Serum Biomarkers for Traumatic Brain Injury

Serum Biomarkers for Traumatic Brain Injury

Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAPUCH-L1S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies 1).


Unlike other organ-based diseases where rapid diagnosis employing biomarkers from blood tests are clinically essential to guide diagnosis and treatment, there are no rapid, definitive diagnostic blood tests for TBI. Over the last decade there has been a myriad of studies exploring many promising biomarkers. Despite the large number of published studies there is still a lack of any FDA-approved biomarkers for clinical use in adults and children. There is now an important need to validate and introduce them into the clinical setting 2).


Richter et al. aimed to assess if day of injury serum protein biomarkers could identify critically ill TBI patients in whom the risks of transfer are compensated by the likelihood of detecting management-altering neuroimaging findings.

Data were obtained from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Eligibility criteria included: TBI patients aged ≥ 16 years, Glasgow Coma Score (GCS) < 13 or patient intubated with unrecorded pre-intubation GCS, CT with Marshall score < 3, serum biomarkers (GFAP, NFL, NSE, S100B, Tau, UCH-L1) sampled ≤ 24 h of injury, MRI < 30 days of injury. The degree of axonal injury on MRI was graded using the Adams-Gentry classification. The association between serum concentrations of biomarkers and Adams-Gentry stage was assessed and the optimum threshold concentration identified, assuming different minimum sensitivities for the detection of brainstem injury (Adams-Gentry stage 3). A cost-benefit analysis for the USA and UK health care settings was also performed.

Among 65 included patients (30 moderate-severe, 35 unrecorded) axonal injury was detected in 54 (83%) and brainstem involvement in 33 (51%). In patients with moderate-severe TBI, brainstem injury was associated with higher concentrations of NSETauUCH-L1 and GFAP. If the clinician did not want to miss any brainstem injury, NSE could have avoided MRI transfers in up to 20% of patients. If a 94% sensitivity was accepted considering potential transfer-related complications, GFAP could have avoided 30% of transfers. There was no added net cost, with savings up to £99 (UK) or $612 (US). No associations between proteins and axonal injury were found in intubated patients without a recorded pre-intubation GCS.

Serum protein biomarkers show potential to safely reduce the number of transfers to MRI in critically ill patients with moderate-severe TBI at no added cost 3).

Mozaffari et al. created a comprehensive appraisal of the most prominent serum biomarkers used in the assessment and care of TBI.The PubMed, Scopus, Cochrane, and Web of Science databases were queried with the terms “biomarker” and “traumatic brain injury” as search terms with only full-text, English articles within the past 10 years selected. Non-human studies were excluded, and only adult patients fell within the purview of this analysis. A total of 528 articles were analyzed in the initial search with 289 selected for screening. A further 152 were excluded for primary screening. Of the remaining 137, 54 were included in the final analysis. Serum biomarkers were listed into the following broad categories for ease of discussion: immune markers and markers of inflammationhormones as biomarkers, coagulation and vasculature, genetic polymorphisms, antioxidants and oxidative stressapoptosis and degradation pathways, and protein markers. Glial fibrillary acidic protein(GFAP), S100, and neurons specific enolase (NSE) were the most prominent and frequently cited markers. Amongst these three, no single serum biomarker demonstrated neither superior sensitivity nor specificity compared to the other two, therefore noninvasive panels should incorporate these three serum biomarkers to retain sensitivity and maximize specificity for TBI 4).


