brain

Brain metastases

Brain metastases

see also Intracranial metastases.

Epidemiology

Brain Metastases Epidemiology.

Classification

Brain Metastases Classification.

Scales

Karnofsky Performance Score.

Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM).

Trials

Despite the frequency of brain metastases, prospective trials in this patient population are limited, and the criteria used to assess response and progression in the CNS are heterogeneous 1).

This heterogeneity largely stems from the recognition that existing criteria sets, such as RECIST 2) 3).

Genes involved

Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown.

Brastianos et al. detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases 4).

COX2

HBEGF

ST6GALNAC5

HK2

FOXC1

HER2

VEGFA

LEF1

HOXB9

CDH2, KIFC1, and FALZ3

STAT3

αvβ3

HDAC3, JAG2, NUMB, APH1B, HES4, and PSEN1

Clinical Features

see Brain metastases Clinical Features.

Diagnosis

see Brain metastases diagnosis.

Differential diagnosis

see Brain metastases differential diagnosis.

Treatment

see Brain metastases treatment.

Outcome

Brain metastases outcome.

Recurrence

see Brain metastases recurrence.

Randomized controlled trials

There is a lack of prospective randomized studies. Based on retrospective case series, international guidelines recommend the harvesting (if required, stereotactically guided) of tissue for histological and molecular diagnosis in cases of unknown or possibly competing for underlying systemic malignant diseases, in cases of suspected tumor recurrence, and with regard to the evaluation of targeted therapies taking into account molecular heterogeneity of primary and secondary tumors. Surgical resection is particularly valuable for the treatment of up to three space-occupying cerebral metastases, especially to achieve clinical stabilization to allow further non-surgical treatment For cystic metastasis, a combination of stereotactic puncture and radiotherapy may be useful. Meningeal carcinomatosis can be treated with intrathecal medication via an intraventricular catheter system. Ventriculoperitoneal shunts represent an effective treatment option for patients with tumor-associated hydrocephalus.

Neurosurgical procedures are of central importance in the multimodal treatment of cerebral metastases. The indications for neurosurgical interventions will be refined in the light of more effective radiation techniques and systemic treatments with new targeted therapeutic approaches and immunotherapies on the horizon 5).

Case series

see Brain metastases case series.

Research

Zhu et al. reported a medium-throughput drug screening platform (METPlatform) based on organotypic cultures that allow evaluating inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastases, they identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastases, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. The work validates METPlatform as a potent resource for metastases research integrating drug screening and unbiased omics approaches that are compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere 6).

1)

NU Lin, EQ Lee, H Aoyama, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group Lancet Oncol, 14 (2013), pp. e396–e406
2)

EA Eisenhauer, P Therasse, J Bogaerts, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer, 45 (2009), pp. 228–247
3)

P Therasse, SG Arbuck, EA Eisenhauer, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst, 92 (2000), pp. 205–216
4)

Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG 2nd, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015 Sep 26. [Epub ahead of print] PubMed PMID: 26410082.
5)

Thon N, Karschnia P, Baumgarten LV, Niyazi M, Steinbach JP, Tonn JC. Neurosurgical Interventions for Cerebral Metastases of Solid Tumors. Dtsch Arztebl Int. 2023 Mar 10;(Forthcoming):arztebl.m2022.0410. doi: 10.3238/arztebl.m2022.0410. Epub ahead of print. PMID: 36650742.
6)

Zhu L, Retana D, García-Gómez P, Álvaro-Espinosa L, Priego N, Masmudi-Martín M, Yebra N, Miarka L, Hernández-Encinas E, Blanco-Aparicio C, Martínez S, Sobrino C, Ajenjo N, Artiga MJ, Ortega-Paino E, Torres-Ruiz R, Rodríguez-Perales S; RENACER, Soffietti R, Bertero L, Cassoni P, Weiss T, Muñoz J, Sepúlveda JM, González-León P, Jiménez-Roldán L, Moreno LM, Esteban O, Pérez-Núñez Á, Hernández-Laín A, Toldos O, Ruano Y, Alcázar L, Blasco G, Fernández-Alén J, Caleiras E, Lafarga M, Megías D, Graña-Castro O, Nör C, Taylor MD, Young LS, Varešlija D, Cosgrove N, Couch FJ, Cussó L, Desco M, Mouron S, Quintela-Fandino M, Weller M, Pastor J, Valiente M. A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis. EMBO Mol Med. 2022 Feb 17:e14552. doi: 10.15252/emmm.202114552. Epub ahead of print. PMID: 35174975.

Preoperative Embolization for Brain Arteriovenous Malformation

Preoperative Embolization for Brain Arteriovenous Malformation

Latest Pubmed Related Articles

Systematic Review and Meta-analysis

Preoperative embolization has traditionally been regarded as a safe and effective adjunct to cerebral arteriovenous malformation surgery. However, there is currently no high-level evidence to ascertain this presumption.

Sattari et al. from the Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Tehran School of Medicine, Tehran University of Medical Science, Tehran, Iran. compared the outcomes of microsurgery (MS) vs microsurgery with preoperative embolization (E + MS) in patients with cerebral arteriovenous malformation through a systematic review.

