Omental flap transplantation for Moyamoya disease

  1. What is Moyamoya disease characterized by? a) Progressive stenosis and occlusion of coronary arteries b) Progressive stenosis and occlusion of internal carotid arteries c) Progressive stenosis and occlusion of pulmonary arteries d) Progressive stenosis and occlusion of femoral arteries
  2. Why is cerebral revascularization important in Moyamoya disease? a) To treat high blood pressure b) To improve blood flow and prevent stroke c) To reduce cholesterol levels d) To manage migraines
  3. What is the traditional approach for harvesting the omental flap for revascularization in Moyamoya disease? a) Laparoscopy b) Angiography c) Laparotomy d) Endoscopy
  4. In the systematic review, how many studies met the inclusion criteria? a) Two b) Three c) Four d) Five
  5. What were the key outcomes of interest in the systematic review? a) Intraoperative and postoperative complications b) Length of hospital stay and surgical technique c) Blood pressure management and postoperative complications d) Postoperative complications and long-term outcomes
  6. What percentage of patients in the systematic review experienced intraoperative complications? a) 3% b) 7.3% c) 10% d) 15%
  7. What is the average length of hospital stay reported in the systematic review? a) 2.0 days b) 4.5 days c) 6.2 days d) 8.0 days
  8. What is the main conclusion drawn from the systematic review regarding laparoscopic omental flap revascularization in Moyamoya disease? a) Laparoscopy is not a suitable approach. b) Laparoscopy has a high rate of intraoperative complications. c) Laparoscopic omental flap mobilization is safe and effective. d) Laparoscopy is only suitable for adult patients.
  9. In one of the referenced studies, what additional imaging technique was used to assess the viability of the omental flap? a) CT scan b) X-ray c) MRI d) Intraoperative fluorescence imaging using indocyanine green
  10. According to the study by Ohtaki et al., what is the range of the clinical observation period for pediatric moyamoya patients who underwent omental transplantation? a) 1.9 to 6.7 years b) 6.7 to 9.2 years c) 1.9 to 10 years d) 0.9 to 5.2 years

Answers:

  1. b) Progressive stenosis and occlusion of internal carotid arteries
  2. b) To improve blood flow and prevent stroke
  3. c) Laparotomy
  4. d) Five
  5. d) Postoperative complications and long-term outcomes
  6. b) 7.3%
  7. c) 6.2 days
  8. c) Laparoscopic omental flap mobilization is safe and effective.
  9. d) Intraoperative fluorescence imaging using indocyanine green
  10. b) 6.7 to 9.2 years

    In patients with Moyamoya disease, cerebral revascularization using a pedicled omental flap has proven to be a viable option following direct revascularization procedures. Historically, harvesting omentum involved laparotomy with the associated risk of complications; herein we describe outcomes from a 10-year experience of laparoscopic harvesting of pedicled omental flap for cerebral revascularization in Moyamoya patients.

    Methods: A retrospective chart review was performed of all patients with Moyamoya disease who underwent laparoscopic omental cerebral transposition between 2011 and 2021. Intraoperative and postoperative complications, length of stay (LOS), and outcomes at follow-up were analyzed.

    Results: Twenty-one patients underwent the procedure during the study period. Three intraoperative complications occurred (one segmental transverse colectomy for mesenteric injury, one converted to omental free flap, and one requiring micro anastomosis). The average overall LOS was 6 ± 6 days, with 3 ± 3.5 days in the ICU (mean±SD). Following discharge, complications included epigastric incisional hernia at the graft fascial exit site, recurrent neck pain at the subcutaneous tunneling site, and partial scalp necrosis. One patient required subsequent direct bypass seven months after the initial procedure owing to the progression of the disease. All other patients had partial or complete resolution of symptoms.

    Conclusion: Our retrospective observational study indicates that laparoscopic pedicled omental flap mobilization and transposition is a safe and effective method of indirect cerebral revascularization in patients with Moyamoya disease 1)

    report our techniques and outcomes in 2 adults with Moyamoya to undergo such a procedure. An omental flap based on the right gastroepiploic artery was created and intraoperative fluorescence imaging using indocyanine green was used to assess the viability of the flap and to guide lengthening of the pedicle. The flap was tunneled subcutaneously using skip incisions. There were no intraoperative complications and no postoperative complications related to the omental flap. Follow-up evaluation demonstrates viable omental flaps and improved cerebral vascularization. This technique is feasible in adults who require salvage cerebral revascularization for Moyamoya disease 2).

    A retrospective chart review of all patients undergoing laparoscopic omental cerebral transposition for moyamoya disease between 2011 and 2014 was performed. Clinical indication, surgical technique, operative times, complications, and outcomes at follow-up were reviewed.

    Results: A total of 7 children underwent the procedure. The general surgery team performed laparoscopic omental mobilization, extraperitonealization, and subcutaneous tunneling, while the neurosurgical team performed craniotomy and cerebral application of the graft. The patients were followed postoperatively with clinic visits and angiography. There was one intraoperative complication (colon injury) and one postoperative complication (intermittent omental hernia at fascial defect for pedicle). All patients had partial to complete symptomatic resolution and demonstrated adequate intracranial revascularization on angiography.

    Conclusion: Laparoscopic omental pedicle flap mobilization and subcutaneous transposition is feasible in children who require salvage cerebral revascularization for moyamoya disease. The procedure should be considered for other conditions requiring extraperitoneal revascularization 3).

    refined a laparoscopic method of harvesting an omental flap that preserves its gastroepiploic arterial supply.

    Methods: The pedicled omentum can be lengthened as needed by dividing it between the vascular arcades. It is transposed to the brain via skip incisions. The flap can be trimmed or stretched to cover ischemic areas of the brain. The cranial exposure is performed in parallel with pediatric surgeons. We performed this technique in 3 pediatric patients with moyamoya disease (aged 5-12 years) with previous superficial temporal artery to middle cerebral artery bypasses and progressive ischemic symptoms. In 1 patient, we transposed omentum to both hemispheres.

    Results: Blood loss ranged from 75 to 250 mL. After surgery, patients immediately tolerated a diet and were discharged in 3 to 5 days. The ischemic symptoms of all 3 children resolved within 3 months postoperatively. Magnetic resonance imaging at 1 year showed improved perfusion and no new infarcts. Angiography showed excellent revascularization of targeted areas and patency of the donor gastroepiploic artery.

    Conclusion: Laparoscopic omental harvest for cranial-omental transposition can be performed efficiently and safely. Patients with moyamoya disease appear to tolerate this technique much better than laparotomy. With this method, we can achieve excellent angiographic revascularization and resolution of ischemic symptoms 4).

    Ohtaki et al. describe the long-term follow-up results for intellectual outcome and performance status and make an evaluation of regional cerebral hemodynamics after extensive omental transplantation spread over both frontal lobes performed as the initial management. In the past 10 years, 10 moyamoya patients less than 12 years of age consecutively underwent omental transplantation. The omental flap was spread over not only the symptomatic hemisphere but also the contralateral frontal lobe after a large craniotomy. Superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis was accomplished simultaneously. On the contralateral hemisphere, STA-MCA anastomosis combined with encephalomyosynangiosis was subsequently performed. The clinical observation period averaged 6.7 years (ranging from 1.9 to 9.2 years). Apart from 2 patients in whom severe mental retardation had been disclosed pre-operatively, full-scale intelligence quotient scores have been maintained at over 90, that is, within the normal intellectual range. With respect to quality of life (QOL), these 8 patients have been leading normal daily lives since the operation. The focal decrease in CBF observed in the frontal lobe pre-operatively in 7 cases had disappeared after surgical treatment. In these patients, serial post-operative MR angiography revealed developed omental vessels and STAs. Deterioration of intellectual functions and QOL as well as cerebral ischaemic events in paediatric moyamoya patients can be prevented by extensive omental transplantation spread over both frontal lobes combined with STA-MCA anastomosis 5)

    Ten patients with ischemic cerebrovascular disease including three with adult moyamoya disease underwent this procedure (omental flap on eight sides and muscle flap on five sides). The muscle used for the flap was the serratus anterior muscle on two sides and the shaved latissimus dorsi muscle on three sides. Angiography and cerebral blood flow studies were performed in all patients preoperatively and postoperatively. All patients demonstrated severely impaired cerebrovascular reserve capacity due to occlusive disease.

    There was one patient each with perioperative death and intracranial infection following omental flap loss, and two patients had perioperative strokes. The average follow-up period was 23.2 months. Of the nine surviving patients, all eight except for the one with flap loss had good outcome with complete resolution of neurologic episodes 6).

    1)

    Salimi-Jazi F, Wood LSY, Jones RE, Chandler J, Rafeeqi T, Dutta S, Steinberg G, Bruzoni M. Ten-year experience with laparoscopic pedicled omental flap for cerebral revascularization in patients with Moyamoya disease. J Pediatr Surg. 2022 Nov;57(11):710-715. doi: 10.1016/j.jpedsurg.2022.01.023. Epub 2022 Jan 31. Erratum in: J Pediatr Surg. 2023 Jul 25;: PMID: 35197196.
    2)

    Schumm M, Simon K, Sacho R, Gould JC. Successful Laparoscopic Harvesting of Omental Pedicle Flap for Salvage Cerebral Revascularization in 2 Adults With Moyamoya Disease: Technique and Lessons Learned. Surg Laparosc Endosc Percutan Tech. 2017 Oct;27(5):e111-e115. doi: 10.1097/SLE.0000000000000448. PMID: 28708772.
    3)

    Bruzoni M, Steinberg GK, Dutta S. Laparoscopic harvesting of omental pedicle flap for cerebral revascularization in children with moyamoya disease. J Pediatr Surg. 2016 Apr;51(4):592-7. doi: 10.1016/j.jpedsurg.2015.10.048. Epub 2015 Oct 19. PMID: 26611331.
    4)

    Navarro R, Chao K, Gooderham PA, Bruzoni M, Dutta S, Steinberg GK. Less invasive pedicled omental-cranial transposition in pediatric patients with moyamoya disease and failed prior revascularization. Neurosurgery. 2014 Mar;10 Suppl 1:1-14. doi: 10.1227/NEU.0000000000000119. PMID: 23921707.
    5)

    Ohtaki M, Uede T, Morimoto S, Nonaka T, Tanabe S, Hashi K. Intellectual functions and regional cerebral haemodynamics after extensive omental transplantation spread over both frontal lobes in childhood moyamoya disease. Acta Neurochir (Wien). 1998;140(10):1043-53; discussion 1052-3. doi: 10.1007/s007010050213. PMID: 9856248.
    6)

    Yoshioka N, Tominaga S, Suzuki Y, Yamazato K, Hirano S, Nonaka K, Inui T, Matuoka N. Cerebral revascularization using omentum and muscle free flap for ischemic cerebrovascular disease. Surg Neurol. 1998 Jan;49(1):58-65; discussion 65-6. doi: 10.1016/s0090-3019(97)00122-5. PMID: 9428896.

Medulloblastoma classification

Medulloblastoma classification

In the 5th edition of the WHO classification, medulloblastomas, which are representative pediatric brain tumors, are categorized into four groups: WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH, based on their molecular background. While the histopathological findings still hold importance in predicting prognosis, the histopathological classification is no longer utilized in this edition. SHH medulloblastomas are further subdivided into two groups based on the presence or absence of TP53 mutation, as their clinical characteristics and prognosis differ. Group 3 and Group 4 medulloblastomas, recognized as distinct molecular groups in clinical practice, are combined into a single group called “non-WNT/non-SHH”, because they lack specific molecular pathway activation. Furthermore, based on methylation profiling, dividing SHH medulloblastoma into four subgroups and non-WNT/non-SHH medulloblastoma into eight subgroups was proposed. Understanding the unique clinical characteristics and prognosis associated with each group is crucial. However, it is important to acknowledge that our current understanding of prognosis is based on treatment approaches guided by clinical risk factors such as postoperative residual tumor volume and the presence of metastatic disease. This molecular-based classification holds promise in guiding the development of optimal treatment strategies for patients with medulloblastoma 1).

Nomenclature

The nomenclature and classification of medulloblastomas are rapidly evolving.

Medulloblastomas, molecularly defined

Medulloblastoma, WNT-activated

Medulloblastoma, SHH-activated and TP53-wildtype

Medulloblastoma, SHH-activated and TP53-mutant

Medulloblastoma non-WNT/non-SSH

In the World Health Organization Classification of Tumors of the Central Nervous System 2021, Group 3 medulloblastoma and group 4 medulloblastomas are grouped together under Medulloblastoma non-WNT/non-SSH, which is in turn divided into 8 subgroups.

Group 3 medulloblastoma

Group 3 medulloblastoma

Group 4 medulloblastoma

Group 4 medulloblastoma.

Misclassification between groups 3 and 4 is common. To address this issue, an AI-based R package called MBMethPred was developed based on DNA methylation and gene expression profiles of 763 medulloblastoma samples to classify subgroups using machine learning and neural network models. The developed prediction models achieved a classification accuracy of over 96% for subgroup classification by using 399 CpGs as prediction biomarkers. We also assessed the prognostic relevance of prediction biomarkers using survival analysis. Furthermore, we identified subgroup-specific drivers of medulloblastoma using functional enrichment analysis, Shapley values, and gene network analysis. In particular, the genes involved in the nervous system development process have the potential to separate medulloblastoma subgroups with 99% accuracy. Notably, our analysis identified 16 genes that were specifically significant for subgroup classification, including EP300, CXCR4, WNT4, ZIC4, MEIS1, SLC8A1, NFASC, ASCL2, KIF5C, SYNGAP1, SEMA4F, ROR1, DPYSL4, ARTN, RTN4RL1, and TLX2. Our findings contribute to enhanced survival outcomes for patients with medulloblastoma. Continued research and validation efforts are needed to further refine and expand the utility of our approach in other cancer types, advancing personalized medicine in pediatric oncology 2)

Standard-Risk Medulloblastoma

Tumor Resection Rate: Patients with standard-risk medulloblastoma typically have a high rate of tumor resection. This means that during surgery, the neurosurgeon was able to remove a significant portion of the tumor from the brain. Metastasis: Standard-risk patients usually do not have evidence of metastasis, which means that the cancer cells have not spread from the primary tumor site in the cerebellum to other parts of the central nervous system (CNS) or outside the CNS.