1)

Mendes Arent A, de Souza LF, Walz R, Dafre AL. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury. Biomed Res Int. 2014;2014:723060. Epub 2014 Feb 13. Review. PubMed PMID: 24689052.
2)

Papa L, Edwards D, Ramia M. Exploring Serum Biomarkers for Mild Traumatic Brain Injury. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 22. PubMed PMID: 26269900.
3)

Richter S, Winzeck S, Czeiter E, Amrein K, Kornaropoulos EN, Verheyden J, Sugar G, Yang Z, Wang K, Maas AIR, Steyerberg E, Büki A, Newcombe VFJ, Menon DK; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Sub-study Participants and Investigators. Serum biomarkers identify critically ill traumatic brain injury patients for MRI. Crit Care. 2022 Nov 29;26(1):369. doi: 10.1186/s13054-022-04250-3. PMID: 36447266.
4)

Mozaffari K, Dejam D, Duong C, Ding K, French A, Ng E, Preet K, Franks A, Kwan I, Phillips HW, Kim DY, Yang I. Systematic Review of Serum Biomarkers in Traumatic Brain Injury. Cureus. 2021 Aug 10;13(8):e17056. doi: 10.7759/cureus.17056. PMID: 34522534; PMCID: PMC8428323.

Brain metastases treatment guidelines

Brain metastases treatment guidelines

Please see the full-text version of this guideline https://www.cns.org/guidelines/browse-guidelines-detail/guidelines-treatment-of-adults-with-metastatic-bra-2 for the target population of each recommendation listed below.

SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo Brain metastases surgeryStereotactic radiosurgery for brain metastases (SRS), or whole brain radiotherapy (WBRT)?

RECOMMENDATIONS:

Level of Evidence 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survivalmedian survival, and local control.

Level of Evidence 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors

Level of Evidence 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits.

SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities?

RECOMMENDATIONS:

Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases.

Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival.

Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT.

SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection?

RECOMMENDATIONS:

Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS.   SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence?

RECOMMENDATION:

Level 3: En bloc resection of the tumor, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases.

QUESTION B:

Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence?

RECOMMENDATION:

Level 3: Gross total resection is recommended over subtotal resection in Recursive partitioning analysis class 1 class I patients to improve overall survival and prolong time to recurrence1)


1)

Nahed BV, Alvarez-Breckenridge C, Brastianos PK, Shih H, Sloan A, Ammirati M, Kuo JS, Ryken TC, Kalkanis SN, Olson JJ. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors. Neurosurgery. 2019 Mar 1;84(3):E152-E155. doi: 10.1093/neuros/nyy542. PubMed PMID: 30629227.

Deep brain stimulation (DBS)

Deep brain stimulation (DBS)

Deep brain stimulation (DBS): Neurosurgical procedure that uses electrical stimulation through surgically implanted electrodes to produce neuromodulation of electrical signals for the purpose of symptom improvement. For many indications, DBS has supplanted ablative procedures in the brain.


Deep brain stimulation (DBS) is a neurosurgical procedure introduced in 1987, involving the implantation of a medical device called a neurostimulator (sometimes referred to as a ‘brain pacemaker’), which sends electrical impulses, through implanted electrodes.

The system consists of a lead that is implanted into a specific deep brain target. The lead is connected to an implantable pulse generator (IPG), which is the power source of the system. The lead and the IPG are connected by an extension wire that is tunneled under the skin between both of them. This system is used to chronically stimulate the deep brain target by delivering a high-frequency current to this target.

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional lead stimulation could increase the efficacy of such therapies 1).


Deep brain stimulation surgery, create an opportunity to conduct cognitive or behavioral experiments during the acquisition of invasive neurophysiology. Optimal design and implementation of intraoperative behavioral experiments require consideration of stimulus presentation, time and surgical constraints. Tekriwal et al., describe the use of a modular, inexpensive system that implements a decision-making paradigm, designed to overcome challenges associated with the operative environment.

They created an auditory, two-alternative forced choice (2AFC) task for intraoperative use. Behavioral responses were acquired using an Arduino based single-hand held joystick controller equipped with a 3-axis accelerometer, and two button presses, capable of sampling at 2 kHz. We include designs for all task relevant code, 3D printed components, and Arduino pin-out diagram.

