Acute ischemic stroke treatment

Acute ischemic stroke treatment

As the second-leading cause of death, stroke faces several challenges in terms of treatment because of the limited therapeutic interventions available. Previous studies primarily focused on metabolic and blood flow properties as a target for ischemic stroke treatment, including recombinant tissue plasminogen activator and mechanical thrombectomy, which are the only USFDA approved therapies. These interventions have the limitation of a narrow therapeutic time window, the possibility of hemorrhagic complications, and the expertise required for performing these interventions. Thus, it is important to identify the contributing factors that exacerbate the acute ischemic stroke outcome and to develop therapies targeting them for regulating cellular homeostasis, mainly neuronal survival and regeneration. Glial cells, primarily microgliaastrocytes, and oligodendrocytes, have been shown to have a crucial role in the prognosis of ischemic brain injury, contributing to inflammatory responses. They play a dual role in both the onset as well as resolution of the inflammatory responses. Understanding the different mechanisms driving these effects can aid in the development of therapeutic targets and further mitigate the damage caused. In a review, Jadhav et al. summarize the functions of various glial cells and their contribution to stroke pathology. The review highlights the therapeutic options currently being explored and developed that primarily target glial cells and can be used as neuroprotective agents for the treatment of ischemic stroke 1).


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 2).

Restoring the circulation is the primary goal in emergency cerebral ischemia treatment. However, better understanding of how the brain responds to energy depletion could inform the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span.


Finding novel agent for cerebral ischemia therapy is urgently required. In a study, Gao et al., aimed to investigate the regulatory mechanism of Ginkgolides B (GB) in hypoxia-injured PC-12 cells.

PC-12 cells were exposed to hypoxia and administrated with GB. Cell viability was detected by MTT assay. Flow cytometry assay was conducted for the detection of cell apoptosis, ROS generation and cell cycle assay. The changes of protein levels of Bax, Pro/Cleaved-Caspase-3, CyclinD1, CDK4, CDK6, PI3K/AKT and MEK/ERK pathways were detected by Western blot. Transfection was conducted for Polo-like kinase 1 (PLK1) knockdown.

Hypoxia-induced decrease of cell viability and increase of ROS generation, apoptosis and cell cycle arrest were ameliorated by GB. Hypoxia disposition hindered PI3 K/AKT and MEK/ERK signaling pathways while GB had the opposite effects. Then we observed that hypoxia exposure suppressed PLK1 expression while GB increased PLK1 expression dose-dependently. Knockdown of PLK1 attenuated the neuroprotective effects of GB on hypoxia-injured PC-12 cells and also inhibited PI3 K/AKT and MEK/ERK pathways.

The above observations corroborated that GB alleviated hypoxia-induced PC-12 cell injury by up-regulation of PLK1 via activating PI3K/AKT and MEK/ERK pathways. These findings implied the neuro-protective impacts in hypoxia-injured PC-12 cells 3).

see also Cerebral venous sinus thrombosis treatment.


Remarkable developments in the field of endovascular neurosurgery have been witnessed in the last decade. The success of endovascular therapy for ischemic stroke treatment is now irrefutable, making it an accepted standard of care 4).

In ischemic stroke or patients with TIA less than five cerebral microbleeds (CMBs) should not affect antithrombotic decisions, although with more than five CMBs the risks of future ICH and ischaemic stroke are finely balanced, and antithrombotics might cause net harm. In lobar ICH populations, a high burden of strictly lobar CMBs is associated with cerebral amyloid angiopathy (CAA) and high ICH risk; antithrombotics should be avoided unless there is a compelling indication 5).

Intravenous recombinant human tissue plasminogen activator for ischemic stroke treatment.

Endovascular intervention for ischemic stroke treatment.

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

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 6).

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 7).

Omega 3 fatty acid enhance cerebral angiogenesis and provide long-term protection after stroke 8).

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 9).

With the emergence of new technologies in imaging, thrombolysis and endovascular intervention, the treatment modalities of acute ischemic stroke will enter a new era 10).

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 11).

see Acute ischemic stroke thrombolysis

see Blood Pressure Management.

Intensive rehabilitation effectively improves physical functions in patients with acute stroke, but the frequency of intervention and its cost-effectiveness are poorly studied. This study aimed to examine the effect of early high-frequency rehabilitation intervention on inpatient outcomes and medical expenses of patients with stroke.

Methods: The study retrospectively included 1759 patients with acute stroke admitted to the Kobe City Medical Center General Hospital between 2013 and 2016. Patients with a transient ischemic attack, subarachnoid hemorrhage, and those who underwent urgent surgery were excluded. Patients were divided into two groups according to the frequency of rehabilitation intervention: the high-frequency intervention group (>2 times/day, n = 1105) and normal-frequency intervention group (<2 times/day, n = 654). A modified Rankin scale score ≤2 at discharge, immobility-related complications and medical expenses were compared between the groups.

Results: The high-frequency intervention group had a significantly shorter time to first rehabilitation (median [interquartile range], 19.0 h [13.1-38.4] vs. 24.7 h [16.1-49.4], P < 0.001) and time to first mobilization (23.3 h [8.7-47.2] vs. 22.8 h [5.7-62.3], P = 0.65) than the normal-frequency intervention group. Despite higher disease severity, the high-frequency intervention group exhibited favorable outcomes at discharge (modified Rankin scale, ≤2; adjusted odds ratio, 1.89; 95% confidence interval, 1.25-2.85; P = 0.002). No significant differences were observed between the two groups concerning the rate of immobility-related complications and total medical expenses during hospitalization.