High-Risk Medulloblastoma

Tumor Resection Rate: Patients with high-risk medulloblastoma often have a lower rate of tumor resection. This indicates that during surgery, it may have been challenging to remove the tumor completely, and some cancerous tissue might remain.

Metastasis: High-risk patients typically have evidence of metastasis. This means that the cancer cells have spread from the primary tumor site in the cerebellum to other areas within the CNS or even outside the CNS, such as the spinal cord or other parts of the body. The classification into standard-risk and high-risk categories is essential for treatment planning and prognosis assessment. Patients with standard-risk medulloblastoma may have a more favorable prognosis because of the higher likelihood of complete tumor removal and the absence of metastasis. In contrast, high-risk patients may face a more challenging treatment course and potentially a poorer prognosis due to the presence of metastasis and the difficulty in achieving complete tumor resection.

It’s important to note that treatment approaches for these two risk groups may differ, with high-risk patients typically receiving more intensive therapies to address the increased complexity and aggressiveness of their disease. Additionally, advances in molecular and genetic profiling have led to further subclassifications within medulloblastoma, providing a more nuanced understanding of the disease and guiding personalized treatment decisions.

EpiGe-App

EpiGe

The diagnosis of medulloblastoma incorporates the histologic and molecular subclassification of clinical medulloblastoma samples into wingless (WNT)-activated, sonic hedgehog (SHH)-activated, group 3 and group 4 subgroups. Accurate medulloblastoma subclassification has important prognostic and treatment implications.

Harmony alignment reveals novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes, including photoreceptor and glutamatergic neuron-like cells in molecular subgroups GP3 and GP4, and a specific nodule-associated neuronally-differentiated subpopulation in subgroup molecular SHH. Riemondy et al. definitively chart the spectrum of MB immune cell infiltrates, which include subpopulations that recapitulate developmentally-related neuron-pruning and antigen presenting myeloid cells. MB cellular diversity matching human samples is mirrored in subgroup-specific mouse models of MB 3)

Medulloblastoma, WNT-activated

Medulloblastoma, WNT-activated

Sonic hedgehog medulloblastoma

Sonic hedgehog medulloblastoma.

Medulloblastoma, SHH-activated

Medulloblastoma, SHH-activated

Medulloblastoma, non-WNT/non-SSH

Medulloblastoma non-WNT/non-SSH

Histology

Medulloblastoma histologically defined:

Classic medulloblastoma

Desmoplastic nodular medulloblastoma

Medulloblastoma with extensive nodularity

Medulloblastoma, large cell/anaplastic

Medulloblastoma, NOS.

Localization

see Cerebellar medulloblastomas

see Cerebellopontine angle medulloblastoma

see Multifocal medulloblastoma.

Subgrouping

Immunohistochemistry (IHC)-based and nanoString-based subgrouping methodologies have been independently described as options for medulloblastoma subgrouping, however, they have not previously been directly compared. D’Arcy described the experience with nanoString-based subgrouping in a clinical setting and compare this with our IHC-based results. Study materials included FFPE tissue from 160 medulloblastomas. Clinical data and tumor histology were reviewed. Immunohistochemical-based subgrouping using β-catenin, filamin A and p53 antibodies and nanoString-based gene expression profiling was performed. The sensitivity and specificity of IHC-based subgrouping of WNT and SHH-activated medulloblastomas was 91.5% and 99.54%, respectively. Filamin A immunopositivity highly correlated with SHH/WNT-activated subgroups (sensitivity 100%, specificity 92.7%, p < 0.001). Nuclear β-catenin immunopositivity had a sensitivity of 76.2% and specificity of 99.23% for the detection of WNT-activated tumors. Approximately 23.8% of WNT cases would have been missed using an IHC-based subgrouping method alone. nanoString could confidently predict medulloblastoma subgroup in 93% of cases and could distinguish group 3/4 subgroups in 96.3% of cases. nanoString-based subgrouping allows for a more prognostically useful classification of clinical medulloblastoma samples 4).

Molecular subgrouping was performed by immunohistochemistry (IHC) for beta catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array.

IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation.

Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice 5).

The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon 6).

Pediatric Medulloblastoma

Pediatric Medulloblastoma.

Test and Answers

In the 5th edition of the WHO classification, how are medulloblastomas categorized based on their molecular background? a) Low-risk and high-risk b) Classic and desmoplastic nodular c) WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH d) Standard-risk and high-risk

Which subgroup of medulloblastoma is characterized by activation of the WNT pathway? a) Group 3 b) SHH-activated c) WNT-activated d) Non-WNT/non-SHH

What is the significance of TP53 mutation in SHH medulloblastomas? a) It indicates a better prognosis b) It indicates a worse prognosis c) It has no impact on prognosis d) It classifies the tumor as a WNT-activated subtype

How many subgroups are non-WNT/non-SHH medulloblastomas divided into based on methylation profiling in the 5th edition of the WHO classification? a) 2 b) 4 c) 6 d) 8

What are the clinical risk factors often used for prognosis assessment in medulloblastoma? a) Molecular subgroups b) Histopathological findings c) Age and gender d) Tumor location and size

Which of the following statements is true regarding the classification of medulloblastoma? a) Histopathological classification is the primary method used in the 5th edition of the WHO classification. b) Molecular subgroups are not considered relevant for treatment planning. c) Molecular subgroups guide the development of optimal treatment strategies. d) All medulloblastomas are classified into two main subgroups: WNT and SHH-activated.

What is the main difference between standard-risk and high-risk medulloblastoma? a) The presence of TP53 mutation b) The rate of tumor resection c) The age of the patient d) The presence of metastasis

Which of the following is NOT a method used for molecular subgrouping of medulloblastoma? a) Immunohistochemistry (IHC) b) NanoString Assay c) FISH for MYC amplification d) DNA methylation analysis

What is the advantage of using NanoString Assay for molecular subgrouping of medulloblastoma? a) It can classify older-archived tumor samples. b) It has a higher success rate in classifying tumors. c) It is based on DNA methylation profiling. d) It cannot be used in clinical practice.

Which subgroup of medulloblastoma is characterized by MYC amplification in some cases? a) WNT-activated b) SHH-activated c) Group 3 d) Group 4

Answers:

c) WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH c) WNT-activated b) It indicates a worse prognosis d) 8 c) Age and gender c) Molecular subgroups guide the development of optimal treatment strategies. b) The rate of tumor resection d) DNA methylation analysis a) It can classify older-archived tumor samples. c) Group 3

References

1)

Yamaguchi S, Fujimura M. [Medulloblastoma]. No Shinkei Geka. 2023 Sep;51(5):858-866. Japanese. doi: 10.11477/mf.1436204827. PMID: 37743337.
2)

Sharif Rahmani E, Lawarde A, Lingasamy P, Moreno SV, Salumets A, Modhukur V. MBMethPred: a computational framework for the accurate classification of childhood medulloblastoma subgroups using data integration and AI-based approaches. Front Genet. 2023 Sep 7;14:1233657. doi: 10.3389/fgene.2023.1233657. PMID: 37745846; PMCID: PMC10513500.
3)

Riemondy KA, Venkataraman S, Willard N, Nellan A, Sanford B, Griesinger AM, Amani V, Mitra S, Hankinson TC, Handler MH, Sill M, Ocasio J, Weir SJ, Malawsky DS, Gershon TR, Garancher A, Wechsler-Reya RJ, Hesselberth JR, Foreman NK, Donson AM, Vibhakar R. Neoplastic and immune single cell transcriptomics define subgroup-specific intra-tumoral heterogeneity of childhood medulloblastoma. Neuro Oncol. 2021 Jun 2:noab135. doi: 10.1093/neuonc/noab135. Epub ahead of print. PMID: 34077540.
4)

D’Arcy CE, Nobre LF, Arnaldo A, Ramaswamy V, Taylor MD, Naz-Hazrati L, Hawkins CE. Immunohistochemical and nanoString-Based Subgrouping of Clinical Medulloblastoma Samples. J Neuropathol Exp Neurol. 2020 Jan 30. pii: nlaa005. doi: 10.1093/jnen/nlaa005. [Epub ahead of print] PubMed PMID: 32053195.
5)

Kaur K, Jha P, Pathak P, Suri V, Sharma MC, Garg A, Suri A, Sarkar C. Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres. J Neurooncol. 2019 May 18. doi: 10.1007/s11060-019-03187-y. [Epub ahead of print] PubMed PMID: 31104222.
6)

Mullarkey MP, Nehme G, Mohiuddin S, et al. Posttreatment Maturation of Medulloblastoma into Gangliocytoma: Report of 2 Cases [published online ahead of print, 2020 Sep 3]. Pediatr Neurosurg. 2020;1-10. doi:10.1159/000509520

Glioblastoma prognostic markers

Glioblastoma prognostic markers

Latest PubMed Glioblastoma prognostic markers related articles

Glioblastoma (GBM) is an aggressive form of brain cancer, and predicting patient outcomes is a complex task. Prognostic markers are factors or characteristics that can help healthcare professionals estimate a patient’s likely disease course and survival. In the context of glioblastoma, several prognostic markers have been studied. Here are some of them:

Age: Increasing age is a well-established negative prognostic marker in glioblastoma. Older patients often have poorer outcomes.

Karnofsky Performance Score (KPS): This is a measure of a patient’s functional impairment and general well-being. A lower KPS score is associated with poorer prognosis.

Extent of Surgical Resection: The degree to which the tumor can be surgically removed is a significant prognostic factor. More extensive resection is associated with better outcomes.

O6-methylguanine-DNA Methyltransferase (MGMT) Methylation: Methylation of the MGMT gene promoter is associated with better responses to chemotherapy and improved survival.

Corticosteroid Use: The use of corticosteroids is associated with poor prognosis in glioblastoma patients.

Density of White Matter Tracts: Recent research has suggested that the density of white matter tracts in the brain near the tumor may be a prognostic marker. Lower tract density may indicate longer survival.

STAT5b: STAT5b activation is associated with poorer survival in glioblastoma patients.

SPTSSA Expression: SPTSSA expression may serve as a prognostic biomarker for glioma patients.

Lymphopenia: Baseline lymphopenia (a low lymphocyte count) is associated with worse overall survival in elderly glioblastoma patients.

c-Met and VEGFR2: Overexpression of c-Met and VEGFR2 may predict poorer responses to anti-angiogenic therapies in glioblastoma.

SII (Systemic Immune-Inflammation Index) and AGR (Albumin-to-Globulin Ratio): High SII and low AGR values are promising prognostic markers for identifying high-grade glioma (HGG) patients with poor prognoses.

ALK (Anaplastic Lymphoma Kinase): The role of ALK as a prognostic marker in glioblastoma is not well-established and remains controversial.

ATP-Binding Cassette Transporters: The activity of ATP-binding cassette transporters may impact prognosis by reducing drug penetration into tumor cells, but their use as isolated prognostic markers is not supported.

Tumor Geometry: Tumor shape and geometric heterogeneity can be used as prognostic markers. Patients with tumors exhibiting certain geometric characteristics may have better prognoses.

Neurologic Status: A proposed neurologic index may help predict poor outcomes in glioblastoma patients receiving tumor resection.

It’s important to note that glioblastoma is a complex and heterogeneous disease, and multiple factors can influence patient outcomes. Prognostic markers are used in combination to provide a more accurate prediction of prognosis. Additionally, ongoing research continues to uncover new markers and refine our understanding of glioblastoma prognosis.

Prognostic markers in glioblastoma are complex. In addition to previously recognized prognostic variables such as age and Karnofsky performance score, tumor size, total resection and proliferative index were identified as predictors of survival in a series of patients with glioblastoma multiforme 1).

Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells.

The most consistent and well-described clinical prognostic factors associated with poor survival include: increasing age, poor performance status (PS), low degree of surgical resection of the tumor, and the use of corticosteroids 2) 3) 4) 5)

Salvalaggio et al. examined two Groups of Patients: The first group, called the “discovery cohort,” included 112 patients from Italy who had surgery between February 2015 and November 2020. The second group, known as the “replicative cohort,” included 70 patients from Germany who had surgery between September 2012 and November 2015.

What They Measured: The researchers were interested in something called “white matter tracts” in the patients’ brains. They measured how dense or crowded these tracts were in the area where the GBM was located.

Main Findings:

In the first group (discovery cohort), they found that the density of these white matter tracts was related to how long patients lived after surgery. When the tracts were less dense, patients tended to live longer.

This relationship between white matter tract density and survival was stronger and more consistent compared to other factors that are commonly used to predict how GBM patients will do, like age, performance status, a specific type of DNA change (O6-methylguanine-DNA methyltransferase methylation), and how much of the tumor was removed during surgery. They confirmed these findings in the second group (replicative cohort), which makes the results more reliable. Using the density of white matter tracts, they were able to predict whether a patient would have a higher or lower chance of surviving for at least 18 or 24 months after surgery with a high level of accuracy. Conclusion: This study suggests that the density of white matter tracts in the area around the GBM may be a useful predictor of how long patients with GBM will live after surgery. It could be valuable in clinical trials and medical practice to help doctors make decisions about treatment and prognosis.

In simple terms, the study found that the structure of certain brain pathways is related to how long patients with brain cancer live after surgery. This could be a helpful tool for doctors when treating these patients. 6).

STAT5b

STAT5b is frequently activated in Glioblastoma and correlates inversely with patient survival. It does not contribute to the growth and resistance of these tumors and is thus rather a potential prognostic marker than a therapeutic target in these tumors 7).

