Scientists Develop Enhanced Vitamin K Compound That May Help Repair Brain Damage

 

Ask your competent? doctor how to eat healthy if on warfarin and can't consume Vitamin K foods.  You do want good cognition and no inflammation, right? That requires a diet protocol and I bet your incompetent doctor doesn't have one for you! Is your doctor also FUCKING INCOMPETENT  in not getting human testing going?

Scientists Develop Enhanced Vitamin K Compound That May Help Repair Brain Damage

Asundexian Reduces Risk of Future Ischemic Stroke as Secondary Prevention

 What is your doctor's guaranteed protocol to prevent the next stroke? Oh, just warfarin(rat poison) and then aspirin! Those are just guidelines; NOT PROTOCOLS!

Of course, your competent? doctor knew about this earlier this year, right!

Asundexian (2 posts to April 2025)

Asundexian Reduces Risk of Future Ischemic Stroke as Secondary Prevention

 

Key Takeaways

 Asundexian reduced ischemic stroke risk without increasing major bleeding in patients with prior non-cardioembolic ischemic strokes or high-risk transient ischemic attacks. Stroke is a leading global cause of death, with high recurrence rates and severe consequences, necessitating new treatment options. Asundexian shows promise in reducing ischemic stroke risk without increasing major bleeding, offering hope for secondary stroke prevention. In the phase 3 OCEANIC-STROKE study (NCT05686070), asundexian (Bayer), an investigational, once-daily, oral factor XIa (FXIa) inhibitor, reduced the risk of ischemic stroke compared with placebo in combination with antiplatelet therapy. The effects were seen in a cohort of patients who previously experienced a non-cardioembolic ischemic stroke or a high-risk transient ischemic attack. Ischemic stroke could lead to debilitating impacts and a recurrent stroke in the future. | Image Credit: © samunella - stock.adobe.com Critically, there was no increase in the risk of major bleeding as defined by the International Society on Thrombosis and Haemostasis in patients treated with asundexian compared with placebo. The results were announced in a news release from Bayer, with future data expected to be presented at an upcoming scientific meeting, according to the authors. “As clinicians, we see every day how devastating a recurrent stroke can be for patients and their families. Even with currently available therapies, the risk of another stroke remains high, and each recurrence can have profound consequences,” Mike Sharma, MD, a principal investigator of the OCEANIC-STROKE study and director of the stroke program at Hamilton Health Services, said in the news release. Stroke constitutes a major burden globally; it’s the second leading cause of death across the world, and each year, 12 million individuals experience a stroke. After a stroke, the resulting disability is often significant. Patients could face paralysis on one side of their body, difficulties speaking or finding which words to say, memory loss, and vision problems, among others. Beyond the physical impacts after a stroke, many patients ultimately experience a recurrent stroke. There is a concerning increase in stroke incidence among young and middle-aged individuals, necessitating new treatment capabilities. “The topline results from OCEANIC-STROKE indicate that asundexian may become a new treatment option to reduce this risk—representing a potential major step forward in secondary stroke prevention,” Sharma continued¹ 

Asundexian's Background, Safety, and Tolerability

 OCEANIC-STROKE has enrolled over 12,000 patients since its initiation. Results from the multicenter, international, randomized, placebo-controlled, double-blind, parallel-group, event-driven study could further bolster asundexian’s regulatory status. In 2022, the FDA granted the agent fast track designation based on positive results from a phase 2 (NCT04304508) study. Future clinical trial research could mean further regulatory movement for asundexian based on FDA decisions.^1,5Asundexian is a small molecule that binds and inhibits the activity of FXIa. The agent selectively inhibits the intrinsic coagulation pathway, thereby preventing thrombosis without hindering clotting responses that initiate after an injury. Although FXIa only has a small role in the formation of a seal at the site of a vessel injury, it is thought to contribute to the formation of pathological thrombus growth and vessel blockage. Asundexian achieves reductions in thrombus formation without major increases in rates of significant bleeding. In phase 1 studies, asundexian appeared to be well-tolerated. Common treatment-emergent adverse events included headache and nasopharyngitis, but all events were considered mild. Furthermore, all events were considered mild, with no clinically significant examinations or procedures observed in any patients. The current phase 3 results did not fully reveal safety indications, but the lack of increase in risk of major bleeding was a major demonstration of tolerability across the population.