They searched MEDLINE, PubMed, and Embase. The primary outcome was cerebral arteriovenous malformation obliteration. Secondary outcomes were intraoperative bleeding (mL), complications, worsened modified Rankin Scale (mRS), and mortality. The pooled proportions of outcomes were calculated through the logit transformation method. The odds ratio (OR) of categorical data and the mean difference of continuous data were estimated through the Mantel-Haenszel and the inverse variance methods, respectively.

Thirty-two studies met the eligibility criteria. One thousand eight hundred twenty-eight patients were treated by microsurgery alone, and 1088 were treated by microsurgery with preoperative embolization, respectively. The meta-analysis revealed no significant difference in AVM obliteration (94.1% vs 95.6%, OR = 1.15 [0.63-2.11], P = .65), mortality (1.7% vs 2%, OR = 0.88 [0.30-2.58], P = .82), procedural complications (18.2% vs 27.2%, OR = 0.47 [0.19-1.17], P = .10), worsened mRS (21.2% vs 18.5%, OR = 1.08 [0.33-3.54], P = .9), and intraoperative blood loss (mean difference = 182.89 [-87.76, 453.55], P = .19).

The meta-analysis showed no significant difference in AVM obliteration, mortality, complications, worse mRS, and intraoperative blood loss between MS and E + MS groups. For AVMs where MS alone has acceptable results, it is reasonable to bypass unnecessary preoperative embolization given the higher postoperative complication risk 1).

In a meta-analysis, preoperative embolization appears to have substantially reduced the lesional volume with active AV shunting before AVM resection. Anecdotally, preoperative embolization facilitates safe and efficient resection; however, differences in outcomes were not significant. The decision to pursue preoperative embolization remains a nuanced decision based on individual lesion anatomy and treatment team experience 2).

Brosnan et al. performed a systematic review of randomized trials and cohort studies evaluating preoperative embolization of bAVMs published between 01 January 2000 and 31 March 2021 and appraise its role in clinical practice. A MEDLINE search was performed, and articles reporting on outcomes following preoperative embolization, as an adjunct to microsurgery, were eligible for inclusion. PRISMA reporting and Cochrane Handbook guidelines were followed. The primary outcome measure was the risk of complications associated with preoperative embolization. The study was registered with PROSPERO (CRD42021244231). Of the 1661 citations, 8 studies with 588 patients met predefined inclusion criteria. No studies specifically compared outcomes of surgical excision of bAVMs between those with and without preoperative embolization. Spetzler Martin (SM) grading was available in 301 cases. 123 of 298 (41⋅28%) patients presented with hemorrhage. Complications related to embolization occurred in 175/588 patients (29.4%, 95% CI 19.6-40.2). Permanent neurological deficits occurred in 36/541 (6%, 95% CI 3.9-8.5) and mortality in 6/588 (0.41%, 95% CI 0-1.4). This is the first systematic review evaluating the preoperative embolization of bAVMs. Existing studies assessing this intervention are of poor quality. Associated complication rates are significant. Based on published literature, there is currently insufficient evidence to recommend the preoperative embolization of AVMs. Further studies are required to ascertain if there are benefits of this procedure and if so, in which cases 3).

Case series

A study included patients with brain AVM who underwent embolization at our hospital between April 2011 and May 2021. Risk factors for peri- and postoperative complications were analyzed.

During the study period, 36 AVMs were treated during 58 embolization sessions. The goal of the embolization was preoperative in 24 (67%), pre-radiosurgical in 9 (25%), and palliative in 3 (8%) cases. The overall complication rate was 43% (25 of 58) per session and 36% (13 of 36) per patient. Ischemic and hemorrhagic complications were observed in 14 (24%) and 14 (24%) cases, respectively. n-Butyl cyanoacrylate (n-BCA) embolization was detected as the significant risk for postoperative hemorrhage in the univariate (79% vs. 36%, P = 0.012; Fisher exact test) and the multivariable analysis (odds ratio 4.90, 95% confidence interval 1.08-22.2, P = 0.039). The number of embolized feeder in a single session also tended to be higher in a hemorrhagic complication group (median 3.5 vs. 2.0, P = 0.11; Mann-Whitney U-test).

The risk of embolization in multimodality treatment for complex brain AVM was substantial. n-BCA embolization may carry a higher risk of postoperative hemorrhage. An accumulation of cases is awaited to investigate the effectiveness of minimal target embolization in the future 4).

A total of 11 patients who underwent 12 preoperative SPE procedures were included for analysis. Five AVMs were ruptured (45%), and the median nidus volume was 3.0 cm3 (range: 1.3-42.9 cm3). The Spetzler-Martin grade was I-II in seven patients (64%) and III-IV in four patients (36%). The degree of nidal obliteration was less than 25% in two procedures (17%), 25-50% in one procedure (8%), 50-75% in eight procedures (67%), and greater than 75% in one procedure (8%). The rates of post-embolization AVM hemorrhage and mortality were 8% and 0%, respectively. The postoperative angiographic obliteration rate was 100%, and the modified Rankin Scale score improved or stable in 91% of patients (median follow-up duration 2 months).

Preoperative AVM SPE affords a reasonable risk-to-benefit profile for appropriately selected patients 5)

Embolization of intracranial arteriovenous malformations (AVMs) is generally a preoperative adjunctive procedure in the USA.

Preoperative embolization may also be a contributing factor with the potential for recurrence of unresected but embolized portions of an AVM. Follow-up angiography at 1 to 3 years appears to be warranted 6).

