Microbleeds, Cerebral Hemorrhage, and Functional Outcome After Stroke Thrombolysis

I don't see anything here that is going to get patients 100% recovered. Problem description but no resolution. 

Microbleeds, Cerebral Hemorrhage, and Functional Outcome After Stroke Thrombolysis

Individual Patient Data Meta-Analysis

Andreas Charidimou, Guillaume Turc, Catherine Oppenheim, Shenqiang Yan, Jan F. Scheitz, Hebun Erdur, Pascal P. Klinger-Gratz, Marwan El-Koussy, Wakoh Takahashi, Yusuke Moriya, Duncan Wilson, Chelsea S. Kidwell, Jeffrey L. Saver, Asma Sallem, Solene Moulin, Myriam Edjlali-Goujon, Vincent Thijs, Zoe Fox, Ashkan Shoamanesh, Gregory W. Albers, Heinrich P. Mattle, Oscar R. Benavente, H. Rolf Jäger, Gareth Ambler, Junya Aoki, Jean-Claude Baron, Kazumi Kimura, Wataru Kakuda, Shunya Takizawa, Simon Jung, Christian H. Nolte, Min Lou, Charlotte Cordonnier, David J. Werring

https://doi.org/10.1161/STROKEAHA.116.012992

Stroke. 2017;48:2084-2090

Originally published July 18, 2017

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Abstract

Background and Purpose—We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome.

Methods—We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2–4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2).

Results—In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09–2.07; P=0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73–5.35; P<0.001) but not symptomatic ICH. Both cerebral amyloid angiopathy and noncerebral amyloid angiopathy patterns of CMBs were associated with PH and PHr. Increasing CMB burden category was associated with the risk of symptomatic ICH (P=0.014), PH (P=0.013), and PHr (P<0.00001). Five or more and >10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10–3.12; P=0.020; and odds ratio: 3.99; 95% confidence interval: 1.55–10.22; P=0.004, respectively).

Conclusions—Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

High Burden of Brain Microbleed May Up tPA Bleeding Risk

I would think the solution to this is reduce the size of the bolus substantially and direct the tPA directly to the clot. I could see no solution that was presented to fix this problem. Don't just tell me there is a problem, suggest a solution. What a waste of research dollars otrherwise.