Stroke symptoms(really they meant warning signs) can appear a decade before

 None of these applied to me at all. Had my stroke at age 50 from something on a whitewater canoe trip down the Dog River in Ontario dropping 1150 feet in 23 miles. Some hairy whitewater in fully loaded solo canoes. Swam a few of the rapids. Tore the plaque lining my right carotid artery, clotted and let go when I got home. My doctors did nothing to reduce my future risk of more plaque tearing. I don't consider the warfarin use an effective enough prevention since that doesn't address plaque tearing at all.

Stroke symptoms can appear a decade before

Early warning signs may show up long before a stroke strikes, offering a crucial window for prevention. New research suggests cognitive changes and daily task struggles can signal risk years in advance.

Rapid mental decline predicts stroke

A long-term cohort of 5 810 middle-aged adults in the Whitehall II study had reasoning, memory, vocabulary and verbal fluency assessed three times over 10 years¹. Researchers found that those in the highest midlife stroke-risk quartile experienced accelerated decline in global cognition up to ten years before their first stroke.

Daily tasks become challenging

Up to three years before a stroke, participants began reporting greater difficulty with routine activities—dressing, showering and meal preparation all became markedly harder². Such early functional impairments may be overlooked, but they offer a clear snapshot of rising stroke risk.

Women at higher risk

Globally, women account for approximately 56 % of all stroke cases³, highlighting a gender disparity in stroke vulnerability. Carriers of the APOE ε4 allele—best known for its association with Alzheimer’s disease—may also face elevated stroke risk⁴.

Did you know? Women’s lifetime risk of stroke is roughly 1 in 5, compared with about 1 in 6 for men³.

Prevention through lifestyle changes

Public health bodies emphasise that around 90 % of strokes are attributable to modifiable risk factors⁵. Experts recommend key lifestyle changes:

• Engage in at least 150 minutes of moderate exercise per week (e.g. brisk walking)

• Follow a diet rich in fruits, vegetables and whole grains, limiting salt intake

• Monitor and manage blood pressure, cholesterol and blood sugar with regular checks and medical advice
  

By spotting subtle warning signs and adopting these habits early, individuals can significantly reduce their stroke risk and protect long-term brain health.

The Role of Vitamins in Neurodegeneration: A Brief Review of Mechanisms, Clinical Evidence, and Therapeutic Perspectives

 Pretty useless, nothing on how to test for this and NOTHING ON AMOUNTS!

The Role of Vitamins in Neurodegeneration: A Brief Review of Mechanisms, Clinical Evidence, and Therapeutic Perspectives

Alberto Raggi 1, Raffaele Ferri 2

Affiliations 

• PMID: 40659185
 
• DOI: 10.1111/psyg.70071

Abstract

This review evaluates the role of vitamins in neurodegeneration. 

Low levels of B vitamins have been associated with cognitive decline. B vitamins may help inhibit amyloid plaque aggregation. 

Vitamin D deficiency has been linked to an increased risk of cognitive impairment, correlating with Alzheimer's pathology. 

Vitamin E may help delay Alzheimer's disease progression and support functional abilities. 

In Parkinson's disease, vitamin D shows promise in reducing dopaminergic neuron loss and improving motor and cognitive outcomes. 

Vitamin C reduces oxidative stress and preserves neuronal integrity. 

Vitamin K has gained attention for its role in cognitive health, with studies suggesting that higher levels may be linked to improved cognitive performance.(Not to be taken while on warfarin(rat poison)) In conclusion, a better understanding of the translational potential of these vitamins may inform preventive and therapeutic strategies for neurodegenerative diseases. Clinicians should consider vitamin supplementation for aging-related conditions. Further studies are needed to confirm its therapeutic potential and clarify underlying mechanisms in neurodegeneration.

Keywords: Alzheimer's disease; cognitive impairment; neurodegeneration; neuroprotection; oxidative damage; vitamin supplementation.

© 2025 Japanese Psychogeriatric Society.

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Low Vitamin K Intake Impairs Cognition, Neurogenesis, and Elevates Neuroinflammation in C57BL/6 Mice

 Ask your competent? doctor how to eat healthy if on warfarin and can't consume Vitamin K foods.  You do want good cognition and no inflammation, right? That requires a diet protocol and I bet your incompetent doctor doesn't have one for you! 