A total of 107 patients were treated for cAVMs during the study period. Of those patients, 41 underwent cAVM embolizations with Onyx in 82 procedures.

Results: After the embolization, the cAVM diameter was reduced from 3.71 +/- 1.55 cm to 3.06 +/- 1.89 cm (P < .05). Median volume reduction was 75%. Complete occlusion with embolization alone was achieved in 4 (10%) cAVMs. The recurrence rate for completely occluded cAVMs was 50% (2 patients). A total of 71% of the 41 patients treated with Onyx underwent surgery, and 15% underwent radiosurgery. There were 9% who have not yet received definitive treatment of their residual cAVMs. A new permanent neurologic deficit occurred in 5 patients (6.1% per procedure or 12.2% per patient).

A considerable risk for a permanent neurologic deficit remains for cAVM embolization with Onyx. The risk has to be carefully weighted against the benefit of volume reduction in the treatment of cAVMs 7).

1)

Sattari SA, Shahbandi A, Yang W, Feghali J, Xu R, Huang J. Microsurgery versus Microsurgery With Preoperative Embolization for Brain Arteriovenous Malformation Treatment: A Systematic Review and Meta-analysis. Neurosurgery. 2023 Jan 1;92(1):27-41. doi: 10.1227/neu.0000000000002171. Epub 2022 Oct 26. PMID: 36519858.
2)

Park MT, Essibayi MA, Srinivasan VM, Catapano JS, Graffeo CS, Lawton MT. Surgical management outcomes of intracranial arteriovenous malformations after preoperative embolization: a systematic review and meta-analysis. Neurosurg Rev. 2022 Dec;45(6):3499-3510. doi: 10.1007/s10143-022-01860-x. Epub 2022 Sep 27. PMID: 36168072.
3)

Brosnan C, Amoo M, Javadpour M. Preoperative embolisation of brain arteriovenous malformations: a systematic review and meta-analysis. Neurosurg Rev. 2022 Jun;45(3):2051-2063. doi: 10.1007/s10143-022-01766-8. Epub 2022 Mar 9. PMID: 35260972; PMCID: PMC9160113.
4)

Koizumi S, Shojima M, Shinya Y, Ishikawa O, Hasegawa H, Miyawaki S, Nakatomi H, Saito N. Risk Factors of Brain Arteriovenous Malformation Embolization as Adjunctive Therapy: Single-Center 10-Year Experience. World Neurosurg. 2022 Sep 18:S1878-8750(22)01346-8. doi: 10.1016/j.wneu.2022.09.069. Epub ahead of print. PMID: 36130658.
5)

Conger JR, Ding D, Raper DM, Starke RM, Durst CR, Liu KC, Jensen ME, Evans AJ. Preoperative Embolization of Cerebral Arteriovenous Malformations with Silk Suture and Particles: Technical Considerations and Outcomes. J Cerebrovasc Endovasc Neurosurg. 2016 Jun;18(2):90-99. doi: 10.7461/jcen.2016.18.2.90. Epub 2016 Jun 30. PMID: 27790398; PMCID: PMC5081503.
6)

Ivanov AA, Alaraj A, Charbel FT, Aletich V, Amin-Hanjani S. Recurrence of Cerebral Arteriovenous Malformations Following Resection in Adults: Does Preoperative Embolization Increases the Risk? Neurosurgery. 2016 Apr;78(4):562-71. doi: 10.1227/NEU.0000000000001191. PubMed PMID: 26702837.
7)

Hauck EF, Welch BG, White JA, Purdy PD, Pride LG, Samson D. Preoperative embolization of cerebral arteriovenous malformations with onyx. AJNR Am J Neuroradiol. 2009 Mar;30(3):492-5. doi: 10.3174/ajnr.A1376. Epub 2008 Dec 26. PMID: 19112062; PMCID: PMC7051448.

Brain abscess

Brain abscess

J.Sales-Llopis

Neurosurgery Service, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL – FISABIO Foundation), Alicante, Spain.

A brain abscess is a focal area of necrosis starting in an area of cerebritis surrounded by a membrane.

Brain abscesses are suppurative infections of the brain parenchyma surrounded by a vascularized capsule.

see also Intracranial abscess.

It is a potentially life-threatening condition requiring prompt radiological identification and rapid treatment.

Classification

Brain abscess classification.

Epidemiology

The most frequent intracranial locations (in descending order of frequency) are: frontal-temporal, frontal-parietal, parietal, cerebellar, and occipital lobes.

In a article, Chen review the literature to find out how the epidemiology of this disease has changed through the years and re-visit the basic pathological process of abscess evolution and highlight the new research in the biochemical pathways that initiate and regulate this process 1).

The epidemiology of brain abscess has changed with the increasing incidence of this infection in immunocompromised patients, particularly solid organ and bone marrow transplant recipients, and the decreasing incidence of brain abscess related to sinusitis and otitis 2).

There have been several trends in the epidemiology of brain abscess over recent decades. One trend is that there appears to be a trend toward a decreasing incidence of brain abscess. In a population-based study of residents of Olmstead County, Minnesota, the incidence rate was 1.3 per 100,000 patient-years from 1935 to 1944 compared with 0.9 per 100,000 patient-years from 1965 to 1981 3).

Etiology

see Brain abscess etiology.

Clinical features

Clinical presentation is non-specific, with many cases having no convincing inflammatory or septic symptoms.