Conclusions: High-frequency intervention was associated with improved outcomes and decreased medical expenses in patients with stroke. Our results may contribute to reducing medical expenses by increasing the efficiency of care delivery 12).


1)

Jadhav P, Karande M, Sarkar A, Sahu S, Sarmah D, Datta A, Chaudhary A, Kalia K, Sharma A, Wang X, Bhattacharya P. Glial Cells Response in Stroke. Cell Mol Neurobiol. 2022 Jan 23. doi: 10.1007/s10571-021-01183-3. Epub ahead of print. PMID: 35066715.
2)

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.
3)

Gao J, Kang M, Han Y, Zhang T, Jin H, Kang C. Ginkgolides B alleviates hypoxia-induced PC-12 cell injury by up-regulation of PLK1. Biomed Pharmacother. 2019 Apr 25;115:108885. doi: 10.1016/j.biopha.2019.108885. [Epub ahead of print] PubMed PMID: 31029888.
4)

Levy EI, Munich SA, Rosenwasser RH, Kan P, Thompson BG. Introduction: Endovascular Neurosurgery. Neurosurg Focus. 2019 Jan 1;46(Suppl_1):V1. doi: 10.3171/2019.1.FocusVid.Intro. PubMed PMID: 30611172.
5)

Wilson D, Werring DJ. Antithrombotic therapy in patients with cerebral microbleeds. Curr Opin Neurol. 2016 Nov 24. [Epub ahead of print] PubMed PMID: 27898582.
6)

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.
7)

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.
8)

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.
9)

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.
10)

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.
11)

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.
12)

Oyanagi K, Kitai T, Yoshimura Y, Yokoi Y, Ohara N, Kohara N, Sakai N, Honda A, Onishi H, Iwata K. Effect of early intensive rehabilitation on the clinical outcomes of patients with acute stroke. Geriatr Gerontol Int. 2021 Jun 8. doi: 10.1111/ggi.14202. Epub ahead of print. PMID: 34101957.

MRI-negative epilepsy treatment

MRI-negative epilepsy treatment

Several methods for processing MRI postacquisition data have identified either previously undetectable or overlooked MRI abnormalities. The resection of these abnormalities is associated with excellent postsurgical seizure control. There have been major advances in functional imaging as well, one of which is the application of statistical parametric mapping analysis for comparing patient data against normative data. This approach has specifically improved the usefulness of both PET and single-photon emission computed tomography in MRI-negative epilepsy surgery evaluation. One other development of importance is that of PET-MRI coregistration, which has recently been shown to be superior to conventional PET. More recent publications on magnetoencephalography have added to the literature of its use in MRI-negative epilepsy surgery evaluation, which up to now remains somewhat limited. However, recent data now indicate that a single magnetoencephalography cluster is associated with better chance of concordance with intracranial EEG localization, and with excellent postsurgical seizure control if completely resected.

Summary: Advanced MRI and functional imaging and subsequent intracranial EEG confirmation of the seizure-onset zone are essential to make MRI-negative epilepsy surgery possible and worthwhile for the patient 1).


The optimal management of MRI-negative epilepsy may involve invasive monitoring followed by resection or responsive neurostimulation in most cases, as these treatments were associated with the best seizure outcomes in a cohort of the Yale New Haven Hospital. Unless multifocal epileptogenesis is clear from the non-invasive evaluation, epilepsy invasive monitoring is preferred before pursuing deep brain stimulation or vagus nerve stimulation directly 2).


Magnetoencephalography (MEG) is valuable for guiding in resective epilepsy surgery. MEG is a useful supplement for patients with MRI-negative epilepsy. MEG can be applied in minimally invasive treatment. MEG clusters can help identify better candidates and provide a valuable target for stereoelectroencephalography guided radiofrequency thermocoagulation, which leads to better outcomes. 3).


1)

So EL, Lee RW. Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol. 2014 Apr;27(2):206-12. doi: 10.1097/WCO.0000000000000078. PMID: 24553461.
2)

McGrath H, Mandel M, Sandhu MRS, Lamsam L, Adenu-Mensah N, Farooque P, Spencer DD, Damisah EC. Optimizing the surgical management of MRI-negative epilepsy in the neuromodulation era. Epilepsia Open. 2022 Jan 17. doi: 10.1002/epi4.12578. Epub ahead of print. PMID: 35038792.
3)

Gao R, Yu T, Xu C, Zhang X, Yan X, Ni D, Zhang X, Ma K, Qiao L, Zhu J, Wang X, Ren Z, Zhang X, Zhang G, Li Y. The value of magnetoencephalography for stereo-EEG-guided radiofrequency thermocoagulation in MRI-negative epilepsy. Epilepsy Res. 2020 Mar 20;163:106322. doi: 10.1016/j.eplepsyres.2020.106322. [Epub ahead of print] PubMed PMID: 32278277.

Diffuse midline glioma H3 K27M-mutant treatment

Diffuse midline glioma H3 K27M-mutant treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27M-mutant have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.


Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).


Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).


Although GD2CAR T-cells demonstrated significant anti-tumor activity against Diffuse midline glioma H3 K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. de Billy et al. investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.

Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.

GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual Insulin-like growth factor 1 receptor( IGF1R/IR) antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.

The study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for Diffuse midline glioma H3 K27M-mutant treatment and, potentially, by pHGG 3).


Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 4).


1)

Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.
2)

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.
3)

de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2021 Dec 29:noab300. doi: 10.1093/neuonc/noab300. Epub ahead of print. PMID: 34964902.
4)

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.
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