https://orcid.org/0000-0003-3086-4689
Abstract
Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.
Graphical Abstract
Plain Language Summary
The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack is incomplete. Reduction of secondary ischemic stroke risk following an initial stroke or TIA is achievable through medication, lifestyle, and nutritional interventions detailed in the Guideline.
The common patient subgroups with renal failure and/or MTHFR C677T polymorphisms are at higher risk for homocysteine elevation, ischemic stroke, and toxicity from excessive folic acid and cyanocobalamin.
The natural forms, L-methylfolate and methylcobalamin, are recommended for these high-risk subpopulations with renal failure and common polymorphisms of the MTHFR and DHFR.
Non-invasive imaging of retinal vessels offers real-time monitoring of small vessel ischemia in stroke patients. A recent study has shown improved retinal perfusion using a cocktail of antioxidants, L-methylfolate, and methylcobalamin. This supports the use of L-methylfolate and methylcobalamin to lower homocysteine and improve CNS perfusion, which would be beneficial for stroke prevention.
We recommend revision of the 2021 Guideline to include homocysteine reduction with low dose folic acid, or better, L-methylfolate and B12 as methylcobalamin.
Abbreviations
AHA, American Heart Association; ASA, American Stroke Association; CNS, Central Nervous System; CSPPT, China Stroke Primary Prevention Trial; DHFR, dihydrofolate reductase; DIVINe Trial, Diabetic Intervention With Vitamins to Improve Nephropathy Trial; MTHFR, methylenetetrahydrofolate reductase; OCTA, Ocular Coherence Tomographic Angiography; RFI, Retinal Function Imager; TIA, transient ischemic attack.
Disclosure
Dr Brown is a managing partner for Global Healthcare Focus, the manufacturers of Ocufolin®, a medical food used to address retinal ischemia. In addition, Dr Craig Brown has the patents: US 8822431B2, US 9770464B2, US 10278987B2, US 11,351,189; and Canada 2836445, and 2876169. All are licensed to Global Healthcare Focus. The authors report no other conflicts of interest in this work.