When taking warfarin, it is crucial to avoid foods that can interact with the medication and affect its effectiveness. Here are some foods to avoid: 

Foods High in Vitamin K: Green leafy vegetables (e.g., spinach, kale, broccoli, collard greens)

• Liver
• Brussels sprouts
• Asparagus
• Cauliflower

Foods Containing Flavonoids: grapefruit juice, green tea, and cranberry juice. Other Foods: alcohol, black licorice, turmeric, avocado, and olive oil

Low Vitamin K Intake Impairs Cognition, Neurogenesis, and Elevates Neuroinflammation in C57BL/6 Mice

Tong Zheng

, , , , , ,

https://doi.org/10.1016/j.tjnut.2025.01.023

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Abstract

Background

In addition to its important roles in blood coagulation and bone formation, vitamin K (VK) contributes to brain function. Low dietary VK intake, which is common among older adults, is associated with age-related cognitive impairment.

Objective

To elucidate the biological mechanisms underlying VK’s effects on cognition, we investigated the effects of low VK (LVK) intake on cognition in C57BL/6 mice.

Methods

Male and female 9-month old C57BL/6 mice (n=60) were fed a LVK diet or a control diet for 6 months. Behavioral tests were performed on a subset of animals (n=26) at 15 months and brain tissues were collected for follow-up analyses.

Results

Menaquinone-4 (MK4), the predominant VK form in the brain, was significantly lower in LVK animals compared to controls (15.6±13.3 vs 189±186 pmol/g, respectively, p<0.01). LVK animals showed reduced recognition memory in the novel object test by spending a lower percentage of time exploring the novel object compared to controls (47.45%± 4.17 vs. 58.08%±3.03, p=0.04). They also spent a significantly longer time learning the task of locating the platform in the Morris water maze test. Within the hippocampal dentate gyrus, LVK animals had a significantly lower number of proliferating cells, and fewer newly generated immature neurons compared to control animals. Additionally, more activated microglia cells were identified in the LVK animals.

Conclusion

Our data indicate that LVK intake reduced MK4 levels in brain tissues and impaired learning- and memory-related cognitive function. This impairment may be related to the observed reduced hippocampal neurogenesis and elevated neural inflammation.

Introduction

Within the next decade, it is estimated that there will be more Americans over the age of 65 years than under the age of 18 years [1], and many of these older adults will develop age-related cognitive impairments [2]. Modifiable factors, such as nutrition, have been implicated as important modulators for cognition [3], [4]. Growing evidence has shown that low vitamin K may have a role in age-related cognitive decline [5]. Green leafy vegetables are the main source of phylloquinone (PK), the primary form of dietary vitamin K [6], [7]. Concerningly, most adults do not consume the recommended quantity of these foods, leading to inadequate phylloquinone intake, especially among older adults in the U.S. [8]. Mostly known for its role in blood coagulation, phylloquinone is believed to also have important functions in the nervous system [9], [10]. Through recent and novel stable isotope experiments in rodent models, it has been shown that manipulation of dietary vitamin K causes rapid changes to the concentration of menaquinone-4 (MK4), which is the predominant form of vitamin K in the brain [11]. We also now know that all dietary forms of vitamin K convert to MK4 [12].

Observational data from the Rush Memory and Aging Project (MAP) demonstrated that higher postmortem brain levels of MK4 were associated with better cognitive function proximate to death. Further investigation of neuropathologically-defined outcomes also revealed that higher brain MK4 concentrations were associated with lower global dementia pathology, specifically fewer neurofibrillary tangles [13]. While these findings are encouraging, MK4 in the brain may simply be tracking healthy dietary patterns associated with higher vegetable intakes. Furthermore, the underlying biological mechanisms have yet to be elucidated. Thus, there is a critical need to establish the biological mechanism(s) underlying the cognition-protective effects of vitamin K in an animal model to overcome the limitations of observational data. Given that: 1) inflammation, which is closely associated with aging and neurodegeneration, impairs hippocampal neurogenesis; and 2) age-related cognitive decline is accompanied by reduced neurogenesis in the hippocampus, we propose that vitamin K’s protective effects on cognition and brain resilience may function through maintaining hippocampal neurogenesis and anti-inflammation.