SPTSSA

SPTSSA expression might be used as a prognostic biomarker for glioma and a potential target for novel glioma therapy 8)

Lymphopenia

Baseline lymphopenia is associated with worse OS, which may be considered a prognostic biomarker for elderly glioblastoma outcome patients 9)

c-Met and VEGFR2

c-Met and VEGFR2 overexpression have a role in the development of glioblastoma early resistance and might predict poorer responses to anti-angiogenic therapies. 10)

Liang et al., demonstrated that high SII and low AGR values may serve as promising prognostic markers to identify HGG patients with poor prognosis 11).

ALK

Data on the prognostic role of ALK in Glioblastoma are very limited and remain controversial 12) 13) 14).

ATP-binding cassette transporter

The activity of ATP-binding cassette transporters severely reduces the amount of therapeutics that penetrates the tumor cells. Roy et al. hypothesized that ABC transporter expression could correlate with survival surrogates. They assessed the expression of four commonly expressed ABC transporters in GBM samples and investigated if mRNA levels could serve as a prognostic biomarker.

The expression of the four ABC transporters evaluated would not be suitable prognostic biomarkers. They believe that when estimating prognosis, the plethora of mechanisms implicated in chemoresistance should be analyzed as a multi-facetted entity rather than isolated units 15).

Geometry

Patients with tumours having small geometric heterogeneity and/or spherical rim widths had significantly better prognosis. These imaging biomarkers have a strong individual and combined prognostic value for Glioblastoma patients 16) 17).

Multi-channel MR image derived texture features, tumor shape, and volumetric features, and patient age were obtained for 163 Glioblastoma patients. In order to assess the impact of tumor shape features on OS prediction, two feature sets, with and without tumor shape features, were created. For the feature set with tumor shape features, the mean prediction error (MPE) was 14.6 days and its 95% confidence interval (CI) was 195.8 days. For the feature set excluding shape features, the MPE was 17.1 days and its 95% CI was observed to be 212.7 days. The coefficient of determination (R2) value obtained for the feature set with shape features was 0.92, while it was 0.90 for the feature set excluding shape features. Although marginal, the inclusion of shape features improves OS prediction in Glioblastoma patients. The proposed OS prediction method using regression provides good accuracy and overcomes the limitations of Glioblastoma OS classification, like choosing data-derived or pre-decided thresholds to define the OS groups. Graphical abstract Two feature sets: with and without tumor shape features were extracted from T1-weighted contrast-enhanced, T2-weighted and FLAIR MRI. These feature sets were analyzed using the Mean Prediction Error (MPE) and its 95% Confidence Interval (CI) obtained from the Bland-Altman plot, along with the coefficient of determination (R2) value to assess the impact of tumor shape features on overall survival prediction of glioblastoma multiforme patients 18).

Neurologic status

Neurologic status is one of the major prognostic factors; however, no consensus exists on a clinical index for predicting patient outcomes.

One proposed neurologic index enables significant identification of glioblastoma patients receiving tumor resection with poor outcomes, independent of other common prognostic factors. Using the index provides a preoperative predictor of prognosis in glioblastoma patients receiving tumor resection 19).

Test and Answers

What are prognostic markers used for in medicine? a) To diagnose diseases b) To predict the likely outcome of a disease in a patient c) To treat diseases d) To prevent diseases

In glioblastoma, which of the following factors were identified as predictors of survival in addition to age and performance score? a) Blood pressure and cholesterol levels b) Tumor size and total resection c) DNA mutations and tumor grade d) Blood type and genetic markers

What did Salvalaggio et al. measure in the brains of glioblastoma patients to assess prognosis? a) Blood flow b) White matter tract density c) Tumor size d) Brain volume

What was the main finding of the study conducted by Salvalaggio et al. regarding white matter tracts? a) White matter tract density was unrelated to patient survival. b) Patients with denser white matter tracts tended to live longer. c) White matter tracts were unrelated to tumor location. d) White matter tracts were unrelated to age.

Which of the following is NOT mentioned as a clinical prognostic factor associated with poor survival in glioblastoma? a) Increasing age b) Poor performance status (PS) c) Extent of surgical resection d) Use of corticosteroids

What is the potential role of STAT5b in glioblastoma? a) It contributes to tumor growth and resistance. b) It is a therapeutic target for glioblastoma. c) It is a prognostic marker. d) It has no role in glioblastoma.

What is SPTSSA expression potentially used for in glioma? a) Diagnosis b) Prognostic marker c) Treatment d) Disease prevention

What is lymphopenia considered as in elderly glioblastoma outcome patients? a) A marker of good prognosis b) A marker of disease progression c) A prognostic biomarker for poor outcome d) A diagnostic marker

What do c-Met and VEGFR2 overexpression predict in glioblastoma? a) Positive response to anti-angiogenic therapies b) Increased tumor size c) Resistance to chemotherapy d) No impact on patient outcomes

Which statement about ALK as a prognostic marker in glioblastoma is true? a) It is a well-established prognostic marker. b) Data on its prognostic role are limited and controversial. c) It is a therapeutic target for glioblastoma. d) It is not associated with patient survival.

What are prognostic markers used for in medicine? Answer: b) To predict the likely outcome of a disease in a patient

In glioblastoma, which of the following factors were identified as predictors of survival in addition to age and performance score? Answer: b) Tumor size and total resection

What did Salvalaggio et al. measure in the brains of glioblastoma patients to assess prognosis? Answer: b) White matter tract density

What was the main finding of the study conducted by Salvalaggio et al. regarding white matter tracts? Answer: b) Patients with denser white matter tracts tended to live longer.

Which of the following is NOT mentioned as a clinical prognostic factor associated with poor survival in glioblastoma? Answer: d) Use of corticosteroids

What is the potential role of STAT5b in glioblastoma? Answer: c) It is a prognostic marker.

What is SPTSSA expression potentially used for in glioma? Answer: b) Prognostic marker

What is lymphopenia considered as in elderly glioblastoma outcome patients? Answer: c) A prognostic biomarker for poor outcome

What do c-Met and VEGFR2 overexpression predict in glioblastoma? Answer: a) Positive response to anti-angiogenic therapies

Which statement about ALK as a prognostic marker in glioblastoma is true? Answer: b) Data on its prognostic role are limited and controversial.

1)

Donato V, Papaleo A, Castrichino A, Banelli E, Giangaspero F, Salvati M, Delfini R. Prognostic implication of clinical and pathologic features in patients with glioblastoma multiforme treated with concomitant radiation plus temozolomide. Tumori. 2007 May-Jun;93(3):248-56. PubMed PMID: 17679459.
2)

Gittleman H, Lim D, Kattan MW, Chakravarti A, Gilbert MR, Lassman AB, et al. An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825. Neuro Oncol (2017) 19(5):669–77. doi: 10.1093/neuonc/now208
3)

Helseth R, Helseth E, Johannesen TB, Langberg CW, Lote K, Ronning P, et al. Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme. Acta Neurol Scand (2010) 122(3):159–67. doi: 10.1111/j.1600-0404.2010.01350.x
4)

Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol (2008) 9(1):29–38. doi: 10.1016/S1470-2045(07)70384-4
5)

Li H, He Y, Huang L, Luo H, Zhu X. The Nomogram Model Predicting Overall Survival and Guiding Clinical Decision in Patients With Glioblastoma Based on the SEER Database. Front Oncol (2020) 10:1051:1051. doi: 10.3389/fonc.2020.01051
6)

Salvalaggio A, Pini L, Gaiola M, Velco A, Sansone G, Anglani M, Fekonja L, Chioffi F, Picht T, Thiebaut de Schotten M, Zagonel V, Lombardi G, D’Avella D, Corbetta M. White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma. JAMA Neurol. 2023 Sep 25. doi: 10.1001/jamaneurol.2023.3284. Epub ahead of print. PMID: 37747720.
7)

Dubois N, Berendsen S, Tan K, Schoysmans L, Spliet W, Seute T, Bours V, Robe PA. STAT5b is a marker of poor prognosis, rather than a therapeutic target in glioblastomas. Int J Oncol. 2022 Oct;61(4):124. doi: 10.3892/ijo.2022.5414. Epub 2022 Sep 7. PMID: 36069226.
8)

Wang Z, Ge X, Shi J, Lu B, Zhang X, Huang J. SPTSSA Is a Prognostic Marker for Glioblastoma Associated with Tumor-Infiltrating Immune Cells and Oxidative Stress. Oxid Med Cell Longev. 2022 Aug 24;2022:6711085. doi: 10.1155/2022/6711085. PMID: 36062185; PMCID: PMC9434331.
9)

Song AJ, Ding K, Alnahhas I, Laperriere NJ, Perry J, Mason WP, Winch C, O’Callaghan CJ, Menten JJ, Brandes AA, Phillips C, Fay MF, Nishikawa R, Osoba D, Cairncross JG, Roa W, Wick W, Shi W. Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial. Neurooncol Adv. 2021 Oct 15;3(1):vdab153. doi: 10.1093/noajnl/vdab153. Erratum in: Neurooncol Adv. 2022 Jan 27;4(1):vdac011. PMID: 34765975; PMCID: PMC8577525.
10)

Carvalho B, Lopes JM, Silva R, Peixoto J, Leitão D, Soares P, Fernandes AC, Linhares P, Vaz R, Lima J. The role of c-Met and VEGFR2 in glioblastoma resistance to bevacizumab. Sci Rep. 2021 Mar 16;11(1):6067. doi: 10.1038/s41598-021-85385-1. PMID: 33727583.
11)

Liang R, Li J, Tang X, Liu Y. The prognostic role of preoperative systemic immune-inflammation index and albumin/globulin ratio in patients with newly diagnosed high-grade glioma. Clin Neurol Neurosurg. 2019 Jun 24;184:105397. doi: 10.1016/j.clineuro.2019.105397. [Epub ahead of print] PubMed PMID: 31306893.
12)

Elsers D, Temerik DF, Attia AM, Hadia A, Hussien MT. Prognostic role of ALK-1 and h-TERT expression in glioblastoma multiforme: correlation with ALK gene alterations. J Pathol Transl Med. 2021;55:212–224.
13)

Karagkounis G, Stranjalis G, Argyrakos T, et al. Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome. J Clin Pathol. 2017;70:593–9.
14)

Franceschi E, De Biase D, Di Nunno V, et al. The clinical and prognostic role of ALK in glioblastoma. Pathol Res Pract. 2021;221:153447.
15)

Roy LO, Lemelin M, Blanchette M, Poirier MB, Aldakhil S, Fortin D. Expression of ABCB1, ABCC1 and 3 and ABCG2 in glioblastoma and their relevance in relation to clinical survival surrogates. J Neurooncol. 2022 Nov 7. doi: 10.1007/s11060-022-04179-1. Epub ahead of print. PMID: 36342588.
16)

Pérez-Beteta J, Martínez-González A, Molina D, Amo-Salas M, Luque B, Arregui E, Calvo M, Borrás JM, López C, Claramonte M, Barcia JA, Iglesias L, Avecillas J, Albillo D, Navarro M, Villanueva JM, Paniagua JC, Martino J, Velásquez C, Asenjo B, Benavides M, Herruzo I, Delgado MD, Del Valle A, Falkov A, Schucht P, Arana E, Pérez-Romasanta L, Pérez-García VM. Glioblastoma: does the pre-treatment geometry matter? A postcontrast T1 MRI-based study. Eur Radiol. 2017 Mar;27(3):1096-1104. doi: 10.1007/s00330-016-4453-9. PubMed PMID: 27329522.
17)

Molina D, Pérez-Beteta J, Luque B, Arregui E, Calvo M, Borrás JM, López C, Martino J, Velasquez C, Asenjo B, Benavides M, Herruzo I, Martínez-González A, Pérez-Romasanta L, Arana E, Pérez-García VM. Tumour heterogeneity in glioblastoma assessed by MRI texture analysis: a potential marker of survival. Br J Radiol. 2016 Jun 20:20160242. [Epub ahead of print] PubMed PMID: 27319577.
18)

Sanghani P, Ang BT, King NKK, Ren H. Regression based overall survival prediction of glioblastoma multiforme patients using a single discovery cohort of multi-institutional multi-channel MR images. Med Biol Eng Comput. 2019 May 18. doi: 10.1007/s11517-019-01986-z. [Epub ahead of print] PubMed PMID: 31104273.
19)

Liang HK, Wang CW, Tseng HM, Huang CY, Lan KH, Chen YH, You SL, Cheng JC, Cheng AL, Kuo SH. Preoperative prognostic neurologic index for glioblastoma patients receiving tumor resection. Ann Surg Oncol. 2014 Nov;21(12):3992-8. doi:10.1245/s10434-014-3793-4. Epub 2014 May 23. PubMed PMID: 24854491.

DNA methylation in intracranial aneurysm pathogenesis

DNA methylation in intracranial aneurysm pathogenesis

Latest DNA methylation in intracranial aneurysm pathogenesis PubMed related Articles

Epigenetic modifications

Epigenetic modifications, including DNA methylation, are thought to play a role in the intracranial aneurysm pathogenesis. Here’s how:

Gene Expression Regulation: DNA methylation can regulate the expression of genes involved in various aspects of vascular biology, including inflammation, vascular smooth muscle cell function, and extracellular matrix remodeling. Aberrant DNA methylation patterns in these genes may contribute to the weakening of blood vessel walls and the development of aneurysms.

Inflammation and Immune Response: Chronic inflammation and immune system activation are associated with IA development. DNA methylation can influence the expression of genes involved in the regulation of immune responses. Altered DNA methylation patterns in immune-related genes may contribute to the chronic inflammation observed in IA pathogenesis.

Vascular Smooth Muscle Cell Dysfunction: Proper functioning of vascular smooth muscle cells (VSMCs) is essential for maintaining blood vessel integrity. Dysregulated DNA methylation in genes related to VSMC contractility and function may lead to VSMC dysfunction and contribute to aneurysm formation.