Abscess formation should be considered in case of clinical deterioration, headache, and any neurological deficit after febrile episodes.

Similar to any other mass lesion but tend to progress rapidly.

Symptoms of raised intracranial pressure, seizures and focal neurological deficits are the most common forms of presentation

Eventually, many abscesses rupture into the ventricular system, which results in a sudden and dramatic worsening of the clinical presentation and often heralds a poor outcome.

Pathology

Cerebral abscesses result from pathogens growing within the brain parenchyma. Initial parenchymal infection is known as cerebritis, which may progress into a cerebral abscess.

Cerebral infection is commonly divided into four stages with distinct imaging and histopathologic features:

early cerebritis (a focal infection without a capsule or pus formation,can resolve or develop into frank abscess) late cerebritis

early abscess/encapsulation – may occur 10 days after infection

late abscess/encapsulation – may occur >14 days after infection

Diagnosis

see Brain abscess diagnosis.

Differential diagnosis

see Brain abscess differential diagnosis.

Treatment

see Brain abscess treatment.

Management

see Brain abscess management.

Outcome

Significant advances in the diagnosis and management of bacterial brain abscess over the past several decades have improved the expected outcome of a disease once regarded as invariably fatal. Despite this, intraparenchymal abscess continues to present a serious and potentially life-threatening condition 4).

There has been a gradual improvement in the outcome of patients with brain abscess over the past 50 years, which might be driven by improved brain imaging techniques, minimally invasive neurosurgical procedures, and protocoled antibiotic treatment. Multicenter prospective studies and randomized clinical trials are needed to further advance treatment and prognosis in brain abscess patients.

Our understanding of brain abscesses has increased by meta-analysis on clinical characteristics, ancillary investigations, and treatment modalities. Prognosis has improved over time, likely due to improved brain imaging techniques, minimally invasive neurosurgical procedures, and protocoled antibiotic treatment 5).

Current evidences suggest that for encapsulated brain abscess in superficial non-eloquent area, abscess resection compared to abscess aspiration had lower post-operative residual abscess rate; lower re-operation rate; higher rate of improvement in neurological status within 1 month after surgery, shorter duration of post-operative antibiotics and average length of hospital stay. There was no statistically significant difference in the rate of improvement in neurological status at 3 months post-operative and the mortality 6).

Complications

Intraventricular rupture of brain abscess (IVROBA)

Strongly influences poor outcome in patients with cyanotic heart disease. The key to decreasing poor outcomes may be the prevention and management of IVROBA. To reduce operative and anesthetic risk in these patients, abscesses should be managed by less invasive aspiration methods guided by computed tomography. Abscesses larger than 2 cm in diameter, in deep-located or parieto-occipital regions, should be aspirated immediately and repeatedly, mainly using computed tomography-guided methods to decrease intracranial pressure and avoid IVROBA. IVROBA should be aggressively treated by aspiration methods for the abscess coupled with the appropriate intravenous and intrathecal administration of antibiotics while evaluating intracranial pressure pathophysiology 7).

Case series

Brain abscess case series.

Case reports

see Brain abscess case reports.

Brain abscess case reports from the General University Hospital Alicante

Known space-occupying lesion, centered in the right frontal anterior white matter, with estimated diameters of 3.5 x 3 x 3.5 cm. It shows well-defined contours and a practically spherical shape. A predominantly hypointense signal on T1 and homogeneously hyperintense on T2, with a wall with hypointense behavior on T2-weighted sequences. After contrast administration, only enhancement of its wall was observed, in a fine and linear way, without identifying solid poles. The lesion shows diffusion sequence restriction and low values ​​of rVSC in perfusion. Marked surrounding vasogenic edema, which causes a mass effect on the neighboring sulci, as well as mild subfalcian herniation, with a deviation from the midline of approximately 6 mm (significant improvement compared to previous CT control). The discrete mass effect is also on the knee of the corpus callosum and the frontal horn of the right ventricle. The findings are compatible with a brain abscess. A small solution of continuity is observed in its anterior wall, in contact with the meninge, which is thickened in a laminar manner in relation to inflammatory involvement, without clearly identifying empyema. Extensive occupation of the frontal sinus bilaterally, with an enhancement of its wall. Retrospectively, the CT study showed slight permeation on the posterior wall of one of the loculations of the frontal sinus close to the abscess. Small hyperintense foci in subcortical and periventricular white matter with a chronic ischemic profile of a small vessel, to a mild degree. Diagnostic impression: Findings compatible with a right frontal parenchymal abscess, 3.5 cm in diameter, with inflammatory changes and thickening of the adjacent pachymeninge, although without clear associated empyema.

Books

see Brain abscess books.