Magnetic nanoparticles could stop blood clot-caused strokes

High Burden of Brain Microbleed May Up tPA Bleeding Risk

Stroke patients with cerebral microbleeds had a twofold greater risk for intracerebral hemorrhage following intravenous thrombolysis (tPA), and bleeding risk increased by as much as 12-fold among patients with the highest (>10) microbleed burden, according to a meta-analysis.
The risk of symptomatic brain bleeds after treatment was found to be higher in patients with evidence of cerebral microbleeds compared with patients without cerebral microbleeds (risk ratio 2.36, 95% CI 1.21-4.61, P=0.01), reported Georgios Tsivgoulis, MD, of the University of Athens School of Medicine in Greece, and colleagues
Nine studies were included in the analysis, which showed high cerebral microbleed (CMB) burden, identified through MRI, to be a significant independent risk factor for symptomatic brain bleeds in stroke patients treated with tPA, they wrote in JAMA Neurology.
The findings suggest that pre-treatment MRI assessment of cerebral microbleed burden can serve as an independent predictor of brain bleeding risk in ischemic stroke patients receiving tPA, the authors wrote.
They added that the reliance on CT scans, and not MRI, for patient assessment in the stroke emergency care setting remains a significant challenge to identifying cerebral microbleed burden.
While cerebral microbleeds are considered an independent predictor of higher cerebral bleeding risk, earlier studies assessing their clinical impact on brain bleed risk in stroke patients treated with tPA have been mixed and many have not assessed the impact of cerebral microbleed burden, the researchers noted.
"The potential association of CMB presence with the risk of symptomatic intracerebral hemorrhage in patients with acute ischemic stroke treated with intravenous thrombolysis remains controversial," they wrote.
In an effort to better understand the impact of a high cerebral microbleed burden detected by MRI scan prior to tPA treatment on symptomatic intracerebral hemorrhage risk in the ischemic stroke setting, the researchers analyzed studies reporting intracerebral bleeding rates in ischemic stroke patients with known pre-tPA cerebral microbleed burden.
The meta-analysis, which included a total of 2,479 patients, confirmed a higher risk for symptomatic brain bleeds following treatment with tPA in patients with a cerebral microbleed burden of more than 10, compared with patients with zero to 10 cerebral microbleeds or one to 10 cerebral microbleeds on pretreatment MRI.
The authors also reported a higher risk for symptomatic intracerebral hemorrhage after tPA treatment was detected in patients with high cerebral microbleed burden (>10) when compared with patients with zero to 10 cerebral microbleeds (RR 12.10, 95% CI 4.36-33.57, P<0.001) or one to 10 cerebral microbleeds (RR 7.01, 95% CI 3.20-15.38, P<0.001) on pretreatment MRI.
In an individual-patient data meta-analysis, high cerebral microbleed burden was associated with increased likelihood of symptomatic brain bleeding before (unadjusted odds ratio 31.06, 95% CI 7.12-135.44, P<0.001) and after (adjusted OR 18.17, 95% CI 2.39-138.22, P=0.005) adjusting for potential confounders.
A study limitation was the lack of data on brain bleed risk by cerebral microbleed count stratification in four of the nine studies included in the meta-analysis and lack of information on key baseline characteristics in three of the nine studies. There was also incomplete information on antithrombotic medications taken before hospital admission for stroke treatment.
Despite these limitations, the researchers concluded that cerebral microbleed burden should be considered in the stroke, pre-tPA risk stratification setting.
"The challenge remains in identifying CMB burden without MRI in the setting of acute ischemic stroke management where only a noncontrast computed tomography is standard of care," they stated.
In an accompanying editorial, Mark Fisher, MD, of the University of California Irvine School of Medicine, noted that cerebral microbleeds have been shown to be present in more than 20% of older people, while they are rare in younger populations.
"Cerebral microbleeds have received enormous attention in the literature," he wrote. "Nevertheless, the nature of the underlying lesion of cerebral microbleeds has proved elusive."
Fisher noted that despite the meta-analysis findings, the critical factor relevant to tPA treatment "appears to be not the microbleeds themselves, but the arteriolar injury contributing to micro hemorrhage development."
"The principal challenge for the clinician addressing microbleeds in acute ischemic stroke will be to distinguish primary from secondary microbleeds," he wrote. "It is the disseminated processes of primary microbleeds that create the substrate of the brain vulnerable to arteriolar ischemic necrosis and development of intracerebral hemorrhage. The more restricted process or prior ischemic injury producing secondary microbleeds will be of far less concern in this context. Ultimately, the number of cerebral microbleeds present will be less important than the nature of the process driving microbleed development."

• Primary Source

  JAMA Neurology

  Source Reference: Tslvgoulis G, et al "Risk of symptomatic intracerebral hemorrhage after intravenous thrombolysis in patients with acute ischemic stroke and high cerebral microbleed burden: a meta-analysis" JAMA Neurol 2016; DOI: 10.1001/jamaneurol.2016.0292.

• Secondary Source

  JAMA Neurology

  Source Reference: Fisher M "Cerebral microbleeds and thrombolysis: Clinical consequences and mechanistic implications" JAMA Neurol 2016; DOI: 10.1001/jamaneurol.2016.0576.

Antidepressant use is associated with an increased risk of developing microbleeds

Well shit, your doctor is going to have to analyze the benefits of antidepressant use in helping your recovery vs.  these microbleeds. Does your doctor even know about the positives of antidepressants?
You'll have to ask your doctor why antidepressants were selected as the cause of the microbleeds rather than aspirin or warfarin use or something else entirely. This would seem to be research that was intent on proving something rather than finding the real reason.
http://www.mdlinx.com/internal-medicine/medical-news-article/2016/01/11/antidepressive-agents-cerebral-microbleeds-cerebral-small/6469902/?news_id=881&newsdt=011616&subspec_id=488&utm_source=WeeklyNL&utm_medium=newsletter&utm_content=Weeks-Best-Article&utm_campaign=article-section&category=latest-weekly

Stroke, 01/11/2016 Akoudad S, et al.

In this study, the authors investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds. Antidepressant use was associated with an increased risk of developing microbleeds. The results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users.

Methods

• In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds.
• Antidepressant use (yes versus no) was assessed between baseline and follow-up scan.
• In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors.
• The authors used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds.