Extracellular Matrix Remodeling: The extracellular matrix (ECM) provides structural support to blood vessel walls. DNA methylation can affect the expression of genes involved in ECM remodeling and integrity. Changes in DNA methylation patterns may disrupt the balance between ECM synthesis and degradation, making blood vessels more susceptible to aneurysm formation.

Risk Factors and Environmental Influences: Environmental factors, such as smoking, hypertension, and inflammation, are known risk factors for IAs. These factors can influence DNA methylation patterns in genes related to vascular health, further contributing to IA development in susceptible individuals.

Research in this area is ongoing, and studies are actively exploring the epigenetic mechanisms, including DNA methylation, that underlie IA pathogenesis. Identifying specific DNA methylation changes associated with IAs may lead to the development of novel diagnostic markers or therapeutic targets for this condition. However, it’s important to note that IA development is likely influenced by a complex interplay of genetic, epigenetic, and environmental factors, and more research is needed to fully understand the precise mechanisms involved.

Maimaiti et al. employed a comprehensive bioinformatics investigation of DNA methylation in IA, utilizing a transcriptomics-based methodology that encompassed 100 machine learning algorithms, genome-wide association study (GWAS), Mendelian randomization (MR), and summary-data-based Mendelian randomization (SMR). The sophisticated analytical strategy allowed for a systematic assessment of differentially methylated genes and their implications on the onset, progression, and rupture of IA.

They identified DNA methylation-related genes (MRGs) and associated molecular pathways, and the MR and SMR analyses provided evidence for potential causal links between the observed DNA methylation events and IA predisposition.

These insights not only augment our understanding of the molecular underpinnings of IA but also underscore potential novel biomarkers and therapeutic avenues. Although the study faces inherent limitations and hurdles, it represents a groundbreaking initiative in deciphering the intricate relationship between genetic, epigenetic, and environmental factors implicated in IA pathogenesis 1).

Gene expression

The IL6/JAK/STAT signaling pathway (ISP) is significant positively correlated with intracranial aneurysm onset. The biological function of the ISP is positively correlated with that of the estrogen response pathway (ERP), and is significantly associated with immune cells activities. CSF2RB, FAS, IL6, PTPN1, STAT2, TGFB1 of the ISP gene set and ALDH3A2, COX6C, IGSF1, KRT18, MICB, NPY1R of the ERP gene set were proved to be the characteristic genes. The STAT2 gene can be the potential biomarker of IA onset. The immune score of IA samples was significantly higher than the controls. The STAT2 gene expression is associated with infiltration of immune cells. The WGCNA results were consistent with our finds. Acetaminophen can be a potential therapeutic drug for IA targeting STAT2

They identified that the ISP was one of the most significant positively correlated pathways in IA onset, and it was activated in this process concordant with the ERP and immune responses. Except for beneficial effects, complex and multiple roles of estrogen may be involved in IA formation. STAT2 could be a potential biomarker and a promising therapeutic target of IA pathogenesis 2).

Inflammation and Immune Response

Saccular intracranial aneurysm rupture leads to subarachnoid hemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the Saccular intracranial aneurysm wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in saccular intracranial aneurysm (sIAs) has remained unexplored. Huuska et al. studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for Lymphatic endothelial cells (LEC)markers. Of these LEC-markers, both extracellular and intracellular LYVE1, podoplanin, VEGFR-3, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the saccular intracranial aneurysm pathogenesis 3).

Vascular Smooth Muscle Cell Dysfunction

Dysfunction of vascular smooth muscle cells (VSMCs) plays a critical role in the intracranial aneurysm pathogenesis (IA). Circular RNAs (circRNAs) have been implicated by reducing microRNA (miRNA) activity. Qin et al. investigated the precise roles of circRNA ADP ribosylation factor interacting protein 2 (circ-ARFIP2, circ_0021001) in VSMC dysfunction. The levels of circ-ARFIP2, miR-338-3p and kinase insert domain receptor (KDR) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Ribonuclease (RNase) R and subcellular fractionation assays were used to assess the stability and localization of circ-ARFIP2, respectively. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell invasion was measured by transwell assay. Cell proliferation was gauged by 5-Ethynyl-2′-Deoxyuridine (EdU) assay. Cell migration was evaluated by transwell and wound-healing assays. Targeted correlations among circ-ARFIP2, miR-338-3p and KDR were validated by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Circ-ARFIP2 and KDR were underexpressed and miR-338-3p was overexpressed in the arterial wall tissues of IA patients. Overexpression of circ-ARFIP2 in human umbilical artery smooth muscle cells (HUASMCs) showed a significant promotion in cell proliferation, migration and invasion. Mechanistically, circ-ARFIP2 targeted miR-338-3p, and circ-ARFIP2 regulated cell behaviors by miR-338-3p. KDR was a direct and functional target of miR-338-3p. Moreover, KDR was a downstream effector of circ-ARFIP2 function. Circ-ARFIP2 regulated KDR expression by targeting miR-338-3p.The findings demonstrated that the increased level of circ-ARFIP2 enhanced HUASMC proliferation, migration and invasion at least in part by the miR-338-3p/KDR axis 4).

Extracellular Matrix Remodeling

Pathogenic inflammation contributes to aneurysm formation by mediating the destruction of the endothelium and the extracellular matrix and promoting the pathogenic proliferation of smooth muscle cells. In mouse models, tolerance-inducing T regulatory (Treg) cells could significantly reduce the incidence and severity of aneurysms. Hence, it should be investigated why in human intracranial aneurysm (IA) patients, Treg cells failed to provide protection against aneurysm formation. In this study, the frequency and function of Treg cells in IA patients were examined. The frequency of Foxp3+ Treg cells was significantly lower in IA patients than in healthy controls. This downregulation was only specific to the Treg subset of CD4+ T cells, as the frequency of total CD4+ T cell was increased in IA patients. Subsequently, we found that the expressions of Treg-associated molecules, including Foxp3, CTLA-4, TGF-β, and IL-10, were significantly lower in Foxp3+ Treg cells from IA patients than in Foxp3+ Treg cells from healthy controls. In both healthy controls and IA patients, Foxp3+ Treg cells were distinguished into a more potent Tim-3+ subset and a less potent Tim-3- subset. The Tim-3+ subset of Foxp3+ Treg cells was significantly reduced in IA patients. Signaling via IL-2, IL-7, IL-15 and IL-21 was shown to promote Tim-3 upregulation in CD4+ and CD8+ T cells. Interestingly, we found that Tim-3 could be upregulated in Treg cells via the same mechanism, but compared to the Treg cells from healthy controls, the Treg cells from IA patients presented defects in Tim-3 upregulation upon cytokine stimulation. Together, our results demonstrated that Foxp3+ Treg cells in IA patients presented reduced function, which was associated with a defect in Tim-3 upregulation 5).

Test and Answers

here’s a multiple-choice test based on the information provided about epigenetic modifications and their role in intracranial aneurysm (IA) pathogenesis:

What is the primary role of DNA methylation in gene expression regulation?

a) Activating gene expression b) Repressing gene expression c) Altering DNA sequences d) Enhancing protein translation

In the context of IA pathogenesis, what role does DNA methylation play in vascular biology?

a) Promoting blood vessel dilation b) Reducing inflammation c) Regulating immune responses d) Weakening blood vessel walls

Which of the following is NOT a component of the extracellular matrix (ECM)?

a) Collagen b) Elastin c) Fibronectin d) Lymphocytes

How do matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) contribute to ECM remodeling?

a) MMPs inhibit ECM degradation, while TIMPs promote it. b) Both MMPs and TIMPs promote ECM degradation. c) MMPs promote ECM degradation, while TIMPs inhibit it. d) MMPs and TIMPs have no role in ECM remodeling.

What type of cells are responsible for synthesizing and secreting ECM components?

a) Neurons b) Vascular smooth muscle cells c) Red blood cells d) Epithelial cells

How does DNA methylation relate to the risk factors and environmental influences associated with IA development?

a) It decreases the risk of IA. b) It has no impact on IA risk factors. c) It can be influenced by environmental factors and may contribute to IA development. d) It is solely determined by genetic factors.

What is the primary role of circular RNAs (circRNAs) in the context of vascular smooth muscle cell (VSMC) dysfunction in IA?

a) Promoting VSMC proliferation b) Suppressing VSMC migration c) Inhibiting DNA methylation d) Regulating immune responses

What is the significance of the IL6/JAK/STAT signaling pathway in IA onset?

a) It has no relevance to IA. b) It negatively regulates immune responses. c) It is positively correlated with IA onset and influences immune cell activities. d) It directly causes IA formation.

What is the main function of T regulatory (Treg) cells in the context of IA?

a) Promoting inflammation b) Reducing the severity of IA c) Causing aneurysm formation d) Increasing the frequency of IA

How do Tim-3+ subsets of Foxp3+ Treg cells differ between IA patients and healthy controls?

a) They are more potent in IA patients. b) They are less potent in IA patients. c) They are equally potent in both groups. d) They have no impact on IA.

Answers:

b) Repressing gene expression d) Weakening blood vessel walls d) Lymphocytes c) MMPs promote ECM degradation, while TIMPs inhibit it. b) Vascular smooth muscle cells c) It can be influenced by environmental factors and may contribute to IA development. a) Promoting VSMC proliferation c) It is positively correlated with IA onset and influences immune cell activities. b) Reducing the severity of IA b) They are less potent in IA patients

1)

Maimaiti A, Turhon M, Abulaiti A, Dilixiati Y, Zhang F, Axieer A, Kadeer K, Zhang Y, Maimaitili A, Yang X. DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data. J Transl Med. 2023 Sep 23;21(1):660. doi: 10.1186/s12967-023-04512-w. PMID: 37742034.
2)

Wu A, Zhao C, Mou S, Li S, Cui X, Zhang R. Integrated analysis identifies the IL6/JAK/STAT signaling pathway and the estrogen response pathway associated with the pathogenesis of intracranial aneurysms. Front Immunol. 2022 Nov 14;13:1046765. doi: 10.3389/fimmu.2022.1046765. PMID: 36451838; PMCID: PMC9702531.
3)

Huuska N, Netti E, Lehti S, Kovanen PT, Niemelä M, Tulamo R. Lymphatic vessels are present in human saccular intracranial aneurysms. Acta Neuropathol Commun. 2022 Sep 5;10(1):130. doi: 10.1186/s40478-022-01430-8. PMID: 36064651.
4)

Qin K, Tian G, Zhou D, Chen G. Circular RNA circ-ARFIP2 regulates proliferation, migration and invasion in human vascular smooth muscle cells via miR-338-3p-dependent modulation of KDR. Metab Brain Dis. 2021 Apr 10. doi: 10.1007/s11011-021-00726-3. Epub ahead of print. PMID: 33837886.
5)

Zhang HF, Liang GB, Zhao MG, Zhao GF, Luo YH. Patients with intracranial aneurysms presented defects in regulatory T cells, which were associated with impairment in Tim-3 upregulation. Int Immunopharmacol. 2018 Sep 19;64:350-355. doi: 10.1016/j.intimp.2018.09.020. [Epub ahead of print] PubMed PMID: 30243071.

Lenticulostriate artery aneurysm

Lenticulostriate artery aneurysm

Charcot-Bouchard aneurysms are minute aneurysms (microaneurysms) in the brain that occur in small penetrating blood vessels with a diameter that is less than 300 micrometers. The most common vessels involved are the lenticulostriate branches (LSA) of the middle cerebral artery (MCA). LSAs originate from the MCA just before its bifurcation, and they can vary between 2 to 12 in number (average 8.1). Most branches arise medially (99.2%), close to the internal carotid artery. They supply the basal ganglia, and more specifically, the putamen and caudate, followed by the thalamus, pons, and cerebellum.

Charcot-Bouchard aneurysms are named after the French physician Jean-Martin Charcot and his student Charles Joseph Bouchard. In the 19th century, Bouchard discovered these aneurysms during his research under Charcot. Cole and Yates strengthened Charcot and Bouchard’s work by demonstrating that aneurysms truly exist using microangiographic techniques in the 1960s. However, it has been a topic of lively debate if it is, in fact, the rupture of these aneurysms that are responsible for the intracerebral bleeds.

Individuals with chronic systemic hypertension are at high risk of developing atrophy of the outer muscular layer. With the loss of integrity of the vessel wall, microaneurysms develop in LSA, which are at high risk of rupture. Bleeding of aneurysms into the deep structures of the brain parenchyma is also referred to as intraparenchymal hemorrhage or, more broadly, as intracerebral hemorrhage. Clinically the deficits that present can point towards the location of the bleed. The first-line diagnostic modality for these patients is a non-contrast computed tomography (CT) of the head to visualize the bleed. Depending on the severity and location of the hemorrhage, the treatment options vary from observation to neurosurgical intervention 1)

Epidemiology

Aneurysms of lenticulostriate artery (LSA) perforators are uncommon. There are few data on their natural history, and opinions differ on the treatment strategies.

Classification

Aneurysms of the lenticulostriate artery (LSA) are rare lesions that are categorized into either proximal (at the junction of the middle cerebral artery trunk) or distal (within the basal ganglia).

Vargas et al, report a case series and summarize the most recent literature with current treatment recommendations, and propose an anatomical classification for these entities.

A retrospective review of all patients who were diagnosed with an LSA aneurysm on cerebral angiogram was performed. An extensive online literature search was performed to identify other studies reporting on the diagnosis and management of ruptured and unruptured lenticulostriate aneurysms.

48 cases were identified in the literature and reviewed: 27 patients were treated surgically; five cases were treated with endovascular therapy; two cases underwent gamma knife radiosurgery; and 13 cases were managed conservatively.