Latest news

1)

Chen M, Low DCY, Low SYY, Muzumdar D, Seow WT. Management of brain abscesses: where are we now? Childs Nerv Syst. 2018 Oct;34(10):1871-1880. doi: 10.1007/s00381-018-3886-7. Epub 2018 Jul 3. PubMed PMID: 29968000.
2)

Calfee DP, Wispelwey B. Brain abscess. Semin Neurol. 2000;20(3):353-60. Review. PubMed PMID: 11051299.
3)

Nicolosi A, Hauser WA, Musicco M, Kurland LT: Incidence and prognosis of brain abscess in a defined population: Olmsted County, Minnesota, 1935-1981. Neuroepidemiology 1991;10:122-131.
4)

atel K, Clifford DB. Bacterial brain abscess. Neurohospitalist. 2014 Oct;4(4):196-204. doi: 10.1177/1941874414540684. PubMed PMID: 25360205; PubMed Central PMCID: PMC4212419.
5)

Brouwer MC, van de Beek D. Epidemiology, diagnosis, and treatment of brain abscesses. Curr Opin Infect Dis. 2016 Nov 8. [Epub ahead of print] PubMed PMID: 27828809.
6)

Zhai Y, Wei X, Chen R, Guo Z, Raj Singh R, Zhang Y. Surgical outcome of encapsulated brain abscess in superficial non-eloquent area: A systematic review. Br J Neurosurg. 2015 Nov 16:1-6. [Epub ahead of print] PubMed PMID: 26569628.
7)

Takeshita M, Kagawa M, Yato S, Izawa M, Onda H, Takakura K, Momma K. Current treatment of brain abscess in patients with congenital cyanotic heart disease. Neurosurgery. 1997 Dec;41(6):1270-8; discussion 1278-9. PubMed PMID: 9402578.

Pediatric traumatic brain injury outcome

Pediatric traumatic brain injury outcome

see also Traumatic brain injury outcome.

Latest articles

Neuropsychological and behavioral outcomes for injured children vary with the severity of the injury, child age at injury, premorbid child characteristics, family factors, and the family’s socioeconomic status. Each of these factors needs to be taken into account when designing rehabilitation strategies and assessing factors related to outcomes 1)

The Functional Status Score (FSS) can be implemented as part of routine practice in two different healthcare systems and the relationships observed between the FSS and patient characteristics can serve as a baseline for work going forward in the coming years. As a field, establishing which outcomes tests can be readily administered while also measuring relevant outcomes for various populations of children with TBI is an essential next step in developing therapies for this disorder that is highly prevalent and morbid 2).

The multi-center, prospectively collected CENTER-TBI core and registry databases were screened and patients were included when younger than 18 years at enrollment and admitted to the regular ward (admission stratum) or intensive care unit (ICU stratum) following TBI. Patient demographics, injury causes, clinical findings, brain CT imaging details, and outcome (GOSE at 6 months follow-up) were retrieved and analyzed. Injury characteristics were compared between patients admitted to the regular ward and ICU and a multivariate analysis of factors predicting an unfavorable outcome (GOSE 1-4) was performed. Results from the core study were compared to the registry dataset which includes larger patient numbers but no follow-up data. Results: Two hundred and twenty-seven patients in the core dataset and 687 patients in the registry dataset were included in this study. In the core dataset, road-traffic incidents were the most common cause of injury overall and in the ICU stratum, while incidental falls were most common in the admission stratum. Brain injury was considered serious to severe in the majority of patients and concurrent injuries in other body parts were very common. Intracranial abnormalities were detected in 60% of initial brain CTs. Intra- and extracranial surgical interventions were performed in one-fifth of patients. The overall mortality rate was 3% and the rate of unfavorable outcomes was 10%, with those numbers being considerably higher among ICU patients. GCS and the occurrence of secondary insults could be identified as independent predictors of an unfavorable outcome 3).

There are few specific prognostic models specifically developed for the pediatric traumatic brain injury (TBI) population.

Fang et al. aimed to combine multiple machine learning approaches to building hybrid models for predicting the prognosis and length of hospital stay for adults and children with TBI.

They collected relevant clinical information from patients treated at the Neurosurgery Center of the Second Affiliated Hospital of Anhui Medical University between May 2017 and May 2022, of which 80% was used for training the model and 20% for testing via screening and data splitting. They trained and tested the machine learning models using 5 cross-validations to avoid overfitting. In the machine learning models, 11 types of independent variables were used as input variables and the Glasgow Outcome Scale score, was used to evaluate patients’ prognosis, and patient length of stay was used as the output variable. Once the models were trained, we obtained and compared the errors of each machine-learning model from 5 rounds of cross-validation to select the best predictive model. The model was then externally tested using clinical data of patients treated at the First Affiliated Hospital of Anhui Medical University from June 2021 to February 2022.

Results: The final convolutional neural network-support vector machine (CNN-SVM) model predicted the Glasgow Outcome Scale score with an accuracy of 93% and 93.69% in the test and external validation sets, respectively, and an area under the curve of 94.68% and 94.32% in the test and external validation sets, respectively. The mean absolute percentage error of the final built convolutional neural network-support vector regression (CNN-SVR) model predicting inpatient time in the test set and external validation set was 10.72% and 10.44%, respectively. The coefficient of determination (R2) was 0.93 and 0.92 in the test set and external validation set, respectively. Compared with a back-propagation neural network, CNN, and SVM models built separately, our hybrid model was identified to be optimal and had high confidence.

This study demonstrates the clinical utility of 2 hybrid models built by combining multiple machine learning approaches to accurately predict the prognosis and length of stay in hospital for adults and children with TBI. Application of these models may reduce the burden on physicians when assessing TBI and assist clinicians in the medical decision-making process 4).

Mikkonen et al., tested the predictive performance of existing prognostic tools, originally developed for the adult TBI population, in pediatric TBI patients requiring stays in the ICU.

