Acute ischemic stroke treatment

Acute ischemic stroke treatment

In the complete absence of blood flowneuronal death occurs within 2–3 minutes from the exhaustion of energy stores. However, in most strokes, there is a salvageable penumbra (tissue at risk) that retains viability for a period of time through suboptimal perfusion from collaterals. Local cerebral edema from the stroke results in a compromise of these collaterals and progression of the ischemic penumbra to infarction if the flow is not restored and maintained. Prevention of this secondary neuronal injury drives the treatment of stroke and has led to the creation of designated Primary Stroke Centers that offer appropriate and timely triage and treatment of all potential stroke patients.

Time delays from initial CTA acquisition to neuroendovascular surgery (NES) team notification can prevent expedient treatment with endovascular thrombectomy (ET). Process improvements and automated stroke detection on imaging with automated notification of the NES team may ultimately improve the time to reperfusion 1).

American Heart Association Guidelines for the Early Management of Patients With Acute Ischemic Stroke

see Endovascular intervention for ischemic stroke treatment..

see Hypothermia for acute ischemic stroke treatment.


Brain ischemia and treatment are one of the important topics in neurological science. Free oxygen radicals and inflammation formed after ischemia are accepted as the most important causes of damage. Currently, there are studies on many chemopreventive agents to prevent cerebral ischemia damage. The aim of Aras et al is to research the preventive effect of the active ingredient in genistein There is currently no promising pharmacotherapy aside from intravenous or intra-arterial thrombolysis. Yet because of the narrow therapeutic time window involved, thrombolytic application is very restricted in clinical settings. Accumulating data suggest that non-pharmaceutical therapies for stroke might provide new opportunities for stroke treatment 2).

Progression of focal stroke symptoms still constitutes a serious clinical problem for which heparin has insufficient effectiveness in clinical practice. New therapies, ideally preventive, are needed 3).

Omega 3 fatty acid enhance cerebral angiogenesis and provide long-term protection after stroke 4).

After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke.

Improvements in acute ischemic stroke (AIS) outcomes have been achieved with intravenous thrombolytics (IVT) and intra-arterial thrombolytics vs supportive medical therapy. Given its ease of administration, noninvasiveness, and most validated efficacy, IVT is the standard of care in AIS patients without contraindications to systemic fibrinolysis. However, patients with large-vessel occlusions respond poorly to IVT. Recent trials designed to select this population for randomization to IVT vs IVT with adjunctive endovascular therapy have not shown improvement in clinical outcomes with endovascular therapy. This could be due to the lack of utilization of modern thrombectomy devices such as Penumbra aspiration devices, Solitaire stent-trievers, or Trevo stent-trievers, which have shown the best recanalization results. Continued improvement in the techniques with using these devices as well as randomized controlled trials using them is warranted 5).

With the emergence of new technologies in imaging, thrombolysis and endovascular intervention, the treatment modalities of acute ischemic stroke will enter a new era 6).

Within 3 h from symptom onset, the existence of FLAIR-positive lesions on pretreatment MRI is significantly associated with an increased bleeding risk due to systemic thrombolysis. Therefore, considering FLAIR-positive lesions on baseline MRI might guide treatment decisions in ischemic stroke 7).

see Acute ischemic stroke thrombolysis

see Blood Pressure Management


1)

Yaeger KA, Rossitto CP, Marayati NF, Lara-Reyna J, Ladner T, Hardigan T, Shoirah H, Mocco J, Fifi JT. Time from image acquisition to endovascular team notification: a new target for enhancing acute stroke workflow. J Neurointerv Surg. 2021 Apr 8:neurintsurg-2021-017297. doi: 10.1136/neurintsurg-2021-017297. Epub ahead of print. PMID: 33832969.
2)

Chen F, Qi Z, Luo Y, Hinchliffe T, Ding G, Xia Y, Ji X. Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications. Prog Neurobiol. 2014 Jan 6. pii: S0301-0082(13)00147-0. doi: 10.1016/j.pneurobio.2013.12.007. [Epub ahead of print] PubMed PMID: 24407111.
3)

