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  1. Sreedharan S, Veeramuthu V, Hariri F, Hamzah N, Ramli N, Narayanan V
    Int J Oral Maxillofac Surg, 2020 Sep;49(9):1183-1192.
    PMID: 32224001 DOI: 10.1016/j.ijom.2020.03.002
    Isolated traumatic maxillofacial injury without concomitant brain injury may cause delayed post-concussive symptoms. Early identification allows optimal diagnosis, prognostication, and therapeutic intervention. The aim of this prospective observational study was to investigate longitudinal microstructural changes of the white matter (WM) tracts based on diffusion tensor imaging (DTI) indices in patients with isolated maxillofacial injuries, immediately and 6 months post-trauma, and to correlate these DTI indices with neuropsychological changes observed. Twenty-one patients with isolated maxillofacial injuries and 21 age-matched controls were recruited. DTI was performed and indices were calculated for 50 WM tracts. The neuropsychological evaluation was done using the screening module of the Neuropsychological Assessment Battery. Patients were subjected to repeat DTI and neuropsychological evaluation at 6 months post-trauma. Reduced fractional anisotropy (FA) and increased median (MD) and radial diffusivity (RD) in the acute phase were seen in major association, projection, and commissural fibre bundles, indicative of vasogenic oedema. These changes correlated with attention and executive function deficits in the acute phase, as well as improvement in memory and visuospatial function in the chronic phase. Isolated maxillofacial trauma patients develop WM microstructural damage, which may impair cognitive performance acutely and over time. DTI indices can serve as predictive imaging biomarkers for long-term cognitive deficits in isolated maxillofacial injuries.
  2. Veeramuthu V, Hariri F, Narayanan V, Tan LK, Ramli N, Ganesan D
    J Oral Maxillofac Surg, 2016 Jun;74(6):1197.e1-1197.e10.
    PMID: 26917201 DOI: 10.1016/j.joms.2016.01.042
    The aim of the present study was to establish the incidence of maxillofacial (MF) injury accompanying mild traumatic brain injury (mTBI) and the associated neurocognitive deficits and white matter changes.
  3. Hamzah N, Mohamad NA, Thiruselvam I, Hariri F, Veeramuthu V, Mazlan M, et al.
    Appl Neuropsychol Adult, 2019 08 21;28(4):416-426.
    PMID: 31431094 DOI: 10.1080/23279095.2019.1648264
    This study assessed the validity (construct validity) and reliability (internal consistency) of the Neuropsychological Assessment Battery Screening Module (S-NAB) in detecting mild cognitive deficit/alteration in multicultural, multilingual, and multiethnic mild traumatic brain injury (mTBI) population of Malaysia. S-NAB and Montreal Cognitive Assessment (MoCA) data from 114 patients with mTBI (93 males; 21 females) aged 18 to 60 years old were obtained at University Malaya Medical Center, Malaysia. The mean age was 28.17 ± 8.57 years and mean education years was 12.40 ± 2.01. Convergent validity was assessed between S-NAB domain scores and MoCA total scores by using Pearson's correlation and internal consistency was assessed using Cronbach's alpha. Acceptable internal consistency (α ≥ .70) was found for Attention, Language, and Memory domains but weak internal consistencies (α 
  4. Veeramuthu V, Seow P, Narayanan V, Wong JHD, Tan LK, Hernowo AT, et al.
    Acad Radiol, 2018 09;25(9):1167-1177.
    PMID: 29449141 DOI: 10.1016/j.acra.2018.01.005
    RATIONALE AND OBJECTIVES: Magnetic resonance spectroscopy is a noninvasive imaging technique that allows for reliable assessment of microscopic changes in brain cytoarchitecture, neuronal injuries, and neurochemical changes resultant from traumatic insults. We aimed to evaluate the acute alteration of neurometabolites in complicated and uncomplicated mild traumatic brain injury (mTBI) patients in comparison to control subjects using proton magnetic resonance spectroscopy (1H magnetic resonance spectroscopy).

    MATERIAL AND METHODS: Forty-eight subjects (23 complicated mTBI [cmTBI] patients, 12 uncomplicated mTBI [umTBI] patients, and 13 controls) underwent magnetic resonance imaging scan with additional single voxel spectroscopy sequence. Magnetic resonance imaging scans for patients were done at an average of 10 hours (standard deviation 4.26) post injury. The single voxel spectroscopy adjacent to side of injury and noninjury regions were analysed to obtain absolute concentrations and ratio relative to creatine of the neurometabolites. One-way analysis of variance was performed to compare neurometabolite concentrations of the three groups, and a correlation study was done between the neurometabolite concentration and Glasgow Coma Scale.

    RESULTS: Significant difference was found in ratio of N-acetylaspartate to creatine (NAA/Cr + PCr) (χ2(2) = 0.22, P 

  5. Veeramuthu V, Narayanan V, Ramli N, Hernowo A, Waran V, Bondi MW, et al.
    World Neurosurg, 2017 Jan;97:416-423.
    PMID: 27751922 DOI: 10.1016/j.wneu.2016.10.041
    OBJECTIVE: To compare the extent of persistent neuropsychological impairment in patients with complicated mild traumatic brain injury (mTBI) and those with uncomplicated mTBI.