Results

• Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse.
• When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17).
• Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence.

Dementia and Stroke Rates Were Lower Among Patients Receiving Long-term Anticoagulation Therapy With Novel Oral Anticoagulants Compared to Warfarin

Just in case you need to know about this for your post stroke interventions.
http://circ.ahajournals.org/content/132/Suppl_3/A11919.short

1. Victoria Jacobs1;
2. Heidi T May1;
3. Tami L Bair1;
4. Jeffrey L Anderson2;
5. Brian G Crandall1;
6. Michael Cutler1;
7. John D Day1;
8. Charles D Mallender1;
9. Jeffrey S Osborn1;
10. Scott M Stevens1;
11. J P Weiss1;
12. Scott C Woller1;
13. T J Bunch1

+ Author Affiliations

1. ¹Intermountain Heart Institute, Intermountain Med Cntr, Murray, UT
2. ²Intermountain Heart Institute, Intermountain Med Cntr, Univ of Utah, Murray, UT

Abstract

Introduction: Patients with atrial fibrillation (AF) are at an increased risk of developing dementia, and this risk appears sensitive to quality of warfarin control. Longstanding warfarin use predisposes AF patients to the development of microbleeds if they are over-anticoagulated and microemboli if they are under-anticoagulated. The novel oral anticoagulants (NOACs) offer an alternative to warfarin with a predictable anticoagulant effect, and comparatively favorable intracranial bleeding and thrombosis rates which may lower the risk of dementia.

Hypothesis: The use of NOACs will be associated with a lower risk of stroke, TIA, and dementia compared to warfarin.

Methods: Patients receiving long-term anticoagulation therapy with either warfarin or a single NOAC for thromboembolism prevention were studied (June 2010-December 2014). NOAC and warfarin patients were matched 1:1 by index date (± 6 months) and propensity score (±0.01). Multivariable Cox hazard regression was performed to evaluate the association of NOAC compared to warfarin use for the composite outcome of dementia, stroke, and TIA.

Results: A total of 5,254 (2,627 per group) patients were studied, and those receiving NOACs included: apixaban= 590 (22.5%), dabigatran=583 (22.2%), and rivaroxaban=1,454 (55.3%). Average age was 72.4±10.9 and 59.0% were male. The majority of patients were receiving long-term anticoagulation for AF (warfarin: 96.5% vs. NOAC: 92.7%, p<0.0001). History of a prior stroke/TIA were similar between the groups (warfarin: 10.7% vs. NOAC: 10.8%, p=0.89). Dementia incidence alone was lower in the NOAC group compared to the warfarin group (0.3% vs. 1.6%, p<0.0001). The composite outcome of dementia, stroke, and TIA occurred in 4.7% of warfarin patients and 1.8% of NOAC patients (p<0.0001). After adjustment, patients taking NOACs had a 51% decreased risk of dementia incidence or subsequent stroke or TIA compared to patients taking warfarin (HR=0.49 (0.35, 0.69), p<0.0001).

Conclusions: This study shows the use of NOACs in a community setting to be superior to that of warfarin for the composite outcome of dementia, stroke, and TIA among patients receiving long-term oral anticoagulation.

Pontine Microbleeds and Depression in Stroke

This is just so goddamned f*cking simple to identify the problem. Currently our doctors do not give us any objective diagnosis or any proven repeatable way to recover.  With such lack of information depression is inevitable. Stop the neuronal cascade of death and survivors will be much less disabled and less likely to get depressed. Solve the correct problem you blasted idiots.
http://jgp.sagepub.com/content/27/3/159?etoc

1. W. K. Tang, MD1⇑
2. X. X. Liu, MPhil1
3. Y. K. Chen, PhD2
4. J. Abrigo, MD3
5. Winnie C. W. Chu, MD3
6. V. C. T. Mok, MD4
7. Gabor S. Ungvari, MD, PhD5,6
8. K. S. Wong, MD4

1. ¹Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China
2. ²Department of Neurology, Dongguan People’s Hospital, Dongguan, Guangdong, China
3. ³Department of Imaging and Interventional Radiology, Chinese University of Hong Kong, Hong Kong SAR, China
4. ⁴Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
5. ⁵The University of Notre Dame Australia/Marian Centre, Perth, Australia
6. ⁶School of Psychiatry and Clinical Neuroscience, University of Western Australia, Pert, Australia

1. W. K. Tang, Department of Psychiatry, Shatin Hospital, Shatin, NT, Hong Kong SAR, China. Email: tangwk@cuhk.edu.hk

Abstract

Objectives: Depression is the most common affective disorder following stroke yet the neuroanatomical model of poststroke depression (PSD) remains unclear. This study examined the association between PSD and cerebral microbleeds (CMBs) and hypothesized that CMBs in specific regions would be associated with PSD.