Rödén-Jüllig A, Britton M. Effectiveness of heparin treatment for progressing ischaemic stroke: before and after study. J Intern Med. 2000 Oct;248(4):287-91. PubMed PMID: 11086638.
4)

Wang J, Shi Y, Zhang L, Zhang F, Hu X, Zhang W, Leak RK, Gao Y, Chen L, Chen J. Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke. Neurobiol Dis. 2014 Apr 29. pii: S0969-9961(14)00103-X. doi: 10.1016/j.nbd.2014.04.014. [Epub ahead of print] PubMed PMID: 24794156.
5)

Serrone JC, Jimenez L, Ringer AJ. The role of endovascular therapy in the treatment of acute ischemic stroke. Neurosurgery. 2014 Feb;74 Suppl 1:S133-41. doi: 10.1227/NEU.0000000000000224. PubMed PMID: 24402482.
6)

Lu AY, Ansari SA, Nyström KV, Damisah EC, Amin HP, Matouk CC, Pashankar RD,Bulsara KR. Intra-arterial treatment of acute ischemic stroke: the continued evolution. Curr Treat Options Cardiovasc Med. 2014 Feb;16(2):281. doi:10.1007/s11936-013-0281-2. PubMed PMID: 24398801.
7)

Hobohm C, Fritzsch D, Budig S, Classen J, Hoffmann KT, Michalski D. Predicting intracerebral hemorrhage by baseline magnetic resonance imaging in stroke patients undergoing systemic thrombolysis. Acta Neurol Scand. 2014 Jul 18. doi: 10.1111/ane.12272. [Epub ahead of print] PubMed PMID: 25040041.

Sinus pericranii treatment

Sinus pericranii treatment

Accepted guidelines or recommendations concerning the managementdiagnosis, and treatment of sinus pericranii are still lacking.

Angiography plays a crucial role in the classification of SP and choice of the optimal treatment. Only accessory SP is amenable to treatment, whereas dominant SP must be preserved.

Ellis et al describe a simple and unique method for determining whether intracranial venous outflow may be compromised by sinus pericranii treatment. This involves performing catheter angiography while the lesion is temporarily obliterated by external compression. Analysis of intracranial venous outflow in this setting allows visualization of angiographic changes that will occur once the sinus pericranii is permanently obliterated. Thus, the safety of surgical intervention can be more fully appraised using this technique 1).


There were notable improvements following surgical resection for the abnormal venous lesions and several sclerotherapies 2)


Intraoperative hemostasis is essential while sinus pericranii is detached from the craniumHemostatic agents such as bone wax or absorbable gelatin and heat coagulation seem to be useful. However, complicative hemorrhage concerning to the preceded technique has been also reported. To detect minor shunting points between the sinus pericranii and the intracranial veins, the major venous connection can be manually compressed. Intraoperative manual compression of a major venous connection of sinus pericranii can be an option to manage intraoperative bleeding 3).

The endovascular approach is becoming increasingly relevant and has proven to be safe and effective 4).

The surgical treatment involves the resection of the extracranial venous package and ligation of the emissary communicating vein. In some cases of SP, surgical excision is performed for cosmetic reasons. The endovascular technique has been described by transvenous approach combined with direct puncture and the recently endovascular embolization with Onyx 5).


1)

Ellis JA, Mejia Munne JC, Feldstein NA, Meyers PM. Determination of sinus pericranii resectability by external compression during angiography: technical note. J Neurosurg Pediatr. 2015 Oct 16:1-5. [Epub ahead of print] PubMed PMID: 26474103.
2)

Ryu JY, Lee JH, Lee JS, Lee JW, Lee SJ, Lee JM, Lee SY, Huh S, Kim JY, Hwang SK, Chung HY. Combined treatment of surgery and sclerotherapy for sinus pericranii. Arch Craniofac Surg. 2020 Apr;21(2):109-113. doi: 10.7181/acfs.2019.00521. Epub 2020 Apr 20. PMID: 32380811; PMCID: PMC7206457.
3)