They classified these aneurysms into three types: type 1 describes aneurysms arising from the middle cerebral artery next to a perforating LSA; type 2 is an LSA aneurysm from which the perforating artery or arteries arise-the type 2A subtype is one in which the aneurysm neck incorporates the origin of the perforating arteries and the type 2B describes perforating arteries arising from the dome of the aneurysm; and type 3 describes a fusiform aneurysm beyond the first loop or turn of an LSA.

LSA aneurysms are rare entities that present several treatment challenges 2).

These lesions have been reported against the background of a diverse array of pathologies including hypertension, vascular malformations, moyamoya disease, substance abuse, systemic lupus erythematosus, ventricular neurocytoma, and Sneddon syndrome; however, most cases are idiopathic.

The ruptured aneurysm has a high risk of re-bleeding with a consequent marked decreased risk of patient survival and functional independence, for proximal LSA aneurysm, neurosurgery has been the mainstay of treatment, but its efficacy remains controversial.

Development of devices and improved operator experience have rendered endovascular coiling an alternative and acceptable option for such patients 3).

Systematic Reviews

2021

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a literature search was conducted in the PubMed, Cochrane, EBSCOhost, Scopus, Web of Science, and ProQuest search engines to identify reported studies of LSA aneurysms until July 1, 2020. A descriptive analysis was performed.

Results: A total of 71 studies with 112 cases of LSA aneurysms were included. Patient age ranged from 2 months to 83 years (median, 44.5 years). Male and female patients were affected similarly (49% and 51%, respectively). The most common presentation was aneurysmal rupture (78%), and headache was the most frequently reported symptom (36%). Overall, 48% of the patients had undergone underwent surgical treatment, 30% conservative management, 21% endovascular treatment, and 1% radiosurgery. Four patients died, all of whom had presented with aneurysmal rupture.

Hinojosa-Gonzalez et al. summarized the reported cases of LSA aneurysms, with their clinical presentation, management, and outcomes, for physicians who may be confronted with this diagnosis. Future studies that use available classification systems and include as much detail as possible should be encouraged to fully elucidate the optimal management strategy for these patients 4).

Case reports

An 81-year-old woman developed consciousness disturbance. Computed tomography revealed hemorrhage in the right caudate nucleus and lateral ventricles. Three-dimensional computed tomographic angiography demonstrated only an aneurysm at the basilar artery. On angiography, on the sixth day, an aneurysm at the right lenticulostriate artery was demonstrated. Then, the aneurysm disappeared on three-dimensional computed tomographic angiography on the 15th day. Subsequent radiological examinations revealed no vascular anomaly in the right lenticulostriate artery.

An aneurysm at this location can show dynamic changes based on radiological findings. Close radiological observation is necessary 5).

Lenticulostriate artery aneurysm in moyamoya disease

Case series

Patients with moyamoya disease and LSA aneurysm rupture admitted to Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medicine School from October 2012 to March 2015 were analyzed retrospectively. They were followed up for 1 year. The modified Rankin Scale (mRS) was used to evaluate the outcomes, and 0-2 was defined as good outcome. The demographic characteristics, image anatomical features, treatment schemes, and outcomes of the patients were summarized. The Pubmed database was used to retrieve other similar studies, which combined with this group of cases for analysis. Results A total of 10 patients were enrolled, 2 males and 8 females, aged 29-72 years, with an average of 43. 6 years. All cases were intracranial hemorrhage, including 3 cases of cerebral hemorrhage, 6 cases of ventricular hemorrhage, and 1 case of subarachnoid hemorrhage. At the time of admission, 7 patients had disturbance of consciousness, and 3 patients underwent emergency extraventricular drainage. Among them, 5 patients received endovascular embolization, 4 had good outcome, 1 had mild neurological deficit (mRS score 3); 2 received surgical treatment, all had good outcome; 3 received conservative treatment, all had re-bleeding, 2 died, and 1 had severe disability (mRS score 4). Fourteen eligible articles were included, and a total of 18 patients were included in the analysis: surgical treatment in 7 cases, endovascular treatment in 6 cases, and conservative treatment in 5 cases (self-healing in 1 case). According to the data of this group of patients and literature reports, the good outcome rate of the patients with early interventional embolization or craniotomy clipping treatment was significantly higher than that of conservative treatment (70. 6％vs. 22. 2％; P = 0. 038). Conclusion There is a certain risk of conservative treatment of Moyamoya disease complicated with LSA aneurysm rupture and requires active treatment. Interventional embolization of the parent artery or surgically clipping of aneurysm can effectively improve the clinical outcome of such patients. Interventional embolization of the parent artery and aneurysm can be selected simultaneously if the condition of the parent artery is allowed. Surgery can be selected when the condition of parent artery is poor and the aneurysm is located in the superficial part 6).

Case reports

A case report of a child with a ruptured distal lenticulostriate artery aneurysm that required careful decision-making and preparation before microsurgical excision. MR angiography was performed in the planning phase and neuronavigation was used during surgery. The surgery was a success, with the patient suffering minimal postoperative focal deficit, which later turned out to be transient 7).

A 42-year-old woman presented with a sudden onset of dysarthria and right hemiparesis. Putaminal hemorrhage from a ruptured aneurysm in the left LSA was detected. Angiographically, moyamoya vessels were revealed. The aneurysm in the left LSA was saccular type and seemed to be related to Moyamoya disease. As the aneurysm was successfully approached with a microcatheter, coil embolization without parent artery occlusion was performed. Rebleeding from the embolized aneurysm in the LSA did not occur. This is the first report of a ruptured LSA aneurysm embolized using coils through a flow-guiding microcatheter without parent artery occlusion in a case of Moyamoya disease 8).

One case of ruptured LSA aneurysm is related to Moyamoya disease (MMD). Surgical treatment of this aneurysm is challenging because of its deep location and complex neural structures around the LSA. They report one case treated with endovascular Onyx embolization, successfully and review the LSA aneurysm associated with MMD 9)

A 49-year-old man who presented with a hemorrhage in the basal ganglia. An angiogram revealed a distal LSA aneurysm in the setting of moyamoya disease. The patient’s aneurysm was successfully embolized by the use of Onyx 18. In this report, we present the first case of onyx embolization of a LSA aneurysm and review all the previous cases that were managed with endovascular techniques.

Conclusion: Treatment of these lesions with either surgery or endovascular therapy is challenging and requires specialized expertise. Given the risks of surgery, we believe that LSA aneurysms are best treated by endovascular means, especially in the setting of moyamoya disease 10).

1)

Gupta K, M Das J. Charcot-Bouchard Aneurysm. 2023 Jul 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 31971704.
2)

Vargas J, Walsh K, Turner R, Chaudry I, Turk A, Spiotta A. Lenticulostriate aneurysms: a case series and review of the literature. J Neurointerv Surg. 2014 Feb 26. doi: 10.1136/neurintsurg-2013-010969. [Epub ahead of print] PubMed PMID: 24574545.
3)

Ma N, Tomancok B, Jiang P, Yang XJ, Ojar D, Jia W. Endovascular Coiling for a Ruptured Proximal Lenticulostriate Artery Aneurysm. Chin Med J (Engl). 2016 May;129(5):606-8. doi: 10.4103/0366-6999.176985. PubMed PMID: 26904998.
4)

Hinojosa-Gonzalez DE, Ferrigno AS, Martinez HR, Farias JS, Caro-Osorio E, Figueroa-Sanchez JA. Aneurysms of the Lenticulostriate Artery: A Systematic Review. World Neurosurg. 2021 Jan;145:471-479.e10. doi: 10.1016/j.wneu.2020.08.160. Epub 2020 Sep 2. PMID: 32889194.
5)

Nomura M, Baba E, Shirokane K, Tsuchiya A. Aneurysm of lenticulostriate artery in a patient presenting with hemorrhage in the caudate nucleus and lateral ventricle-delayed appearance and spontaneous resolution. Surg Neurol Int. 2018 Sep 21;9:192. doi: 10.4103/sni.sni_126_18. PMID: 30294496; PMCID: PMC6169348.
6)

https://pesquisa.bvsalud.org/portal/resource/pt/wpr-732725
7)

Kheyreddin A, Semenov D, Abramyan A. Microsurgical excision of a ruptured distal lenticulostriate aneurysm in a child. BMJ Case Rep. 2023 Sep 25;16(9):e256627. doi: 10.1136/bcr-2023-256627. PMID: 37748812.
8)

Ando M, Maki Y, Hojo M, Hatano T. Ruptured saccular aneurysm of the lenticulostriate artery embolized without parent artery occlusion in a case of moyamoya disease. Neuroradiol J. 2022 May 12:19714009221101307. doi: 10.1177/19714009221101307. Epub ahead of print. PMID: 35545931.
9)

Byeon Y, Kim HB, You SH, Yang K. A Ruptured lenticulostriate artery aneurysm in moyamoya disease treated with Onyx embolization. J Cerebrovasc Endovasc Neurosurg. 2021 Oct 26. doi: 10.7461/jcen.2021.E2021.06.011. Epub ahead of print. PMID: 34696549.
10)

Chalouhi N, Tjoumakaris S, Gonzalez LF, Dumont AS, Shah Q, Gordon D, Rosenwasser R, Jabbour P. Onyx embolization of a ruptured lenticulostriate artery aneurysm in a patient with moyamoya disease. World Neurosurg. 2013 Sep-Oct;80(3-4):436.e7-10. doi: 10.1016/j.wneu.2012.03.030. Epub 2012 Apr 3. PMID: 22484074.

Thiopental

Thiopental

Thiopental (Pentothal®)

Thiopental in neurosurgery

Thiopental administration has been described as an effective method to prevent postoperative neurological deficits in several animal studies 1) 2) 3) 4) 5)

Here are some key points about the use of thiopental in neurosurgery:

Induction of Anesthesia: Thiopental is often used as an induction agent to rapidly induce anesthesia in patients undergoing neurosurgical procedures. Its rapid onset of action makes it suitable for this purpose.

Sedation and Amnesia: Thiopental induces a state of sedation, amnesia, and unconsciousness, which is important for ensuring that patients do not experience pain or awareness during surgery.

Short Duration: One of the advantages of thiopental is its short duration of action. This allows for precise control of anesthesia depth and a quick recovery once the drug is discontinued.

Neuroprotective Properties: Thiopental has been investigated for its potential neuroprotective properties in the context of neurosurgery. It may help reduce the metabolic demands of the brain during surgery, which could be beneficial in cases where brain tissue needs to be protected.

Control of Intracranial Pressure (ICP): Thiopental can temporarily lower intracranial pressure (ICP), which can be important in neurosurgical procedures involving brain tumors or traumatic brain injury. By reducing ICP, it may provide a safer surgical environment.

Barbiturate Coma: In some cases of severe traumatic brain injury or refractory intracranial hypertension, thiopental has been used to induce a controlled barbiturate coma. This coma state is maintained for a specific duration to protect the brain from further damage and reduce ICP.

Administration: Thiopental is administered intravenously, typically as a rapid bolus injection. The dosage and administration rate are carefully controlled by an anesthesiologist to achieve the desired level of anesthesia.

Side Effects: Like all anesthetic drugs, thiopental can have side effects, including respiratory depression, hypotension (low blood pressure), and a risk of allergic reactions. These side effects are closely monitored during surgery.

Availability: The availability of thiopental may vary by region, and its use may be subject to regulatory restrictions. In some places, it has become less commonly used due to concerns about the misuse and availability of lethal injection

Protocol

May be useful when a rapidly acting barbiturate is needed (e.g. intra-op) or when large doses of pentobarbital are not available. One of many protocols is as follows (note: thiopental has not been as well studied for this indication, but is theoretically similar to pentobarbital):

1. Loading dose: thiopental 5 mg/kg (range: 3–5) IV over 10 minutes → transient burst suppression (< 10 minutes) and blood thiopental levels of 10–30 mcg/ml. Higher doses (≈ 35 mg/kg) have been used in the absence of hypothermia to produce longer-duration burst suppression for cardiopulmonary bypass

2. Follow with continuous infusion of 5 mg/kg/hr (range: 3–5) for 24 hours

3. may need to rebolus with 2.5 mg/kg as needed for ICP control

4. After 24 hours, fat stores become saturated, reduce infusion to 2.5 mg/kg/hr

5. titrate to control ICP or use EEG to monitor for electrocerebral silence

6. “therapeutic” serum level: 6–8.5 mg/dl

Chemically, propofol is not related to barbiturates and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia because recovery from propofol is more rapid and “clear” when compared with thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.

Thiopental and decompressive craniectomy are important integrated last-tier treatment options in aneurysmal subarachnoid hemorrhage, but careful patient selection is needed due to the risk of saving many patients a state of suffering 6).

A study showed that thiopental was associated with a lower risk of neurological complications after clipping of Unruptured Intracranial Aneurysm 7).

Test and Answers

What is the primary purpose of using Thiopental in neurosurgery? a) Pain relief b) Rapid induction of anesthesia c) Prolonged sedation d) Reducing blood pressure

Why is Thiopental chosen for induction in neurosurgery? a) It provides prolonged anesthesia. b) It has a rapid onset of action. c) It reduces intracranial pressure. d) It is an effective analgesic.

Which of the following is NOT a characteristic of Thiopental? a) Short duration of action b) Neuroprotective properties c) Rapid bolus injection d) Long-lasting sedation

In what situations might Thiopental be used to induce a controlled barbiturate coma? a) Routine neurosurgical procedures b) Cases of severe traumatic brain injury c) During outpatient surgeries d) For postoperative pain management

How is Thiopental typically administered? a) Orally b) Intramuscularly c) Intravenously d) Subcutaneously

What is the recommended therapeutic serum level of Thiopental? a) 1-2 mg/dl b) 6-8.5 mg/dl c) 20-30 mcg/ml d) 50-60 mg/dl

Why has Propofol largely replaced Thiopental for induction of anesthesia? a) Propofol is cheaper. b) Propofol has a shorter duration of action. c) Propofol is more effective at reducing intracranial pressure. d) Propofol has a faster recovery time.