They demonstrated feasibility both in and out of the operating room with behavioral results represented by three healthy control subjects and two Parkinson’s disease subjects undergoing deep brain stimulator implantation. Psychometric assessment of performance indicated that the subjects could detect, interpret and respond accurately to the task stimuli using the joystick controller. We also demonstrate, using intraoperative neurophysiology recorded during the task, that the behavioral system described here allows us to examine neural correlates of human behavior.

COMPARISON WITH EXISTING METHODS: For low cost and minimal effort, any clinical neural recording system can be adapted for intraoperative behavioral testing with our experimental setup.

CONCLUSION: Our system will enable clinicians and basic scientists to conduct intraoperative awake and behaving electrophysiologic studies in humans 2).

see Deep Brain Stimulation Targets.

Research has demonstrated that multi-target DBS shows some benefits over single target DBS.

Scelzo et al. report a retrospective case series of women, followed in two DBS centers, who became pregnant and went on to give birth to a child while suffering from disabling MD or psychiatric diseases [Parkinson’s disease, dystonia, Tourette’s syndrome (TS), Obsessive Compulsive Disorder (OCD)] treated by DBS. Clinical status, complications and management before, during, and after pregnancy are reported. Two illustrative cases are described in greater detail.

DBS improved motor and behavioral disorders in all patients and allowed reduction in, or even total interruption of disease-specific medication during pregnancy. With the exception of the spontaneous early abortion of one fetus in a twin pregnancy, all pregnancies were uneventful in terms of obstetric and pediatric management. DBS parameters were adjusted in five patients in order to limit clinical worsening during pregnancy. Implanted material limited breast-feeding in one patient because of local pain at submammal stimulator site and led to local discomfort related to stretching of the cable with increasing belly size in another patient whose stimulator was implanted in the abdominal wall.

Not only is it safe for young women with MD, TS and OCD who have a DBS-System implanted to become pregnant and give birth to a baby but DBS seems to be the key to becoming pregnant, having children, and thus greatly improves quality of life 3).

Recent developments in the postoperative evaluation of deep brain stimulation surgery on the group level warrant the detection of achieved electrode positions based on postoperative imaging. Computed tomography (CT) is a frequently used imaging modality, but because of its idiosyncrasies (high spatial accuracy at low soft tissue resolution), it has not been sufficient for the parallel determination of electrode position and details of the surrounding brain anatomy (nuclei). The common solution is rigid fusion of CT images and magnetic resonance (MR) images, which have much better soft tissue contrast and allow accurate normalization into template spaces. Here, we explored a deep-learning approach to directly relate positions (usually the lead position) in postoperative CT images to the native anatomy of the midbrain and group space.

Materials and methods: Deep learning is used to create derived tissue contrasts (white matter, gray matter, cerebrospinal fluid, brainstem nuclei) based on the CT image; that is, a convolution neural network (CNN) takes solely the raw CT image as input and outputs several tissue probability maps. The ground truth is based on coregistrations with MR contrasts. The tissue probability maps are then used to either rigidly coregister or normalize the CT image in a deformable way to group space. The CNN was trained in 220 patients and tested in a set of 80 patients.

Results: Rigorous validation of such an approach is difficult because of the lack of ground truth. We examined the agreements between the classical and proposed approaches and considered the spread of implantation locations across a group of identically implanted subjects, which serves as an indicator of the accuracy of the lead localization procedure. The proposed procedure agrees well with current magnetic resonance imaging-based techniques, and the spread is comparable or even lower.

Postoperative CT imaging alone is sufficient for accurate localization of the midbrain nuclei and normalization to the group space. In the context of group analysis, it seems sufficient to have a single postoperative CT image of good quality for inclusion. The proposed approach will allow researchers and clinicians to include cases that were not previously suitable for analysis 4).