Fujimoto Y, Ishibashi R, Maki Y, Kitagawa M, Kinosada M, Kurosaki Y, Ikeda H, Chin M. A Simple Surgical Technique for Pediatric Sinus Pericranii: Intraoperative Manual Compression of a Major Shunting Point. Pediatr Neurosurg. 2021 Mar 29:1-6. doi: 10.1159/000514478. Epub ahead of print. PMID: 33780955.
4)

Pavanello M, Melloni I, Antichi E, Severino M, Ravegnani M, Piatelli G, Cama A, Rossi A, Gandolfo C. Sinus pericranii: diagnosis and management in 21 pediatric patients. J Neurosurg Pediatr. 2015 Jan;15(1):60-70. doi: 10.3171/2014.9.PEDS13641. PubMed PMID: 25360854.
5)

Rangel-Castilla L, Krishna C, Klucznik R, Diaz O. Endovascular embolization with Onyx in the management of sinus pericranii: a case report. Neurosurg Focus. 2009 Nov;27(5):E13. doi: 10.3171/2009.8.FOCUS09170. PubMed PMID: 19877791.

Glioblastoma treatment

Glioblastoma treatment

From 2005, state-of-the-art therapy in glioblastoma consists of maximal safe resection followed by combined radiotherapy and chemotherapy with temozolomide, according to Stupp regimen 1) , particularly in patients that demonstrate MGMT promoter methylation.

Conflicting reports have emerged regarding the importance of the time interval between these 2 treatments and there is no clear association between duration from surgery to initiation of chemoradiation on overall survival (OS). 2).


From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM 3).

The standard of care management for newly diagnosed glioblastoma multiforme (GBM) includes surgeryradiationtemozolomide (TMZ) chemotherapy, and tumor treating fields 4).

Antiepileptic medications may increase radiosensitivity, and therefore improve clinical outcomes, specifically in glioblastoma multiforme patients 5)

First therapeutic report of temozolomide to treat human glioma6).


The recommended treatment for MGMT promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ).

Although overall survival (OS) is the standard for determining GBM treatment efficacy, using OS as an endpoint when studying new therapeutic strategies can be problematic because of potential influence of therapies prior to or subsequently following the therapy being studied. For example, it is difficult to definitively conclude that bevacizumab has no efficacy in GBM when a large percentage of patients in the placebo arms in both III trials studying efficacy of bevacizumab (i.e. AVAglio and RTOG 0825) eventually crossed over and received bevacizumab (31% in AVAglio) 7) and 48% in RTOG-0825 8). If bevacizumab increased OS when given at any time during treatment, we may expect both treatment arms to have similar median OS since most patients eventually were treated with bevacizumab, disguising any therapeutic effects of the drug. Together, these results suggest OS may not be a suitable endpoint when studying new therapeutics or when there is a high chance of cross over in the control arm 9).

To overcome the limitations associated with using OS as the primary endpoint in studies involving new therapeutics, progression free survival (PFS) and objective response rate (ORR) should be considered important end points 10).

see Glioblastoma surgery.

The recommended treatment for O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ). However, it is well known that the clinical benefit from TMZ is lower in these patients.

Waiting time after surgery and overall time data do not indicate a relevant time factor in the treatment of glioblastoma multiforme in a large contemporary single-centre cohort. Although a study was limited by its retrospective nature, its results indicate that short delays of postoperative radiochemotherapy, e.g. for screening of a patient for a clinical trial, may be uncritical 11).

see Glioblastoma chemotherapy

see Glioblastoma multiforme antiangiogenic therapy.

see Molecular targeted therapy of glioblastoma.

GBM is one of the most active areas of research. Significant efforts are being made to look beyond basic morphology.

The retrospective analysis of the AVAglio trial reported 4.3 months incremental survival in the proneural glioblastoma subgroup 12).

Hence, patient selection and personalization of treatment should be done with more appropriateness in future. However, the complexity of performing these molecular assays in the lab appears to be labor and cost intensive and may limit routine use. In this context, a simplified model incorporating MGMT methylation, human telomerase (TERT) methylation, and IDH mutation may be formulated to dictate the optimum treatment. Treatment personalization may further be refined with the incorporation of these molecular factors along with patient factors like age, performance status, etc., (molecular-clinical profiling). A Large number of newer drugs and virus based therapy are being evaluated in different phase III and phase II trials as well.