    METHODS: Sixty-one patients with mTBI (Glasgow Coma Scale score 13-15) were recruited prospectively, categorized according to baseline computed tomography findings, and subjected to neuropsychological assessment at initial admission (n = 61) as well as at a 6-month follow-up (n = 30). The paired t test, Cohen's d effect size calculation, and repeated-measures analysis of variance were used to establish the differences between the 2 groups in terms of neuropsychological performance.

    RESULTS: A trend toward poorer neuropsychological performance among the patients with complicated mTBI was observed during admission; however, performance in this group improved over time. In contrast, the uncomplicated mTBI group showed slower recovery, especially in tasks of memory, visuospatial processing, and executive functions, at follow-up.

    CONCLUSIONS: Our findings suggest that despite the broad umbrella designation of mTBI, the current classification schemes of injury severity for mild neurotrauma should be revisited. They also raise questions about the clinical relevance of both traumatic focal lesions and the absence of visible traumatic lesions on brain imaging studies in patients with milder forms of head trauma.

  6. Narayanan V, Veeramuthu V, Ahmad-Annuar A, Ramli N, Waran V, Chinna K, et al.
    PLoS One, 2016;11(7):e0158838.
    PMID: 27438599 DOI: 10.1371/journal.pone.0158838
    The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
  7. Veeramuthu V, Narayanan V, Kuo TL, Delano-Wood L, Chinna K, Bondi MW, et al.
    J Neurotrauma, 2015 Oct 1;32(19):1497-509.
    PMID: 25952562 DOI: 10.1089/neu.2014.3750
    We explored the prognostic value of diffusion tensor imaging (DTI) parameters of selected white matter (WM) tracts in predicting neuropsychological outcome, both at baseline and 6 months later, among well-characterized patients diagnosed with mild traumatic brain injury (mTBI). Sixty-one patients with mTBI (mean age=27.08; standard deviation [SD], 8.55) underwent scanning at an average of 10 h (SD, 4.26) post-trauma along with assessment of their neuropsychological performance at an average of 4.35 h (SD, 7.08) upon full Glasgow Coma Scale recovery. Results were then compared to 19 healthy control participants (mean age=29.05; SD, 5.84), both in the acute stage and 6 months post-trauma. DTI and neuropsychological measures between acute and chronic phases were compared, and significant differences emerged. Specifically, chronic-phase fractional anisotropy and radial diffusivity values showed significant group differences in the corona radiata, anterior limb of internal capsule, cingulum, superior longitudinal fasciculus, optic radiation, and genu of corpus callosum. Findings also demonstrated associations between DTI indices and neuropsychological outcome across two time points. Our results provide new evidence for the use of DTI as an imaging biomarker and indicator of WM damage occurring in the context of mTBI, and they underscore the dynamic nature of brain injury and possible biological basis of chronic neurocognitive alterations.
  8. Schnakers C, Hirsch M, Noé E, Llorens R, Lejeune N, Veeramuthu V, et al.
    Brain Sci, 2020 Dec 02;10(12).
    PMID: 33276451 DOI: 10.3390/brainsci10120930
    Covert cognition in patients with disorders of consciousness represents a real diagnostic conundrum for clinicians. In this meta-analysis, our main objective was to identify clinical and demographic variables that are more likely to be associated with responding to an active paradigm. Among 2018 citations found on PubMed, 60 observational studies were found relevant. Based on the QUADAS-2, 49 studies were considered. Data from 25 publications were extracted and included in the meta-analysis. Most of these studies used electrophysiology as well as counting tasks or mental imagery. According to our statistical analysis, patients clinically diagnosed as being in a vegetative state and in a minimally conscious state minus (MCS-) show similar likelihood in responding to active paradigm and responders are most likely suffering from a traumatic brain injury. In the future, multi-centric studies should be performed in order to increase sample size, with similar methodologies and include structural and functional neuroimaging in order to identify cerebral markers related to such a challenging diagnosis.
  9. Estraneo A, Fiorenza S, Magliacano A, Formisano R, Mattia D, Grippo A, et al.
    Neurology, 2020 09 15;95(11):e1488-e1499.
    PMID: 32661102 DOI: 10.1212/WNL.0000000000010254
    OBJECTIVE: This international multicenter, prospective, observational study aimed at identifying predictors of short-term clinical outcome in patients with prolonged disorders of consciousness (DoC) due to acquired severe brain injury.

    METHODS: Patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in minimally conscious state (MCS) were enrolled within 3 months from their brain injury in 12 specialized medical institutions. Demographic, anamnestic, clinical, and neurophysiologic data were collected at study entry. Patients were then followed up for assessing the primary outcome, that is, clinical diagnosis according to standardized criteria at 6 months postinjury.