They used the Finnish Intensive Care Consortium database to identify pediatric patients (< 18 years of age) treated in 4 academic ICUs in Finland between 2003 and 2013. They tested the predictive performance of 4 classification systems-the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) TBI model, the Helsinki CT score, the Rotterdam CT score, and the Marshall CT classification-by assessing the area under the receiver operating characteristic curve (AUC) and the explanatory variation (pseudo-R2 statistic). The primary outcome was 6-month functional outcome (favorable outcome defined as a Glasgow Outcome Scale score of 3-5).

Overall, 341 patients (median age 14 years) were included; of these, 291 patients had primary head CT scans available. The IMPACT core-based model showed an AUC of 0.85 (95% CI 0.78-0.91) and a pseudo-R2 value of 0.40. Of the CT scoring systems, the Helsinki CT score displayed the highest performance (AUC 0.84, 95% CI 0.78-0.90; pseudo-R2 0.39) followed by the Rotterdam CT score (AUC 0.80, 95% CI 0.73-0.86; pseudo-R2 0.34).

Prognostic tools originally developed for the adult TBI population seemed to perform well in pediatric TBI. Of the tested CT scoring systems, the Helsinki CT score yielded the highest predictive value 5).

1)

Keenan HT, Bratton SL. Epidemiology and outcomes of pediatric traumatic brain injury. Dev Neurosci. 2006;28(4-5):256-63. doi: 10.1159/000094152. PMID: 16943649.
2)

Bell MJ. Outcomes for Children With Traumatic Brain Injury-How Can the Functional Status Scale Contribute? Pediatr Crit Care Med. 2016 Dec;17(12):1185-1186. doi: 10.1097/PCC.0000000000000950. PMID: 27918390; PMCID: PMC5142208.
3)

Riemann L, Zweckberger K, Unterberg A, El Damaty A, Younsi A; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Investigators and Participants. Injury Causes and Severity in Pediatric Traumatic Brain Injury Patients Admitted to the Ward or Intensive Care Unit: A Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study. Front Neurol. 2020 Apr 30;11:345. doi: 10.3389/fneur.2020.00345. PMID: 32425879; PMCID: PMC7205018.
4)

Fang C, Pan Y, Zhao L, Niu Z, Guo Q, Zhao B. A Machine Learning-Based Approach to Predict Prognosis and Length of Hospital Stay in Adults and Children With Traumatic Brain Injury: Retrospective Cohort Study. J Med Internet Res. 2022 Dec 9;24(12):e41819. doi: 10.2196/41819. PMID: 36485032.
5)

Mikkonen ED, Skrifvars MB, Reinikainen M, Bendel S, Laitio R, Hoppu S, Ala-Kokko T, Karppinen A, Raj R. Validation of prognostic models in intensive care unit-treated pediatric traumatic brain injury patients. J Neurosurg Pediatr. 2019 Jun 7:1-8. doi: 10.3171/2019.4.PEDS1983. [Epub ahead of print] PubMed PMID: 31174193.

Deep Brain Stimulation for Post-Traumatic Stress Disorder

Deep Brain Stimulation for Post-Traumatic Stress Disorder

In 2018 the application of DBS for PTSD was still strictly investigational and animal models suggest that stimulation of the amygdala, ventral striatum, hippocampus, and prefrontal cortex may be effective in fear extinction and anxiety-like behavior 1).

Neuroimaging, preclinical, and preliminary clinical data suggested that the use of DBS for the treatment of PTSD may be practical 2).

PTSD is the only potential clinical indication for DBS that shows extensive animal research prior to human applications. Nevertheless, DBS for PTSD remains highly investigational. Despite several years of government funding of DBS research in view of treating severe PTSD in combat veterans, ethical dilemmas, recruitment difficulties, and issues related to use of DBS in such a complex and heterogenous disorder remain prevalent 3).

Hamani et al. treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. They show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, they found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcomes. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response 4).

Amygdala Deep Brain Stimulation for Post-Traumatic Stress Disorder

Functional neuroimaging studies have suggested that amygdala hyperactivity is responsible for the symptoms of PTSD. Deep brain stimulation (DBS) can functionally reduce the activity of a cerebral target by delivering an electrical signal through an electrode. We tested whether DBS of the amygdala could be used to treat PTSD symptoms. Rats traumatized by inescapable shocks, in the presence of an unfamiliar object, develop the tendency to bury the object when re-exposed to it several days later. This behavior mimics the symptoms of PTSD. 10 Sprague-Dawley rats underwent the placement of an electrode in the right basolateral nucleus of the amygdala (BLn). The rats were then subjected to a session of inescapable shocks while being exposed to a conspicuous object (a ball). Five rats received DBS treatment while the other 5 rats did not. After 7 days of treatment, the rats were re-exposed to the ball and the time spent burying it under the bedding was recorded. Rats treated with BLn DBS spent on average 13 times less time burying the ball than the sham control rats. The treated rats also spent 18 times more time exploring the ball than the sham control rats. In conclusion, the behavior of treated rats in this PTSD model was nearly normalized. We argue that these results have direct implications for patients suffering from treatment-resistant PTSD by offering a new therapeutic strategy 5)

1)

Lavano A, Guzzi G, Della Torre A, Lavano SM, Tiriolo R, Volpentesta G. DBS in Treatment of Post-Traumatic Stress Disorder. Brain Sci. 2018 Jan 20;8(1):18. doi: 10.3390/brainsci8010018. PMID: 29361705; PMCID: PMC5789349.
2)