Methods: Of the 4766 patients with first ever or recurrent acute ischemic stroke admitted to the Acute Stroke Unit of the Prince of Wales Hospital between June 2004 and October 2010, 229 met the entry criteria and formed the study sample. Patients with a Geriatric Depression Scale score of 7 or above were classified as having PSD. The presence and location of CMBs were evaluated with magnetic resonance imaging.

Results: Compared to the non-PSD group, patients with PSD were more likely to have pontine CMBs (32.0% vs 18.2%; P = .019). The presence of pontine CMBs remained an independent predictor of PSD in the multivariate analysis, with an odds ratio of 2.2 (P = .016).

Conclusion: The results suggest that pontine CMBs are associated with a higher risk of developing PSD.

Climbers Face Lasting Effects if Brain Swells

I did have nausea when I climbed to the top of Mauna Loa in Hawaii at 13,678 feet, but nothing when I got to the top of Galdhøpiggen in Norway at  8100 feet. If this applies to you see your doctor for answers.
http://www.medpagetoday.com/MeetingCoverage/RSNA/36195
Extreme mountaineers who develop serious brain swelling at altitude appear to have lasting evidence of small hemorrhages in their brains, researchers said here.
In a single-center MRI study of 36 mountaineers, patients who'd had high altitude cerebral edema (HACE) had microbleeds in their corpus callosum, while those with other forms of altitude sickness largely did not, Michael Knauth, MD, PhD, of the University Medical Center Goettingen in Germany, and colleagues reported during a press briefing at the Radiological Society of North America meeting here.
"Microbleeds were found almost exclusively in the brains of HACE survivors," Knauth said during the briefing.
HACE typically occurs at altitudes above 7,000 feet and is considered the end stage of severe acute mountain sickness, or altitude sickness.
It's long been thought to be a fully reversible condition if the patient survives, but some work suggests that it does leave traces in the brain – particularly, hemosiderin deposits, or remnants of microbleeds.
These can be picked up on a very sensitive form of MRI called susceptibility-weighted imaging, Knauth said. So he and colleagues conducted these scans on 36 mountaineers, some of whom had experienced various illnesses:

• 10 had HACE
• 11 had severe acute mountain sickness
• 8 had high altitude pulmonary edema (HAPE)
• 7 had been at altitudes above 7,000 feet but had no altitude sickness

Radiologists interpreting the scans were blinded to the climber's status, and classified each as positive, negative, or questionable for microbleeds.
Overall, Knauth and colleagues found that the microbleeds in the corpus callosum occurred almost exclusively in climbers who'd had HACE -- 8 of the 10 of these mountaineers had definite evidence of microbleeds, while two had "questionable" bleeds.
Only one patient with severe acute mountain sickness also showed evidence of microbleeds, the lone false-positive result, Knauth said.
There was one questionable finding in a patient who'd had HAPE and two questionable findings in those who'd been at altitude without becoming ill.
Knauth said the HACE patients who had been most severely affected showed the most prominent evidence of microbleeds, and he cautioned that the findings don't appear to be a function of altitude as much as severity.
"It's not like you can say that at 8,000 [feet] they'll have so many [microbleeds] and at Everest they'll have double," Knauth said. "But those who have the most severe HACE – the ones that almost died -- have the most severe changes on MRI as well."
He also warned that there don't appear to be many clinical effects of the microbleeds at this point in time – though longer-term effects may be a different story.
"The neuropsychological consequences are unclear, but at the present there are no data to support the hypothesis that they are impaired," he said. "They work normally, but subtle testing of their mental capabilities is still to be performed. But it probably [will show] nothing."
Knauth concluded that the findings counter the idea that HACE is fully reversible, given that this evidence of microbleeds remains for years after the initial injury.