    RESULTS: We enrolled 147 patients (44 women; mean age 49.4 [95% confidence interval 46.1-52.6] years; VS/UWS 71, MCS 76; traumatic 55, vascular 56, anoxic 36; mean time postinjury 59.6 [55.4-63.6] days). The 6-month follow-up was complete for 143 patients (VS/UWS 70; MCS 73). With respect to study entry, the clinical diagnosis improved in 72 patients (VS/UWS 27; MCS 45). Younger age, shorter time postinjury, higher Coma Recovery Scale-Revised total score, and presence of EEG reactivity to eye opening at study entry predicted better outcome, whereas etiology, clinical diagnosis, Disability Rating Scale score, EEG background activity, acoustic reactivity, and P300 on event-related potentials were not associated with outcome.

    CONCLUSIONS: Multimodal assessment could identify patients with higher likelihood of clinical improvement in order to help clinicians, families, and funding sources with various aspects of decision-making. This multicenter, international study aims to stimulate further research that drives international consensus regarding standardization of prognostic procedures for patients with DoC.

  10. Estraneo A, Magliacano A, Fiorenza S, Formisano R, Grippo A, Angelakis E, et al.
    Eur J Neurol, 2022 Feb;29(2):390-399.
    PMID: 34657359 DOI: 10.1111/ene.15143
    BACKGROUND AND PURPOSE: Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision-making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2-year mortality rate and bedside predictors of mortality.

    METHODS: We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3 months postinjury. At enrolment, we collected demographic (age, sex), anamnestic (aetiology, time postinjury), clinical (Coma Recovery Scale-Revised [CRS-R], Disability Rating Scale, Nociception Coma Scale-Revised), and neurophysiologic (electroencephalogram [EEG], somatosensory evoked and event-related potentials) data. Patients were followed up to gather data on mortality up to 24 months postinjury.

    RESULTS: Among 143 traumatic (n = 55) and nontraumatic (n = 88) patients (VS/UWS, n = 68, 19 females; MCS, n = 75, 22 females), 41 (28.7%) died within 24 months postinjury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p 

  11. Magliacano A, Liuzzi P, Formisano R, Grippo A, Angelakis E, Thibaut A, et al.
    Brain Sci, 2022 Dec 27;13(1).
    PMID: 36672033 DOI: 10.3390/brainsci13010051
    Prognosis of prolonged Disorders of Consciousness (pDoC) is influenced by patients' clinical diagnosis and Coma Recovery Scale-Revised (CRS-R) total score. We compared the prognostic accuracy of a novel Consciousness Domain Index (CDI) with that of clinical diagnosis and CRS-R total score, for recovery of full consciousness at 6-, 12-, and 24-months post-injury. The CDI was obtained by a combination of the six CRS-R subscales via an unsupervised machine learning technique. We retrospectively analyzed data on 143 patients with pDoC (75 in Minimally Conscious State; 102 males; median age = 53 years; IQR = 35; time post-injury = 1-3 months) due to different etiologies enrolled in an International Brain Injury Association Disorders of Consciousness Special Interest Group (IBIA DoC-SIG) multicenter longitudinal study. Univariate and multivariate analyses were utilized to assess the association between outcomes and the CDI, compared to clinical diagnosis and CRS-R. The CDI, the clinical diagnosis, and the CRS-R total score were significantly associated with a good outcome at 6, 12 and 24 months. The CDI showed the highest univariate prediction accuracy and sensitivity, and regression models including the CDI provided the highest values of explained variance. A combined scoring system of the CRS-R subscales by unsupervised machine learning may improve clinical ability to predict recovery of consciousness in patients with pDoC.
  12. Molteni E, Canas LDS, Briand MM, Estraneo A, Font CC, Formisano R, et al.
    Neurology, 2023 Aug 08;101(6):e581-e593.
    PMID: 37308301 DOI: 10.1212/WNL.0000000000207473
    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.

  13. Farisco M, Formisano R, Gosseries O, Kato Y, Koboyashi S, Laureys S, et al.
    J Neurol, 2024 Jan;271(1):395-407.
    PMID: 37740739 DOI: 10.1007/s00415-023-11956-z
    Diagnostic, prognostic, and therapeutic procedures for patients with prolonged disorders of consciousness (pDoCs) vary significantly across countries and clinical settings, likely due to organizational factors (e.g., research vs. non-academic hospitals), expertise and availability of resources (e.g., financial and human). Two international guidelines, one from the European Academy of Neurology (EAN) and one from the American Academy of Neurology (AAN) in collaboration with the American Congress of Rehabilitation Medicine (ACRM) and the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), were developed to facilitate consistent practice among professionals working with this challenging patient population. While the recommendations of both guidelines agree in principle, it remains an open issue how to implement them into clinical practice in the care pathway for patients with pDoCs. We conducted an online survey to explore health professional clinical practices related to the management of patients with pDoCs, and compare said practices with selected recommendations from both the guidelines. The survey revealed that while some recommendations are being followed, others are not and/or may require more honing/specificity to enhance their clinical utility. Particular attention should be given to the implementation of a multimodal assessment of residual consciousness, to the detection and treatment of pain, and to the impact of restrictions imposed by COVID-19 pandemics on the involvement of patients' families/representatives.
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