What is a potential risk associated with using Thiopental in neurosurgery? a) Rapid recovery b) Allergic reactions c) Hypertension d) Analgesia

When might Thiopental and decompressive craniectomy be considered as treatment options in aneurysmal subarachnoid hemorrhage? a) As a first-line treatment b) As a second-line treatment c) As a last-tier treatment d) Only in cases of minor bleeding

What did a study suggest about the use of Thiopental in clipping of Unruptured Intracranial Aneurysm? a) It had no impact on neurological complications. b) It increased the risk of complications. c) It was associated with a lower risk of neurological complications. d) It prolonged surgical procedures.

Answers:

b) Rapid induction of anesthesia b) It has a rapid onset of action. d) Long-lasting sedation b) Cases of severe traumatic brain injury c) Intravenously b) 6-8.5 mg/dl d) Propofol has a faster recovery time. b) Allergic reactions c) As a last-tier treatment c) It was associated with a lower risk of neurological complications.

References

1)

Michenfelder J.D. The Interdependency of Cerebral Functional and Metabolic Effects Following Massive Doses of Thiopental in the Dog. Anesthesiology. 1974;41:231–236. doi: 10.1097/00000542-197409000-00004.
2)

Drummond J.C., Cole D.J., Patel P.M., Reynolds L.W. Focal cerebral ischemia during anesthesia with etomidate, isoflurane, or thiopental: A comparison of the extent of cerebral injury. Neurosurgery. 1995;37:742–748. doi: 10.1227/00006123-199510000-00019.
3)

Kofke W.A., Nemoto E.M., Hossmann K.A., Taylor F., Kessler P.D., Stezoski S.W. Brain blood flow and metabolism after global ischemia and post-insult thiopental therapy in monkeys. Stroke. 1979;10:554–560. doi: 10.1161/01.STR.10.5.554.
4)

Musch T.I., Pelligrino D.A., Dempsey J.A. Effects of prolonged N2O and barbiturate anaesthesia on brain metabolism and pH in the dog. Respir. Physiol. 1980;39:121–131. doi: 10.1016/0034-5687(80)90040-7.
5)

Zarchin N., Guggenheimer-Furman E., Meilin S., Ornstein E., Mayevsky A. Thiopental induced cerebral protection during ischemia in gerbils. Brain Res. 1998;780:230–236. doi: 10.1016/S0006-8993(97)01188-8.
6)

Björk S, Hånell A, Ronne-Engström E, Stenwall A, Velle F, Lewén A, Enblad P, Svedung Wettervik T. Thiopental and decompressive craniectomy as last-tier ICP-treatments in aneurysmal subarachnoid hemorrhage: is functional recovery within reach? Neurosurg Rev. 2023 Sep 7;46(1):231. doi: 10.1007/s10143-023-02138-6. PMID: 37676578.
7)

Kim BG, Jeon YT, Han J, Bae YK, Lee SU, Ryu JH, Koo CH. The Neuroprotective Effect of Thiopental on the Postoperative Neurological Complications in Patients Undergoing Surgical Clipping of Unruptured Intracranial Aneurysm: A Retrospective Analysis. J Clin Med. 2021 Mar 12;10(6):1197. doi: 10.3390/jcm10061197. PMID: 33809302; PMCID: PMC7999640.

Antibiotics for spondylodiscitis treatment

Antibiotics for spondylodiscitis treatment

Antibiotic therapy is a pillar of treatment for spondylodiscitis and should be a part of the treatment in all cases. Neurologic deficits, sepsis, intraspinal empyema, the failure of conservative treatment, and spinal instability are all indications for surgical treatment 1).

Randomized trials to guide the selection of the appropriate route, duration, or agent for antibiotic therapy are lacking. Practice is based on retrospective case series, expert opinion, and data extrapolated from animal and laboratory data.

Choice

The choice of antibiotics for the treatment of spondylodiscitis depends on several factors, including the suspected or identified causative microorganism, the severity of the infection, and individual patient factors such as allergies and underlying medical conditions. Empirical antibiotic therapy may be initiated before the exact microorganism is identified based on clinical presentation and risk factors. However, once the causative organism is identified through cultures, antibiotic therapy can be adjusted accordingly. Commonly implicated bacteria in pyogenic spondylodiscitis include Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus or MRSA), Streptococcus species, and Escherichia coli.

Here are some antibiotic options commonly used for the treatment of spondylodiscitis:

Empirical Antibiotics: These antibiotics may be started before the specific microorganism is identified. Common choices include:

Intravenous (IV) antibiotics such as ceftriaxone or cefotaxime plus MRSA coverage with vancomycin or daptomycin. Broad-spectrum antibiotics like piperacillin-tazobactam or meropenem in critically ill patients with risk factors for multidrug-resistant organisms. Specific Antibiotics: Once the causative organism is identified, the antibiotics can be tailored to target that particular microorganism. Antibiotics often used for specific bacteria include:

For Staphylococcus aureus, including MRSA: Vancomycin, daptomycin, or linezolid. For Streptococcus species: Penicillin or ceftriaxone. For Escherichia coli and other Gram-negative bacteria: Ceftriaxone, cefotaxime, or fluoroquinolones.

Duration of Treatment

The duration of antibiotic therapy typically ranges from 6 to 12 weeks or longer, depending on the severity of the infection, the response to treatment, and the presence of complications. Prolonged treatment is often necessary to ensure complete eradication of the infection and to prevent relapse.

The appropriate duration of parenteral antibiotic treatment in patients with pyogenic spondylodiscitis after surgical intervention could be guided by the risk factors. The duration of postoperative intravenous antibiotic therapy could be reduced to 3 weeks for patients without positive blood culture or abscess formation 2)

Intravenous to Oral Transition

Intravenous to Oral Transition: In some cases, patients may be transitioned from intravenous to oral antibiotics once they show clinical improvement and are stable. This transition is based on the patient’s clinical response and the recommendations of the healthcare team.

Monitoring

Monitoring: Close monitoring of the patient’s clinical progress, laboratory markers of infection (such as C-reactive protein and erythrocyte sedimentation rate), and imaging studies is essential to assess treatment efficacy and identify any complications.

It’s important for patients to complete the full course of antibiotics as prescribed to prevent relapse and the development of antibiotic resistance.

A nationwide survey of empiric antibiotic treatment for pyogenic spondylodiscitis revealed a large heterogeneity in the standard of care. A combination of a broad-spectrum-β-lactam antibiotic with an additional glycopeptide antibiotic may be justified 3)

Empirical broad-spectrum antibiotic therapy is linked to increased rates of complications such as Clostridium difficile-associated diarrhea and higher healthcare costs 4), and should be reserved for patients presenting with severe sepsis once blood cultures have been taken.

Test

Question 1: Which of the following is NOT an indication for surgical treatment in spondylodiscitis?

A) Neurologic deficits B) Sepsis C) Intraspinal empyema D) Positive blood culture

Question 2: Why might empirical antibiotic therapy be initiated before the exact microorganism is identified in spondylodiscitis?

A) To prevent antibiotic resistance B) To reduce the duration of antibiotic treatment C) To avoid potential side effects of antibiotics D) To provide immediate treatment while awaiting culture results

Question 3: Which of the following is a commonly implicated bacterium in pyogenic spondylodiscitis?

A) Candida albicans B) Escherichia coli C) Mycobacterium tuberculosis D) Streptococcus pneumoniae

Question 4: What is the typical duration of antibiotic therapy for spondylodiscitis?

A) 1-2 weeks B) 2-4 weeks C) 4-6 weeks D) 6-12 weeks or longer

Question 5: Under what circumstances can intravenous antibiotic therapy be reduced to 3 weeks after surgical intervention in spondylodiscitis?

A) Positive blood culture B) Abscess formation C) Clinical improvement D) All of the above

Question 6: When might a patient with spondylodiscitis be transitioned from intravenous to oral antibiotics?

A) Immediately upon diagnosis B) After surgical intervention C) Once blood cultures are taken D) When they show clinical improvement and are stable

Question 7: Why is close monitoring of patients with spondylodiscitis essential during treatment?

A) To assess treatment efficacy B) To prevent antibiotic resistance C) To reduce healthcare costs D) To guide surgical interventions

Question 8: What should patients do to prevent relapse and the development of antibiotic resistance during spondylodiscitis treatment?

A) Start antibiotic treatment as soon as possible B) Take antibiotics until they feel better C) Complete the full course of antibiotics as prescribed D) Reduce the antibiotic dose gradually

Question 9: In what situation might a combination of a broad-spectrum-β-lactam antibiotic with an additional glycopeptide antibiotic be justified in spondylodiscitis treatment?

A) In all cases B) When blood cultures are negative C) In patients with severe sepsis once blood cultures have been taken D) In patients with mild infection

Question 10: What is the potential drawback of starting empirical broad-spectrum antibiotic therapy in spondylodiscitis?

A) Reduced treatment efficacy B) Increased rates of Clostridium difficile-associated diarrhea C) Lower healthcare costs D) Shorter hospital stays

Answers:

D) Positive blood culture D) To provide immediate treatment while awaiting culture results B) Escherichia coli D) 6-12 weeks or longer D) All of the above D) When they show clinical improvement and are stable A) To assess treatment efficacy C) Complete the full course of antibiotics as prescribed C) In patients with severe sepsis once blood cultures have been taken B) Increased rates of Clostridium difficile-associated diarrhea

1)

Herren C, Jung N, Pishnamaz M, Breuninger M, Siewe J, Sobottke R. Spondylodiscitis: Diagnosis and Treatment Options. Dtsch Arztebl Int. 2017 Dec 25;114(51-52):875-882. doi: 10.3238/arztebl.2017.0875. PMID: 29321098; PMCID: PMC5769318.
2)

Li YD, Wong CB, Tsai TT, Lai PL, Niu CC, Chen LH, Fu TS. Appropriate duration of post-surgical intravenous antibiotic therapy for pyogenic spondylodiscitis. BMC Infect Dis. 2018 Sep 17;18(1):468. doi: 10.1186/s12879-018-3377-1. PMID: 30223785; PMCID: PMC6142394.
3)

Lang S, Walter N, Neumann C, Bärtl S, Simon M, Ehrenschwender M, Hitzenbichler F, Alt V, Rupp M. Aktuelle Praxis der empirischen Antibiotikatherapie bei Spondylodiszitis [Current practice of empiric antibiotic treatment for spondylodiscitis]. Orthopadie (Heidelb). 2022 Jul;51(7):540-546. German. doi: 10.1007/s00132-022-04240-x. Epub 2022 Apr 7. PMID: 35391543; PMCID: PMC9249703.
4)

Lillie P, Thaker H, Moss P, et al. Healthcare-associated discitis in the era of antimicrobial resistance. J Clin Rheumatol 2008;14:234-7.

Magnetic resonance image-guided laser interstitial thermal therapy for glioblastoma

Magnetic resonance image-guided laser interstitial thermal therapy for glioblastoma

see Glioblastoma treatment.

see Magnetic resonance image-guided laser interstitial thermal therapy for intracranial tumor.

Magnetic Resonance Image-Guided Laser Interstitial Thermal Therapy (MRg-LITT) is an innovative and minimally invasive medical procedure used in the treatment of certain brain tumors, including glioblastoma.

Here’s an overview of how MRg-LITT works for glioblastoma:

Patient Selection: MRg-LITT is typically considered for patients who have glioblastoma that is difficult to access with traditional surgical methods or for patients who are not candidates for open surgery due to various reasons, such as the tumor’s location within critical brain regions.

Imaging and Planning: Before the procedure, high-resolution magnetic resonance imaging (MRI) scans are used to precisely locate and map the tumor. These images are used to plan the laser treatment.

Laser Ablation: During the MRg-LITT procedure, the patient is typically awake under local anesthesia. A small incision is made in the skull, and a thin, flexible laser probe is inserted into the brain. The laser probe has an optical fiber that delivers laser energy directly to the tumor.

Real-Time MRI Guidance: The critical aspect of MRg-LITT is real-time MRI guidance. As the laser is activated, MRI scans are continuously performed to monitor the temperature changes and precisely control the heat distribution within the tumor and surrounding healthy tissue. This real-time feedback ensures that the tumor is effectively heated and destroyed while minimizing damage to healthy brain tissue.

Treatment Monitoring: The MRI images provide immediate feedback to the medical team, allowing them to adjust the laser’s power and position as needed to optimize tumor ablation.

Thermal Ablation: The laser heats and destroys the tumor cells through thermal ablation, effectively killing the cancerous tissue. The procedure is carefully monitored to ensure the entire tumor is treated.

Post-Procedure Care: After the laser ablation, the probe is removed, and the incision is closed. Patients typically stay in the hospital for a short period for observation and recovery.

MRg-LITT offers several advantages for the treatment of glioblastoma:

Minimally Invasive: It involves a smaller incision compared to traditional open surgery, leading to reduced trauma and a shorter recovery time. Precise Targeting: Real-time MRI guidance allows for highly precise targeting and monitoring of the tumor, minimizing damage to healthy brain tissue. Outpatient Potential: In some cases, MRg-LITT can be performed on an outpatient basis or with shorter hospital stays. Reduced Risk: It may be suitable for patients with tumors in challenging or critical brain areas. However, it’s important to note that MRg-LITT is not suitable for all cases of glioblastoma. Patient eligibility and the choice of treatment method depend on various factors, including tumor size, location, and the patient’s overall health. Treatment decisions are typically made in consultation with a multidisciplinary team of medical professionals, including neurosurgeons, oncologists, and radiologists. Additionally, the long-term effectiveness of MRg-LITT for glioblastoma is an area of ongoing research and clinical trials.

Case series

50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes.

Kamath et al. performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data.

They performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. The average percentage of tumors treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival was 6.6 mo.

LITT appears to be a safe and effective treatment for GBM in properly selected patients 1).