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Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study

 The safety profiles of both are not that reassuring, our stroke medical professionals should be able to do better. This tyranny of low expectations  needs to stop. Accepting failure like this seems to be endemic to stroke; 'Hey, most persons survived, who gives a shit about their quality of life?'

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study

Shadi Yaghi

,

Liqi Shu

,

Ekaterina Bakradze

,

Setareh Salehi Omran

,

James A. Giles

,

Jordan Y. Amar

,

Nils Henninger

,

Marwa Elnazeir

,

Ava L. Liberman

,

Khadean Moncrieffe

,

Jenny Lu

,

Richa Sharma

,

Yee Cheng

,

Adeel S. Zubair

, … See all authors

Originally published10 Feb 2022https://doi.org/10.1161/STROKEAHA.121.037541Stroke. 2022;53:728–738

• This article is commented on by the following:
• is related to
• Other version(s) of this article

Abstract

Background:

A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort.

Methods:

This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups.

Results:

Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140–720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51–1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22–2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48–1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15–0.82]; P=0.02).

Conclusions:

In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

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Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification

You'll need your doctor to monitor this. In my case I was only on it for 2 months, later on they say the median duration was 1.6 years, so I guess I was ok.

Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification

 

Krista Nuotio^1,2*, Suvi M. Koskinen^2,3, Laura Mäkitie^1,2, Jarno Tuimala⁴, Petra Ijäs^1,2, Hanna M. Heikkilä², Jani Saksi², Pirkka Vikatmaa⁵, Pia Sorto², Sonja Kasari², Ilari Paakkari⁶, Heli Silvennoinen³, Leena Valanne³, Mikko I. Mäyränpää⁷, Lauri Soinne^1,2, Petri T. Kovanen⁸ and Perttu J. Lindsberg^1,2

• ¹Neurology, Neurocenter, Helsinki University Hospital, Helsinki, Finland
• ²Clinical Neurosciences, Clinicum, University of Helsinki, Helsinki, Finland
• ³Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
• ⁴Independent Researcher, Helsinki, Finland
• ⁵Abdominal Center, Vascular Surgery, Helsinki University Hospital, Helsinki, Finland
• ⁶Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
• ⁷Pathology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
• ⁸Wihuri Research Institute, Biomedicum Helsinki 1, Helsinki, Finland

Background: Long-term treatment with the vitamin K antagonist warfarin is widely used for the prevention of venous thrombosis and thromboembolism. However, vitamin K antagonists may promote arterial calcification, a phenomenon that has been previously studied in coronary and peripheral arteries, but not in extracranial carotid arteries. In this observational cohort study, we investigated whether warfarin treatment is associated with calcification of atherosclerotic carotid arteries.

Methods: Overall, 500 consecutive patients underwent carotid endarterectomy, 82 of whom had received long-term warfarin therapy. The extent of calcification was assessed with preoperative computed tomography angiography, and both macroscopic morphological grading and microscopic histological examination of each excised carotid plaque were performed after carotid endarterectomy.

Results: Compared with non-users, warfarin users had significantly more computed tomography angiography-detectable vascular calcification in the common carotid arteries (odds ratio 2.64, 95% confidence interval 1.51–4.63, P < 0.001) and even more calcification in the internal carotid arteries near the bifurcation (odds ratio 18.27, 95% confidence interval 2.53–2323, P < 0.001). Histological analysis revealed that the intramural calcified area in plaques from warfarin users was significantly larger than in plaques from non-users (95% confidence interval 3.36–13.56, P = 0.0018).

Conclusions: Long-lasting warfarin anticoagulation associated with increased calcification of carotid atherosclerotic plaques, particularly in locations known to be the predilection sites of stroke-causing plaques. The clinical significance of this novel finding warrants further investigations.

Introduction

An atherosclerotic lesion in the internal carotid artery is a major cause of cerebral ischemic stroke. Although many elements of the underlying pathological processes of atherosclerosis, e.g., lipid accumulation and the inflammatory component, have been well-characterized in developing atherosclerotic lesions (1), the multifaceted roles of calcification in atherosclerotic lesions are still debated and under investigation (2–5).

Atrial fibrillation (AF), the most common sustained arrhythmia (6) poses a significant risk for cerebral embolism, which is most effectively prevented by anticoagulants (7–9). Both warfarin and modern oral anticoagulants are available and neurologists are frequently deciding on anticoagulation on patients with AF, often with simultaneous large artery atherosclerosis.