Harmsen et al. assessed the state of DBS-related research by analyzing the DBS literature as well as active studies sponsored by the National Institutes of Health (NIH) or German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]).In total, 8,974 publications, 172 active NIH-funded projects, and 34 active DFG projects were identified. Records spanned 52 different disorders across 31 distinct brain targets and showed a shift toward studies examining conditions other than movement disorders. Most published works involved human research (80.6% of published studies), of which 10.2% were identified as clinical trials. Increasingly, studies focused on imaging or electrophysiological changes associated with DBS (69.8% NIH-active and 70.6% DFG-active vs. 25.8% published) or developing new stimulation techniques and adaptive technologies (37.8% NIH-active and 17.6% DFG-active vs. 6.5% published).

This overview in 2022 of past and present DBS-related studies provides insight into the status of DBS research and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS 5).

see Deep Brain Stimulation case series

A 79-year-old woman with a history of coarse tremors effectively managed with deep brain stimulation presented with multiple intracranial metastases from a newly diagnosed lung cancer and was referred for whole-brain radiation therapy. She was treated with a German helmet technique to a total dose of 30 Gy in 10 fractions using 6 MV photons via opposed lateral fields with the neurostimulator turned off prior to delivery of each fraction. The patient tolerated the treatment well with no acute complications and no apparent change in the functionality of her neurostimulator device or effect on her underlying neuromuscular disorder. This represents the first reported case of the safe delivery of whole-brain radiation therapy in a patient with an implanted neurostimulator device. In cases such as this, neurosurgeons and radiation oncologists should have discussions with patients about the risks of brain injury, device malfunction or failure of the device, and plans for rigorous testing of the device before and after radiation therapy 6).


1)

Pollo C, Kaelin-Lang A, Oertel MF, Stieglitz L, Taub E, Fuhr P, Lozano AM, Raabe A, Schüpbach M. Directional deep brain stimulation: an intraoperative double-blind pilot study. Brain. 2014 Jul;137(Pt 7):2015-26. doi: 10.1093/brain/awu102. Epub 2014 May 19. PubMed PMID: 24844728.
2)

Tekriwal A, Felsen G, Thompson JA. Modular auditory decision-making behavioral task designed for intraoperative use in humans. J Neurosci Methods. 2018 May 7. pii: S0165-0270(18)30134-1. doi: 10.1016/j.jneumeth.2018.05.004. [Epub ahead of print] PubMed PMID: 29746889.
3)

Scelzo E, Mehrkens JH, Bötzel K, Krack P, Mendes A, Chabardès S, Polosan M, Seigneuret E, Moro E, Fraix V. Deep Brain Stimulation during Pregnancy and Delivery: Experience from a Series of “DBS Babies”. Front Neurol. 2015 Sep 1;6:191. doi: 10.3389/fneur.2015.00191. eCollection 2015. PubMed PMID: 26388833.
4)

Reisert M, Sajonz BEA, Brugger TS, Reinacher PC, Russe MF, Kellner E, Skibbe H, Coenen VA. Where Position Matters-Deep-Learning-Driven Normalization and Coregistration of Computed Tomography in the Postoperative Analysis of Deep Brain Stimulation. Neuromodulation. 2022 Nov 21:S1094-7159(22)01330-7. doi: 10.1016/j.neurom.2022.10.042. Epub ahead of print. PMID: 36424266.
5)

Harmsen IE, Wolff Fernandes F, Krauss JK, Lozano AM. Where Are We with Deep Brain Stimulation? A Review of Scientific Publications and Ongoing Research. Stereotact Funct Neurosurg. 2022 Feb 1:1-14. doi: 10.1159/000521372. Epub ahead of print. PMID: 35104819.
6)

Kotecha R, Berriochoa CA, Murphy ES, Machado AG, Chao ST, Suh JH, Stephans KL. Report of whole-brain radiation therapy in a patient with an implanted deep brain stimulator: important neurosurgical considerations and radiotherapy practice principles. J Neurosurg. 2016 Apr;124(4):966-70. doi: 10.3171/2015.2.JNS142951. Epub 2015 Aug 28. PubMed PMID: 26315009.
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