Reznikov R, Hamani C. Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation. Neuromodulation. 2016 Dec 19. doi: 10.1111/ner.12551. [Epub ahead of print] Review. PubMed PMID: 27992092.
3)

Meeres J, Hariz M. Deep Brain Stimulation for Post-Traumatic Stress Disorder: A Review of the Experimental and Clinical Literature. Stereotact Funct Neurosurg. 2022 Jan 3:1-13. doi: 10.1159/000521130. Epub ahead of print. PMID: 34979516.
4)

Hamani C, Davidson B, Corchs F, Abrahao A, Nestor SM, Rabin JS, Nyman AJ, Phung L, Goubran M, Levitt A, Talakoub O, Giacobbe P, Lipsman N. Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder. Sci Adv. 2022 Dec 2;8(48):eadc9970. doi: 10.1126/sciadv.adc9970. Epub 2022 Dec 2. PMID: 36459550.
5)

Langevin JP, De Salles AA, Kosoyan HP, Krahl SE. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res. 2010 Dec;44(16):1241-5. doi: 10.1016/j.jpsychires.2010.04.022. Epub 2010 May 26. PMID: 20537659.

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 GFAP, UCH-L1, S100B, 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 NSE, Tau, UCH-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).

Systematic reviews

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 inflammation, hormones as biomarkers, coagulation and vasculature, genetic polymorphisms, antioxidants and oxidative stress, apoptosis 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).

S100B in mild traumatic brain injury

S100B in mild traumatic brain injury

Latest articles

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

ASCO-SNO-ASTRO Guideline 2022

https://ascopubs.org/doi/10.1200/JCO.21.02314?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours 2021

https://www.annalsofoncology.org/article/S0923-7534(21)02214-6/fulltext Published:August 05, 2021

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors 2019

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 surgery, Stereotactic 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 survival, median 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 recurrence. 1)

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)

General information

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).

Indications

see Deep brain stimulation indications.

Targets

see Deep Brain Stimulation Targets.

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

Deep Brain Stimulation during Pregnancy and Delivery

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).

Technique

Deep brain stimulation technique.

see Short pulse deep brain stimulation.

Frameless deep brain stimulation

Postoperative evaluation

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).

Complications

see Deep brain stimulation complications.

Case series

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

Case reports

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).

Books

see Deep Brain Stimulation Books.

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.

Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

The onset of aneurysmal subarachnoid hemorrhage (aSAH) elicits activation of the inflammatory cascade, and ongoing neuroinflammation is suspected to contribute to secondary complications, such as vasospasm and delayed cerebral ischemia.

To date, the monitoring of the inflammatory response to detect secondary complications such as DCI has not become part of the clinical routine diagnostic.

Höllig et al. estimated that the wide range of the measured values hampers their interpretation and usage as a biomarker. However, understanding the inflammatory response after aSAH and generating a multicenter database may facilitate further studies: realistic sample size calculations on the basis of a multicenter database will increase the quality and clinical relevance of the acquired results 1).

In a review, of Watson et al. analyze the extent literature regarding the relationship between neuroinflammation and cognitive dysfunction after aSAH. Pro-inflammatory cytokines appear to play a role in maintaining normal cognitive function in adults unaffected by aSAH. However, in the setting of aSAH, elevated cytokine levels may correlate with worse neuropsychological outcomes. This seemingly dichotomous relationship between neuroinflammation and cognition suggests that the action of cytokines varies, depending on their physiologic environment. Experimental therapies which suppress the immune response to aSAH appear to have a beneficial effect on cognitive outcomes. However, further studies are necessary to determine the utility of inflammatory mediators as biomarkers of neurocognitive outcomes, as well as their role in the management of aSAH 2).

Ahn et al. investigated inflammatory markers in subjects with early brain edema which does not resolve, i.e., persistent brain edema after SAH.

Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for Brain edema using the 0-4 ‘subarachnoid hemorrhage early brain edema score‘ (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3-5 days [T3] and 6-8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2).

Of the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002-1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE.

They identified serum cytokines at different time points that were independently associated with persistent Brain edema. Specifically, persistent elevations of Eotaxin is associated with persistent Brain edema after SAH 3).

Leucocytosis and change in IL-6 prior to DCI reflect impending cerebral ischemia. The time-independent association of ESR with DCI after SAH may identify this as a risk factor. These data suggest that systemic inflammatory mechanisms may increase the susceptibility to the development of DCI after SAH 4)

Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity 5).

1)

Höllig A, Stoffel-Wagner B, Clusmann H, Veldeman M, Schubert GA, Coburn M. Time Courses of Inflammatory Markers after Aneurysmal Subarachnoid Hemorrhage and Their Possible Relevance for Future Studies. Front Neurol. 2017 Dec 22;8:694. doi: 10.3389/fneur.2017.00694. PMID: 29312122; PMCID: PMC5744005.
2)

Watson E, Ding D, Khattar NK, Everhart DE, James RF. Neurocognitive outcomes after aneurysmal subarachnoid hemorrhage: Identifying inflammatory biomarkers. J Neurol Sci. 2018 Jun 25;394:84-93. doi: 10.1016/j.jns.2018.06.021. [Epub ahead of print] Review. PubMed PMID: 30240942.
3)