Warfarin has been claimed to have harmful effects on the arterial wall. Evidence from experimental animals has demonstrated that treatment with warfarin is linked to vascular calcification (10, 11), with similar findings from preliminary human studies (12–14). Human studies have suggested that exposure to warfarin may increase calcification in coronary arteries (15, 16), peripheral arteries (17), aorta (18), and aortic valve leaflets (19).

However, there are only a few studies that have investigated the association of warfarin and vascular calcification in carotid arteries (20, 21), and none of them has studied vascular calcification in extracranial carotid arteries. Hence, the present clinical investigation was undertaken to evaluate the hypothesis that chronic warfarin use is associated with vascular calcification in atherosclerotic carotid artery disease. We examined the preoperative computed tomography angiography (CTA) results, macroscopic calcification of the dissected carotid specimens, and histopathology of the plaques to determine the potential presence of calcification, and the extent of different types of calcification. The results obtained in users and non-users of warfarin therapy were compared.

INR blood monitoring

 When I was on warfarin I had to have weekly blood draws which was only possible since my ex was not employed. A much better solution would be something like the Libre blood glucose monitoring system, but using Needle free blood draws or microneedles to monitor INR for warfarin use instead of having to come in for blood draws? We'll never know with our incompetent stroke leadership.

A great stroke association could build this and sell them to the millions of stroke survivors but we have NO STROKE LEADERSHIP. 

 

Brilinta Wins Indication in Recurrent Stroke Prevention

Nothing on whether this is better than warfarin, so your doctor is still just guessing on secondary stroke prevention. Hope you are OK with such guesswork.

Brilinta Wins Indication in Recurrent Stroke Prevention

FDA approval based on THALES give the drug a foothold beyond CVD

by Nicole Lou, Staff Writer, MedPage Today November 6, 2020

FDA granted ticagrelor (Brilinta) an indication for secondary prevention in stroke and high-risk transient ischemic attack (TIA), AstraZeneca announced.

The P2Y12 inhibitor is to be used as part of a dual antiplatelet regimen along with a daily maintenance dose of 75-100 mg aspirin for the reduction of recurrent stroke risk.

The expanded indication was based on the THALES trial, which was published in July in the New England Journal of Medicine.

In the trial with more than 11,000 participants, minor stroke and TIA patients randomized to ticagrelor plus aspirin had lower 30-day composite stroke and death rates than those randomized to aspirin alone (5.5% vs 6.6%, HR 0.83, 95% CI 0.71-0.96).

The benefit had been driven by fewer ischemic strokes (5.0% vs 6.3%, HR 0.79, 95% CI 0.68-0.93), with no significant difference in mortality rates between groups (0.7% vs 0.5%, HR 1.33, 95% CI 0.81-2.19).

Ticagrelor did, however, lead to more severe bleeding (0.5% vs 0.1%, HR 3.99, 95% CI 1.74-9.14) and more intracranial hemorrhage (0.4% vs 0.1%, HR 3.33, 95% CI 1.34-8.28).

THALES investigators estimated a number needed to treat (NNT) of 92 to prevent one stroke or death and a number needed to harm of 263 for severe bleeding.

"One in four patients who have had a stroke will experience a second one, with the risk particularly high within the first 30 days. The approval of Brilinta in combination with aspirin is an important advancement to reduce the risk of recurrent stroke and much-awaited good news for physicians and patients," said THALES lead investigator S. Claiborne Johnston, MD, PhD, of the University of Texas at Austin, in a press release.

Following FDA approval of the new indication, Johnston's group released a secondary analysis of THALES, which showed ticagrelor associated with fewer disabling strokes, from either the progression of the index event or a new stroke.

Incidence of recurrent disabling stroke (with modified Rankin Scale [mRS] scores 2+) or death at 30 days reached 4.0% in the ticagrelor plus aspirin group and 4.7% of those taking aspirin alone (HR 0.83, 95% CI 0.69-0.99).

The NNT was 133 to prevent one disabling stroke or death and 112 to prevent one disabling or fatal ischemic stroke, the investigators reported in JAMA Neurology in conjunction with presentation at the European Stroke Organization/World Stroke Organization virtual conference.

The reduction of disabling stroke was consistent across prespecified subgroups with the exception of people with diabetes. This finding may be due to chance or could reflect hypofibrinolysis in these individuals, Johnston and colleagues suggested.

