vestibular stimulation, findings associated with mTBI normalized and he was able to resume his full participation in sporting activities.  His post treatment scores were. Graded Symptom Checklist symptom severity 1, Standard Assessment of Concussion 24/30, BESS Balance Score 5, Trails Test A 12.4, Trails Test B 34.0, Processing Speed Task 64, Reaction time simple 245 and Reaction time choice 385. He remained asymptomatic at 4 months follow-up post discharge and is participating fully in team hockey activities. This case report describes the integration of vestibular stimulation into neurorehabilitation protocols which appeared to be associated with sustained reduction in disability and improved treatment-refractory symptoms in a patient with traumatic brain injury. It adds to the growing knowledgebase supporting the role of vestibular stimulation as an adjunct modality in the rehabilitation of brain disorders.

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