A study included patients with de novo or recurrent glioblastoma of the corpus callosum (n = 15). The mean patient age was 54.7 yr. The mean pretreatment Karnofsky Performance Scale score was 80.7 and there was no significant difference between subgroups. The mean tumor volume was 18.7 cm3. Hemiparesis occurred in 26.6% of patients. Complications were more frequent in patients with tumors >15 cm3 (RR 6.1, P = .009) and were associated with a 32% decrease in survival postLITT. Median progression-free survival, survival postLITT, and overall survival were 3.4, 7.2, and 18.2 mo, respectively.

LITT is a safe and effective treatment for glioblastoma of the corpus callosum and provides survival benefits comparable to subtotal surgical resection with adjuvant chemoradiation. LITT-associated complications are related to tumor volume and can be nearly eliminated by limiting the procedure to tumors of 15 cm3 or less 2).

A 51-year-old male presented after a fall with progressive dizziness, ataxia, and worsening headaches with a small, frontal ring-enhancing lesion. After clinical and radiographic progression, the patient underwent a stereotactic biopsy, confirming an IDH-WT World Health Organization Grade IV Glioblastoma, followed by LITT. The patient was subsequently started on adjuvant temozolomide, and 60 Gy fractionated – radiotherapy to the post-LITT tumor volume. After 3 months, surgical debulking was conducted due to perilesional vasogenic edema and cognitive decline, with H&E staining demonstrating perivascular lymphocytic infiltration. Postoperative serial imaging over 3 years showed no evidence of tumor recurrence. The patient is currently alive 9 years after diagnosis. Multiplex immunofluorescence imaging of pre-LITT and post-LITT biopsies showed increased CD8 and activated macrophage infiltration and programmed death ligand 1 expression. This is the first depiction of the in-situ immune response to LITT and the first human clinical presentation of increased CD8 infiltration and programmed death ligand 1 expression in post-LITT tissue. The findings point to LITT as a treatment approach with the potential for long-term delay of recurrence and improving response to immunotherapy 3)

Test

Magnetic Resonance Image-Guided Laser Interstitial Thermal Therapy (MRg-LITT)

What is MRg-LITT primarily used for? a. Treating lung cancer b. Treating glioblastoma c. Treating breast cancer d. Treating skin disorders

Why is MRg-LITT considered for glioblastoma patients? a. It is less expensive than traditional surgery. b. It involves a larger incision than traditional surgery. c. It is suitable for all cases of glioblastoma. d. It is considered when traditional surgery is challenging or not an option.

What is the first step in the MRg-LITT procedure? a. Administering chemotherapy b. Conducting a stereotactic biopsy c. Performing a CT scan d. Using high-resolution MRI scans for tumor mapping

During the MRg-LITT procedure, what delivers laser energy directly to the tumor? a. A scalpel b. A robotic arm c. An optical fiber in a laser probe d. A radiation beam

What is the critical aspect of MRg-LITT that ensures precise treatment and minimal damage to healthy tissue? a. Real-time MRI guidance b. Post-operative care c. Chemotherapy administration d. Surgical incision size

How is the laser energy used during MRg-LITT to treat the tumor? a. It cools down the tumor. b. It freezes the tumor. c. It heats and destroys the tumor cells through thermal ablation. d. It directly removes the tumor.

What is one of the advantages of MRg-LITT for glioblastoma treatment? a. Longer hospital stays b. Increased trauma compared to traditional surgery c. Outpatient potential d. Risk reduction for all patients

What factors determine patient eligibility and the choice of treatment method for MRg-LITT? a. The patient’s hair color b. The patient’s blood type c. Tumor size, location, and overall health d. The patient’s age and gender

What is the primary focus of the case series study mentioned? a. The history of MRg-LITT b. The benefits of chemotherapy c. The safety and outcomes of MRg-LITT in GBM patients d. The development of new surgical instruments

According to the study by Kamath et al., what percentage of patients experienced perioperative complications related to MRg-LITT? a. 0% b. 3.4% c. 12% d. 26.6%

Answers:

b. Treating glioblastoma d. It is considered when traditional surgery is challenging or not an option. d. Using high-resolution MRI scans for tumor mapping c. An optical fiber in a laser probe a. Real-time MRI guidance c. It heats and destroys the tumor cells through thermal ablation. c. Outpatient potential c. Tumor size, location, and overall health c. The safety and outcomes of MRg-LITT in GBM patients c. 12%

1)

Kamath AA, Friedman DD, Akbari SHA, Kim AH, Tao Y, Luo J, Leuthardt EC. Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes. Neurosurgery. 2019 Apr 1;84(4):836-843. doi: 10.1093/neuros/nyy375. PMID: 30137606; PMCID: PMC6425465.
2)

Beaumont TL, Mohammadi AM, Kim AH, Barnett GH, Leuthardt EC. Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy for Glioblastoma of the Corpus Callosum. Neurosurgery. 2018 Sep 1;83(3):556-565. doi: 10.1093/neuros/nyx518. PMID: 29438526; PMCID: PMC6939409.
3)

Chandar JS, Bhatia S, Ingle S, Mendez Valdez MJ, Maric D, Seetharam D, Desgraves JF, Govindarajan V, Daggubati L, Merenzon M, Morell A, Luther E, Saad AG, Komotar RJ, Ivan ME, Shah AH. Laser Interstitial Thermal Therapy Induces Robust Local Immune Response for Newly Diagnosed Glioblastoma with Long-term Survival and Disease Control. J Immunother. 2023 Sep 19. doi: 10.1097/CJI.0000000000000485. Epub ahead of print. PMID: 37727953.

Propofol

Propofol

Propofol is a potent intravenous (IV) anesthetic agent used for the induction and maintenance of general anesthesia during surgical procedures and medical interventions. It is one of the most widely used and recognized anesthesia drugs in clinical practice. Here are some key points about propofol:

Induction of Anesthesia: Propofol is often used to rapidly induce anesthesia in patients before surgery or medical procedures. It causes rapid loss of consciousness and a state of general anesthesia.

Maintenance of Anesthesia: In addition to induction, propofol can also be used to maintain anesthesia during surgery. Anesthesia providers can adjust the infusion rate to maintain the desired level of anesthesia.

Rapid Onset and Offset: One of the advantages of propofol is its rapid onset of action, typically within seconds after IV administration. It also has a relatively short duration of action, which allows for a quicker recovery when compared to some other anesthetic agents.

Sedation and Amnesia: Propofol induces a state of sedation, amnesia, and unconsciousness. Patients under the influence of propofol do not feel pain or remember the surgical procedure.

Controlled Infusion: Propofol is administered as a controlled infusion through an IV line. The infusion rate is adjusted to maintain the desired level of anesthesia throughout the procedure.

Side Effects: Common side effects of propofol include respiratory depression, hypotension (low blood pressure), and pain at the injection site. These effects are closely monitored during surgery.

Antiemetic Properties: Propofol has antiemetic (anti-nausea and anti-vomiting) properties, making it useful in preventing postoperative nausea and vomiting.

Propofol-Related Infusion Syndrome (PRIS): In rare cases, prolonged and high-dose use of propofol can lead to a condition called PRIS, which may result in metabolic acidosis, heart and kidney dysfunction, and other serious complications. This is why propofol use is carefully monitored, and its dosage is controlled.

Not an Analgesic: It’s important to note that propofol is not an analgesic (pain reliever). It is typically used in conjunction with analgesic medications such as opioids to manage pain during and after surgery.

Intravenous Administration Only: Propofol is administered exclusively through IV injection. It is not available in oral or other forms.

Rapid Recovery: Due to its short duration of action, patients typically wake up quickly and experience a clear-headed recovery after discontinuation of propofol.

Color and Lipid Emulsion: Propofol is known for its milky white appearance, and it is formulated as a lipid emulsion. This unique formulation contributes to its rapid onset and offset of action.

Special Considerations: Dosage and administration of propofol are tailored to the patient’s age, weight, medical condition, and the type of surgery being performed.

see Agents generally used for induction.

Propofol in neurosurgery

Reduces cerebral metabolism, CBF and ICP. Has been described for cerebral protection and for sedation. Short half-life permits rapid awakening which may be useful for awake craniotomy. Not analgesic.

The exact mechanism of action unknown. Short half-life with no active metabolites. May be used for induction and as a continuous infusion during total intravenous anesthesia (TIVA). It causes a dose-dependent decrease in mean arterial blood pressure (MAP) and ICP.

It is more rapidly cleared than and has largely replaced thiopental.

Dexmedetomidine (Precedex®). Alpha 2 adrenergic receptor agonist, used for control of hypertension postoperatively, as well as for its sedating qualities during awake craniotomy either alone or in conjunction with propofol.

Propofol has a mild effect on evoked potential (EP): total anesthesia with propofol causes less EP depression than inhalational agents at the same depth of anesthesia 1).

Propofol (INN, marketed as Diprivan by Fresenius Kabi) is a short-acting, intravenously administered hypnotic/amnestic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine. It is approved for use in more than 50 countries, and generic versions are available.

Chemically, propofol is not related to barbiturates and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia because recovery from propofol is more rapid and “clear” when compared with thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.

Propofol has been referred to as milk of amnesia (a play on words of milk of magnesia), because of the milk-like appearance of its intravenous preparation.

It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a health system.

Level II: propofol may control ICP after several hours of dosing, but it does not improve mortality or 6-month outcomes. ✖ Caution: high-dose propofol (total dose > 100 mg/kg for > 48 hrs) can cause significant morbidity (see propofol infusion syndrome).

℞: 0.5 mg/kg test dose, then 20–75 mcg/kg/min infusion. Increase by 5–10 mcg/kg/min q 5–10 minutes PRN ICP control (do not exceed 83 mcg/kg/min = 5 mg/kg/hr).

Side effects include propofol infusion syndrome. Use with caution at doses > 5 mg/kg/hr or at any dose for > 48 hrs.

Propofol, an established hypnotic anesthetic agent, has been shown to ameliorate neuronal injury when given after injury in a number of experimental brain studies. We tested the hypothesis that propofol pretreatment confers neuroprotection against SBI and will reduce cerebral edema formation and neurobehavioral deficits in our rat population. Sprague-Dawley rats were treated with low- and high-dose propofol 30 min before SBI. At 24 h post-injury, brain water content and neurobehavioral assessment was conducted based on previously established models. In vehicle-treated rats, SBI resulted in significant cerebral edema and higher neurological deficit scores compared with sham-operated rats. Low- or high-dose propofol therapy neither reduced cerebral edema nor improved neurologic function. The results suggest that propofol pretreatment fails to provide neuroprotection in SBI rats. However, it is possible that an SBI model with less magnitude of injury or that propofol re-dosing, given the short-acting pharmacokinetic property of propofol, may be needed to provide definitive conclusions 2).

Propofol concentration needed for induction of unconsciousness in 50% of patients is reduced in Parkinson’s Disease patients 3).

Complications

Propofol infusion syndrome.

Case series

Malekmohammadi et al. from the Department of Neurosurgery, University of California, Los Angeles, collected local field potentials (LFPs) in 12 awake and anesthetized PD patients undergoing DBS implantation. Spectral power of β (13-35 Hz) and high-frequency oscillations (HFOs: 200-300 Hz) was compared across the pallidum.

Propofol suppressed GPi power by > 20 Hz while increasing power at lower frequencies. A similar power shift was observed in GPe; however, power in the high β range (20-35 Hz) increased with propofol. Before anesthesia both β and HFO activity were significantly greater at the GPi (χ2 = 20.63 and χ2 = 48.81, p < 0.0001). However, during anesthesia, we found no significant difference across the pallidum (χ2 = 0.47, p = 0.79, and χ2 = 4.11, p = 0.12).

GPi and GPe are distinguishable using LFP spectral profiles in the awake condition. Propofol obliterates this spectral differentiation. Therefore, LFP spectra cannot be relied upon in the propofol-anesthetized state for functional mapping during DBS implantation 4).

We analyzed 231 neurosurgery patients. In all patients, propofol was used for standard anesthesia induction. Patient demographics, medical histories, fasting duration, percentage weight loss, baseline blood pressure, and PPV during normal tidal volume breathing and that during forced inspiratory breathing (PPVfi) were recorded. Hemodynamic changes within 10 minutes of intubation were observed. Patients developing hypotension and severe hypotension were determined; lowest mean arterial pressure (MAP) and systolic arterial pressure (SAP) values were recorded, and their differences relative to baseline values were calculated. RESULTS: The incidence of hypotension was 18.6%. Both percentage weight loss and PPVfi were correlated with the changes in MAP and SAP. A PPVfi>14 identified all observed hypotensive episodes with 86% sensitivity and 86.2% specificity, whereas percentage weight loss >1.75% identified all observed hypotensive episodes with 81.4% sensitivity and 70.7% specificity. Furthermore, PPVfi>16.5 identified severe hypotension with 85% sensitivity and 90.5% specificity, whereas percentage weight loss >1.95% identified severe hypotension with 85% sensitivity and 73% specificity. CONCLUSIONS: Percentage weight loss and PPVfi are good predictors of hypotension after anesthesia induction and, thus, may allow anesthesiologists to adopt preventative measures and ensure safer anesthesia induction 5).

Case reports

Acute psychosis following propofol in a patient with Parkinson’s disease: effects of a GABA–dopamine imbalance 6).

Test and answers

What is the primary use of Propofol in clinical practice? a) Pain relief b) Induction and maintenance of general anesthesia c) Treatment of hypertension d) Treatment of epilepsy

What is the advantage of using Propofol for induction of anesthesia? a) It provides prolonged anesthesia. b) It has a slow onset of action. c) It causes rapid loss of consciousness. d) It is available in oral form.

How does Propofol compare to some other anesthetic agents in terms of its duration of action? a) It has a longer duration of action. b) It has a shorter duration of action. c) It has no duration of action. d) Its duration of action depends on the patient’s age.