Ahn SH, Burkett A, Paz A, Savarraj JP, Hinds S, Hergenroeder G, Gusdon AM, Ren X, Hong JH, Choi HA. Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage. J Neuroinflammation. 2022 Aug 4;19(1):199. doi: 10.1186/s12974-022-02564-1. PMID: 35927663.
4)

McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ, Clark S, Rothwell NJ, Tyrrell PJ. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013 Nov;5(6):512-7. doi: 10.1136/neurintsurg-2012-010386. Epub 2012 Sep 5. PMID: 22952245; PMCID: PMC3812893.
5)

Savarraj JPJ, Parsha K, Hergenroeder GW, Zhu L, Bajgur SS, Ahn S, Lee K, Chang T, Kim DH, Liu Y, Choi HA. Systematic model of peripheral inflammation after subarachnoid hemorrhage. Neurology. 2017 Apr 18;88(16):1535-1545. doi: 10.1212/WNL.0000000000003842. Epub 2017 Mar 17. PMID: 28314864; PMCID: PMC5395070.

Cystic brain metastases treatment

Cystic brain metastases treatment

When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decrease the chance of radiation-induced necrosis and provide symptomatic relief from the mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications for improving patient outcomes 1).

Ommaya reservoir implantation during stereotactic cyst aspiration is necessary to prevent fluid reaccumulation, thereby avoiding the need for a second surgical procedure 2).

Flickinger 3) reported that tumors with a cystic component greater than 10 mL did not appear to be effectively controlled by radiosurgery alone. Therefore, it is essential to decrease the volume of the cystic components before treating them with radiosurgery. The combination of cyst aspiration and radiosurgery is one possible method 4) 5) 6) 7) that may be more effective and safer than radiosurgery alone.

Tumor cyst aspiration followed by Gamma Knife radiosurgery (GKRS) for large cystic brain metastases is a reasonable and effective management strategy. However, even with aspiration, the target lesion tends to exceed the dimensions of an ideal target for stereotactic radiosurgery. In this case, the local tumor control rate and the risk of complication might be a critical challenge.

A study aimed to investigate whether fractionated GKRS (f-GKRS) could solve these problems. Between May 2018 and April 2021, eight consecutive patients with nine lesions were treated with f-GKRS in five or ten sessions after cyst aspiration. The aspiration was repeated as needed throughout the treatment course to maintain the cyst size and shape. The patient characteristics, radiologic tumor response, and clinical course were reviewed using medical records. The mean follow-up duration was 10.2 (2-28) months. The mean pre-GKRS volume and maximum diameter were 16.7 (5-55.8) mL and 39.0 (31-79) mm, respectively. The mean tumor volume reduction achieved by aspiration was 55.4%. The tumor volume decreased for all lesions, and symptoms were alleviated in all patients. The median overall survival was 10.0 months, and the estimated 1-year survival rate was 41.7% (95% CI: 10.9-70.8%). The local tumor control rate was 100%. No irradiation-related adverse events were observed. f-GKRS for aspirated cystic brain metastasis is a safe, effective, and less invasive management option for large cystic brain metastases 8).

1)

Kim M, Cheok S, Chung LK, Ung N, Thill K, Voth B, Kwon DH, Kim JH, Kim CJ, Tenn S, Lee P, Yang I. Characteristics and treatments of large cystic brain metastasis: radiosurgery and stereotactic aspiration. Brain Tumor Res Treat. 2015 Apr;3(1):1-7. doi: 10.14791/btrt.2015.3.1.1. Epub 2015 Apr 29. PMID: 25977901; PMCID: PMC4426272.
2)

Lv J, Wu Z, Wang K, Wang Y, Yang S, Han W. Case Report: Clinical and Procedural Implications of Ommaya Reservoir Implantation in Cystic Brain Metastases Followed by Radiosurgery Treatment. Front Surg. 2022 May 16;9:901674. doi: 10.3389/fsurg.2022.901674. PMID: 35651693; PMCID: PMC9149303.
3)

Flickinger JC. Radiotherapy and radiosurgical management of brain metastases. Curr Oncol Rep. 2001 Nov;3(6):484-9. doi: 10.1007/s11912-001-0069-5. PMID: 11595116.
4)

Loeffler JS, Barker FG, Chapman PH. Role of radiosurgery in the management of central nervous system metastases. Cancer Chemother Pharmacol. 1999;43 Suppl:S11-4. doi: 10.1007/s002800051092. PMID: 10357553.
5)

Kim MS, Lee SI, Sim SH. Brain tumors with cysts treated with Gamma Knife radiosurgery: is microsurgery indicated. Stereotact Funct Neurosurg. 1999;72(Suppl 1):38–44.
6)

Niranjan A, Witham T, Kondziolka D, Lunsford LD. The role of stereotactic cyst aspiration for glial and metastatic brain tumors. Can J Neurol Sci. 2000;27:229–235.
7)

Uchino M, Nagao T, Seiki Y, Shibata I, Terao H, Kaneko I. [Radiosurgery for cystic metastatic brain tumor] No Shinkei Geka. 2000;28:417–421.
8)

Noda R, Akabane A, Kawashima M, Oshima A, Tsunoda S, Segawa M, Inoue T. Fractionated Gamma Knife radiosurgery after cyst aspiration for large cystic brain metastases: case series and literature review. Neurosurg Rev. 2022 Jul 14. doi: 10.1007/s10143-022-01835-y. Epub ahead of print. PMID: 35834076.