The subventricular zone (SVZ) forms the lining the lateral ventricles and represents the origin of neural and some cancer stem cells. Gupta et al. reported on dose volume parameters of SVZ in 40 patients of adult GBM. Dose to the ipsilateral SVZ dose was found to be an independent predictor of survival in multivariate analysis in this study. Although a novel finding, this requires further validation in a prospective study 13).


Citalopram with standard RT and Temozolomide TMZ

RT alone versus RT and TMZ for elderly

CCNU/TMZ combination therapy versus standard TMZ (MGMT-methylated cases)

Standard RT plus concomitant and adjuvant OSAG 101 (Theraloc°) plusTMZ versus standard RT plus concomitant and adjuvant TMZ

Rindopepimut/GM-CSF with adjuvantTMZ in EGFvall-positive GBM CDX110-04

DCVax-L, autologous dendritic cells pulsed with tumor Iysate antigen 020221

Adjuvant TMZ with or without Interferon-alpha NCT 01765088

Adjuvant RT and temozolomide with or without Velipari b NCT 02152982

CCNU – Lomustine; TMZ -Temozolomide; MGMT – O‘-methylguanine—DNA methyltransferase; GBM – Glioblastoma multiforme; RT – Radiotherapy,-

GM-CSF -Granulocyte-monocyte colony stimulating factor,- EGFRvIII – Epidermal growth factor receptor variant III.

see Glioblastoma immunotherapy.

ALK inhibitor for Glioblastoma

Extensive dominant lobe glioblastoma

Butterfly glioblastoma.

Glioblastoma in elderly patients

Karnofsky performance score < 70

Multicentric glioblastoma.

see Recurrent glioblastoma treatment.


1)

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. PubMed PMID: 15758009.
2)

Osborn VW, Lee A, Garay E, Safdieh J, Schreiber D. Impact of Timing of Adjuvant Chemoradiation for Glioblastoma in a Large Hospital Database. Neurosurgery. 2018 Nov 1;83(5):915-921. doi: 10.1093/neuros/nyx497. PubMed PMID: 29092047.
3)

Montemurro N. Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature. J Neurol Surg A Cent Eur Neurosurg. 2019 Sep 24. doi: 10.1055/s-0039-1688911. [Epub ahead of print] PubMed PMID: 31550738.
4)

Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumortreating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316
5)

Julie DAR, Ahmed Z, Karceski SC, Pannullo SC, Schwartz TH, Parashar B, Wernicke AG. An overview of anti-epileptic therapy management of patients with malignant tumors of the brain undergoing radiation therapy. Seizure. 2019 Jun 12;70:30-37. doi: 10.1016/j.seizure.2019.06.019. [Epub ahead of print] Review. PubMed PMID: 31247400.
6)

Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998;16: 3851–7
7)

Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345. PubMed PMID: 24552318.
8)

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317; PubMed Central PMCID: PMC4201043.
9)

Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017 Apr;14(2):307-320. doi: 10.1007/s13311-016-0507-6. Review. PubMed PMID: 28108885; PubMed Central PMCID: PMC5398984.
10)

Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4. PubMed PMID: 18356283; PubMed Central PMCID: PMC2613818.
11)

Seidlitz A, Siepmann T, Löck S, Juratli T, Baumann M, Krause M. Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme. Radiat Oncol. 2015 Aug 16;10(1):172. PubMed PMID: 26276734.
12)

Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first line radiotherapy and temozolomide: Retrospective analysis of the AV Aglio trial. J Clin Oncol. 2015:pii–JCO.2015.61.5005. Epub ahead of print.
13)

Mallick S, Gandhi AK, Rath GK. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction. Indian J Med Paediatr Oncol. 2015 Oct-Dec;36(4):229-37. doi: 10.4103/0971-5851.171543. Review. PubMed PMID: 26811592; PubMed Central PMCID: PMC4711221.
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