Ticagrelor did not significantly reduce recurrent non-disabling strokes (mRS 0-1) or death at 30 days in the trial (1.3% vs 1.6%, HR 0.79, 95% CI 0.57-1.08).

Overall, treatment with ticagrelor was associated with less disability when recurrent strokes did occur. In patients with recurrent ischemic stroke, the resulting disability burden favored ticagrelor over aspirin alone (OR 0.77, 95% CI 0.65-0.91).

Independent predictors of recurrent disabling stroke were baseline NIH Stroke Scale score 4 to 5, ipsilateral stenosis of at least 30%, Asian race, older age, and higher systolic blood pressure.

Johnston's team cautioned that residual confounding was possible in the secondary analysis. There was also no disability assessment at day 90, though authors argued that 30-day mRS is highly correlated with 90-day mRS scores.

Ticagrelor's new indication for stroke prevention joins its other existing indications: reduction of risk of cardiovascular death, MI, and stroke in patients with acute coronary syndrome or a history of MI; and reduction of the risk of a first MI or stroke in high-risk patients with coronary artery disease.

Notably, ticagrelor is more expensive than clopidogrel (Plavix), another P2Y12 inhibitor used in secondary stroke prevention.

Unlike ticagrelor, however, clopidogrel did not significantly reduce disabling ischemic strokes when added to aspirin in the POINT trial. It took a pooling of the CHANCE and POINT trials to suggest such a benefit, Johnston and colleagues noted.

The CHANCE-2 trial directly comparing the two P2Y12 inhibitors is ongoing.

Last Updated November 07, 2020

 

Defining causality in COVID-19 and neurological disorders

While these people wait for more clinical evidence to come in, I am using the results from autopsies on lungs showing lots of micro-thrombi to conclude it is a clotting problem. The solution is clot busting tPA and blood thinners like Lovenox and warfarin. I'm not going to die just because my doctor is waiting for clear clinical studies, I will take charge and direct my doctor on what to do. Doing this fast enough should prevent the need for mechanical ventilation.  A friend was on blood thinner eliquis, got COVID-19 and survived, age 70+. But I'm not medically trained so don't listen to me. 

Defining causality in COVID-19 and neurological disorders

1. Mark Ellul1,2,3,
2. Aravinthan Varatharaj4,5,
3. Timothy R Nicholson6,
4. Thomas Arthur Pollak6,
5. Naomi Thomas7,8,
6. Ava Easton9,
7. Michael S Zandi10,
8. Hadi Manji10,
9. Tom Solomon1,2,3,
10. Alan Carson11,
11. http://orcid.org/0000-0003-0267-3180Martin R Turner12,
12. Rachel Kneen1,3,13,
13. http://orcid.org/0000-0002-1268-5102Ian Galea4,5,
14. Sarah Pett14,15,
15. Rhys Huw Thomas7,16,
16. http://orcid.org/0000-0002-8693-8926Benedict Daniel Michael1,2,3
17. CoroNerve Steering Committee

Author affiliations

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http://dx.doi.org/10.1136/jnnp-2020-323667

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When faced with acute neurological presentations in a patient with COVID-19, how confident can one be that SARS-CoV2 is causal?

Introduction

Clinicians are increasingly recognising neurological presentations occur in some patients.1 A case series from Wuhan described associated neurological syndromes (eg, ‘dizziness’ and ‘impaired consciousness’), but with little detail regarding symptomatology, and cerebrospinal fluid (CSF) and neuroimaging findings.2 The extent to which these disorders were caused by the virus per se, rather than being complications of critical illness, unmasking of degenerative disease, or iatrogenic effects of repurposed medications is not clear.

Numerous case reports have since emerged and, at the time of writing, published cases include encephalopathy,3 encephalitis,4 Guillain-Barré syndrome (GBS)5 and stroke.6 In most of these cases, the virus has been identified in respiratory samples, and in a small number in CSF. So far, the reporting of clinical features has been extremely variable, for example, several cases have claimed to report encephalitis without clear evidence of central nervous system (CNS) inflammation, which would not meet established definitions of the disease.7

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is associated with neurological manifestations is of critical importance as this may result in substantial morbidity and mortality.