What state does Propofol induce in patients during surgery? a) Euphoria b) Sedation and amnesia c) Hyperactivity d) Increased pain perception

How is Propofol administered during surgery? a) Orally b) Intramuscularly c) Subcutaneously d) As a controlled IV infusion

What is one of the common side effects of Propofol during surgery? a) Increased heart rate b) Hypertension (high blood pressure) c) Respiratory depression d) Elevated body temperature

What property of Propofol makes it useful in preventing postoperative nausea and vomiting? a) Analgesic effect b) Antidepressant effect c) Antiemetic properties d) Anticoagulant effect

What rare condition can occur with prolonged and high-dose use of Propofol? a) Hypothermia b) Propofol overdose c) Propofol-related infusion syndrome (PRIS) d) Propofol addiction

Which of the following statements about Propofol is true? a) It is commonly used as a standalone analgesic. b) It is available in various forms, including oral tablets. c) It is administered exclusively through IV injection. d) It is primarily used as an anticoagulant.

Why is Propofol known as the “milk of amnesia”? a) It has a white color. b) It is derived from milk. c) It tastes like milk. d) It causes amnesia-like effects.

Answers:

b) Induction and maintenance of general anesthesia c) It causes rapid loss of consciousness. b) It has a shorter duration of action. b) Sedation and amnesia d) As a controlled IV infusion c) Respiratory depression c) Antiemetic properties c) Propofol-related infusion syndrome (PRIS) c) It is administered exclusively through IV injection. a) It has a white color.

1)

Liu EH, Wong HK, Chia CP, et al. Effects of isoflurane and propofol on cortical somatosensory evoked potentials during comparable depth of anaesthesia as guided by bispectral index. Br J Anaesth. 2005; 94:193–197
2)

Pakkianathan C, Benggon M, Khatibi NH, Chen H, Marcantonio S, Applegate R 2nd, Tang J, Zhang J. Propofol Pretreatment Fails to Provide Neuroprotection Following a Surgically Induced Brain Injury Rat Model. Acta Neurochir Suppl. 2016;121:323-7. doi: 10.1007/978-3-319-18497-5_56. PubMed PMID: 26463969.
3)

Xu XP, Yu XY, Wu X, Hu XW, Chen JC, Li JB, Wang JF, Deng XM. Propofol Requirement for Induction of Unconsciousness Is Reduced in Patients with Parkinson’s Disease: A Case Control Study. Biomed Res Int. 2015;2015:953729. Epub 2015 Oct 1. PubMed PMID: 26495319.
4)

Malekmohammadi M, Sparks H, AuYong N, Hudson A, Pouratian N. Propofol Anesthesia Precludes LFP-Based Functional Mapping of Pallidum during DBS Implantation. Stereotact Funct Neurosurg. 2018 Sep 7:1-10. doi: 10.1159/000492231. [Epub ahead of print] PubMed PMID: 30196280.
5)

Ali A, Altiparmak O, Tetik A, Altun D, Sivrikoz N, Buget M, Bolsoy S, Yaman N, Akinci IO. Pulse Pressure Variation and Weight-Loss Percentage Predict Hypotension After Anesthesia Induction in Neurosurgery Patients: A Prospective, Observational, Blinded Study. J Neurosurg Anesthesiol. 2016 Jun 17. [Epub ahead of print] PubMed PMID: 27322092.
6)

Vinckier F, Gaillard R, Taylor G, Murray GK, Plaze M, Bourdillon P, Perin-Dureau F. Acute psychosis following propofol in a patient with Parkinson’s disease: effects of a GABA-dopamine imbalance. Psychiatry Clin Neurosci. 2022 Mar 29. doi: 10.1111/pcn.13360. Epub ahead of print. PMID: 35352434.

Woven EndoBridge (WEB)

Woven EndoBridge (WEB)

The Woven EndoBridge (WEB) (Sequent Medical, Aliso Viejo, California), is a ellipsoid braided-wire embolization device designed to provide flow disruption along the aneurysm neck 1).

Placed in the aneurysm, the device will modify the blood flow at the level of the neck and induce aneurysmal thrombosis. The WEB shape was designed to treat wide necked aneurysm. The device has been developed progressively from a dual-layer version (WEB DL) to single-layer versions (WEB SL and WEB SLS [single-layer spherical]).

This device does not require long-term antiplatelet use.

Design

The WEB device is made of a fine mesh composed of nitinol, a biocompatible metal alloy. It is designed to be delivered through a catheter and deployed within the aneurysm sac.

Indications

The Woven EndoBridge device is a treatment option for bifurcation wide-neck intracranial aneurysm. While this device has had good results, there remains a subset that fail this treatment.

For the treatment of both ruptured and unruptured aneurysms. The WEB has received the CE mark and to date has been used to treat a wide variety of more than 1,400 aneurysms in Europe, Latin America and New Zealand. The WEB is not available for sale or use in the United States.

The WEB is a self-expanding, oblate, braided nitinol mesh.

The device is composed of an inner and outer braid held together by proximal, middle, and distal radiopaque markers, creating 2 compartments: 1 distal and 1 proximal. Depending on the device diame- ter, the inner and outer braids are 108 wires or 144 wires. Therefore, blood flow into a WEB-embolized aneurysm initially encounters 2 layers of wires comprising 216 or 288 wires, with the largest interwire distance ranging from 106 to 181 􏰅m, respectively, depending on the device size. The WEB implant is deployed—or retrieved before de- tachment—in a manner similar to that in endovascular coil systems, through microcatheters with an internal diameter 􏰆0.027 inch. For devices with a diameter of 􏰇7 mm, microcatheters with an internal diameter of 0.027 inch are used; and for devices with a diameter 􏰁7 mm, microcatheters with an internal diameter 0.032 inch are used. The detachment system is electrothermal and instantaneous. 2).

In a study, there was no difference in the early clinical course between those treated with WEB embolization, coil embolization, or neurosurgical clipping. Since WEB embolization is a valuable treatment alternative to coiling, it seems not justified to exclude this procedure from upcoming clinical SAH trials, yet the clinical long-term outcome, aneurysm occlusion, and retreatment rates have to be analyzed in further studies 3).

Trials

WEB Intrasaccular Therapy Study (WEB-IT)

The WEB Clinical Assessment of Intrasaccular Aneurysm Therapy (WEBCAST) trial is a prospective European trial evaluating the safety and efficacy of WEB in wide necked aneurysm of the bifurcation.

Procedure

Angiographic evaluation

The WEB Occlusion Scale (WOS) 4), a Raymond-inspired scale, is up to now the most frequently used for WEB angiographic evaluation, but it may not be optimal for this device. Indeed, the new concept of intrasaccular flow-disruption introduces new analytical issues, such as proximal recess appearance, residual filling of the WEB, and device compression 5).

see Bicêtre Occlusion Scale Score

Limitations

Larger aneurysms are at risk for incomplete occlusion status post WEB treatment. Larger, ruptured aneurysms with minimal difference in aneurysm and WEB diameter that fail to occlude immediately post-treatment are more likely to present as residual aneurysms at short-term follow-up 6).

It does not immediately secure the aneurysm in most subarachnoid hemorrhage cases. Second, it may not be suitable for embolization of wide-neck aneurysms with an unfavorable aspect ratio. To overcome these limitations, Zanaty et al., used the WEB device in conjunction with stenting and/or coiling.

They presented a technical note with an illustrated case-series, and provide a detailed step-by-step description on how the WEB device can be used in adjunct to coiling and/or stenting to achieve successful angiographic results. Accurate sizing of the WEB device before deployment is critical. Larger case-series are required to further assess the safety and success of these combined techniques 7).

Woven EndoBridge Shape Modification

Woven EndoBridge Shape Modification

Systematic review and meta-analysis

Zhang et al. searched the PubMed, Ovid MEDLINE, and EMBASE databases between December 1, 2012 and June 30, 2018.

Studies that included five or more patients undergoing WEB for Wide necked intracranial aneurysms, reported an angiographic or clinical outcome and risk factors, and were published after December 1, 2012 were eligible.

Major outcomes included initial or short-term complete and adequate occlusion. Secondary outcomes included treatment failure, recanalization, mortality, morbidity, and complication (e.g., thromboembolism or intraoperative rupture) rates. A random-effect model was used to pool the data. To assess risk factors for short-term angiographic outcomes and the most common complications, they conducted subgroup analyses and obtained odds ratios with 95% confidence intervals.

They included 36 studies (1759 patients with 1749 aneurysms). The initial complete and adequate occlusion rates were 35% and 77%, respectively. After a mean follow-up of 9.34 months, the short-term complete and adequate occlusion rates were 53% and 80%, respectively. Thromboembolism and recanalization were the most common complications (both 9%), followed by mortality (7%), morbidity (6%), failure (5%) and intraoperative rupture (3%). The following factors were related to higher short-term obliteration rates: unruptured status, in the anterior circulation, a medium neck (4-9.9 mm), newer-generation WEB and treatment without additional devices. Ruptured status, anterior circulation, preoperative antiplatelet therapy and newer-generation WEB were not significantly related to withto thromboembolism.

WEB has a satisfactory safety profile and shows promising efficacy in treating wide-neck intracranial aneurysms. They preliminarily identified several risk factors for short-term angiographic outcomes 8).

Case series

Woven EndoBridge case series.

Case reports

A 68-year-old male patient with known hypertension, coronary artery disease, and Benign Prostatic Hyperplasia was admitted after a ruptured aneurysm of 4.5 mm in the right middle cerebral artery M1 segment and subarachnoid hemorrhage were detected in the emergency room imaging after syncope at home. WEB device was placed into the aneurysm in the patient who was planned for endovascular treatment. After 3 days of the procedure, neurologic examination showed regression. In the brain computed tomography imaging, it was observed that there was an intraparenchymal hematoma of 4,5 cm in the right temporoparietal region, and the aneurysm, which had been treated with endovascular WEB, was ruptured. The aneurysm was clipped in the patient for whom emergency surgical treatment was planned.

As a conclusion, re-bleeding can be seen after aneurysm treatment with the Web device. If it is planned to re-close the aneurysm treated with the web device with a surgical clip, the pressure created by the device against the vessel can be reduced with the additional clip 9).

2022

A case of a shallow basilar tip aneurysm treated with the WEB device that required stabilization with Y-stent through radial access 10).

References

 
1) 

Ding YH, Lewis DA, Kadirvel R, Dai D, Kallmes DF. The Woven EndoBridge: a new aneurysm occlusion device. AJNR Am J Neuroradiol. 2011 Mar;32(3):607-11. doi: 10.3174/ajnr.A2399. Epub 2011 Feb 17. PubMed PMID: 21330397.
2) 

Pierot L, Liebig T, Sychra V, Kadziolka K, Dorn F, Strasilla C, Kabbasch C, Klisch J. Intrasaccular flow-disruption treatment of intracranial aneurysms: preliminary results of a multicenter clinical study. AJNR Am J Neuroradiol. 2012 Aug;33(7):1232-8. doi: 10.3174/ajnr.A3191. Epub 2012 Jun 7. PubMed PMID: 22678844.
3) 

Sauvigny T, Nawka MT, Schweingruber N, Mader MM, Regelsberger J, Schmidt NO, Westphal M, Czorlich P. Early clinical course after aneurysmal subarachnoid hemorrhage: comparison of patients treated with Woven EndoBridge, microsurgical clipping, or endovascular coiling. Acta Neurochir (Wien). 2019 Jul 6. doi: 10.1007/s00701-019-03992-4. [Epub ahead of print] PubMed PMID: 31280480.
4) 

Fiorella D, Arthur A, Byrne J, Pierot L, Molyneux A, Duckwiler G, Mccarthy T, Strother C (2014) Interobserver variability in the assessment of aneurysm occlusion with the WEB aneurysm embolization system. J Neurointerv Surg:1-6. doi:10.1136/neurintsurg2014-011251
5) 

Cognard C, Januel AC (2015) Remnants and recurrences after the use of the WEB intrasaccular device in large-neck bifurcation aneurysms. Neurosurgery 76(5):522–530. doi:10.1227 /NEU.0000000000000669
6) 

Fortunel A, Javed K, Holland R, Ahmad S, Haranhalli N, Altschul D. Impact of aneurysm diameter, angulation, and device sizing on complete occlusion rates using the woven endobridge (WEB) device: Single center United States experience. Interv Neuroradiol. 2022 Mar 7:15910199221084804. doi: 10.1177/15910199221084804. Epub ahead of print. PMID: 35253525.
7) 

Zanaty M, Roa JA, Dandapat S, Samaniego EA, Jabbour P, Hasan D. Diverse Use of the WEB Device: A Technical Note on WEB Stenting and WEB Coiling of Complex Aneurysms. World Neurosurg. 2019 Jul 10. pii: S1878-8750(19)31933-3. doi: 10.1016/j.wneu.2019.07.027. [Epub ahead of print] PubMed PMID: 31301439.
8) 

Zhang SM, Liu LX, Ren PW, Xie XD, Miao J. Effectiveness, safety and risk factors of Woven EndoBridge device in the treatment of wide-neck intracranial aneurysms : systematic review and meta-analysis. World Neurosurg. 2019 Aug 13. pii: S1878-8750(19)32175-8. doi: 10.1016/j.wneu.2019.08.023. [Epub ahead of print] PubMed PMID: 31419591.
9) 

Sahin MC, Oncu F, Karaaslan B. Clipping of a Rebleeding Ruptured Aneurysm After Woven EndoBridge Treatment. Turk Neurosurg. 2023;33(5):916-918. doi: 10.5137/1019-5149.JTN.41381-22.2. PMID: 37715605.
10) 

Nordmann NJ, Weber MW, Dayoub H. Woven Endobridge (WEB) augmented by Y-stent in a shallow basilar tip aneurysm. J Cerebrovasc Endovasc Neurosurg. 2022 Feb 17. doi: 10.7461/jcen.2022.E2021.08.006. Epub ahead of print. PMID: 3517207