Defining causality

It is crucial that neurologists and neuropsychiatrists apply a systematic strategy to determine whether there is evidence that SARS-CoV2 is causing these manifestations, whether they are a consequence of severe systemic disease alone, or simply coincidence. In 1965, Hill proposed criteria on which to build an argument for disease causation, which can be applied to COVID-19.8

What is the strength of the association? So far, it appears fairly weak. >2.5 million people have been infected with SARS-CoV2 and to date (to the authors’ knowledge) there have been only 93 published cases of neurological manifestations (about 5/100 000). However, reported cases are an underestimate of the real incidence, and this underscores the need for proper epidemiological study.

What is the consistency of the association? So far, there have been published reports of neurological manifestations across the globe, including from China, Japan, Italy, France, the USA and the UK. Although the numbers are low, these are not isolated incidences and have occurred throughout the evolution of the pandemic.

To what extent is the relationship specific? The range of neurological manifestations reported in association with SARS-CoV2 is wide, from the CNS through to peripheral nerves. However, in previous pandemics, similar central and peripheral associations have been well recognised.9

What can temporality tell us about the association? The delay between infection and the neurological presentation may give a clue to mechanisms. Direct CNS infection might be expected to be contemporaneous with, or shortly after, fever and respiratory symptoms. Parainfectious disease, owing to innate immune responses, such as acute necrotising encephalopathy, usually occurs in the days following infection. Post-infectious syndromes, due to adaptive immune responses, such as GBS, are typically in the few weeks following infection. In most reported cases, respiratory disease has occurred a few days prior to the onset of the neurological syndrome although significant delays between a neurological presentation and COVID-19 diagnosis in some raise the possibility of nosocomial infection.

Hill asks us to look for a biological gradient. In general, those with neurological manifestations have had severe COVID-19 respiratory disease suggesting the possibility that higher viral loads and/or more fulminant inflammatory responses may be accountable for both.

Is there biological plausibility? Many human viruses can enter the CNS and some coronaviruses exhibit neurotropism in animal models.10 The syndromes described so far could plausibly be related to primary infection with SARS-CoV2, although improved understanding of host responses is needed.

Hill asks us to consider the coherence of the evidence. Perhaps our best sources of coherent data are the SARS and Middle East respiratory syndrome (MERS) epidemics: coronaviruses with about 80% and 50% homology to SARS-CoV2, respectively. Neurological syndromes were reported in association with both, including acute disseminated encephalomyelitis-like presentations with MERS and encephalopathy/encephalitis with SARS.11

Is there any possibility of experimental evidence? The ideal investigational vehicle would be a case control study, but this presents design challenges as exposure is high and we do not yet have validated widespread antibody testing to ascertain seroprevalence.

Can we learn by analogy with other similar scenarios? Other respiratory viruses, most notably influenza, are well-established triggers of CNS damage. During the H1N1 pandemic, neurological syndromes were well described, including acute necrotising encephalopathy bearing striking resemblance to the case recently described with COVID-19.9 So, the emergence of neurological disorders associated with pandemic viral infections is less the exception, and more the norm.

Conclusions

As always, our evidence must be founded on clear and systematic assessment of the clinical syndromes, supported by well-designed laboratory studies. Cases must be reported in line with clear clinical case definitions, both systematically and transparently, and with honesty about negative or missing results.

These aims are best served by standardisation and centralisation of case reporting, which calls for a truly collaborative approach between neurologists, neuropsychiatrists and allied colleagues.

To address this, we have established the CoroNerve Studies Group as a collaboration between professional bodies in the UK (CoroNerve.com), and similar studies are underway in other countries. However, a joined-up international approach is necessary. To begin this process, a complimentary initiative, the COVID-Neuro Network, through Brain Infections Global, is supporting collaboration among several lower and middle-income countries.

We all must learn the lessons from previous pandemics, and the principles of Bradford Hill if we are to translate these rapidly growing datasets into meaningful advances in our understanding of the neurological complications of COVID-19.

Acknowledgments

CoroNerve Study Management Group: Mark Ellul, Ian Galea, Rachel Kneen, Benedict Michael, Sarah Pett, Naomi Thomas, Rhys Thomas, Ara Varantharaj. CoroNerve Steering Committee: Laura Benjamin, Jonathan Coles, Nicholas WS Davies, Ava Easton, Hadi Manji, David Menon, Craig Smith, Tom Solomon, Michael Zandi.