FAQ Episode 86: A damaged blood-brain barrier in migraine: who has it, how to manage it
Frequently Asked Questions about Natural Migraine Relief
We each live in a compartmentalized earthsuit. Skin around our body, flexible yet fibrous sheaths around organs, and walls encircling each cell announce that “this part is not like the other parts.” Each cell and each organ have specified functions that require semi-permiable protective barriers. For instance, we can’t have key neurotransmitters leaking out of the brain, or undigested foreign proteins (from corn, cow, etc.) coming in from the bowel and interacting with the immune system in our bloodstream. We can think of these barriers as a “molecular sieve” between cells or organs.
When protective barriers lose their integrity, unintended biochemical and immune interactions can promote inflammation, which in turn can become one of the core root cause factors that promote migraines. There are two key barrier systems I’d like to address: one involves the gut, which will be addressed in an upcoming post, while today I’d like to consider the role of the blood brain barrier (BBB) in migraines. As an aside, I was interested to find in my review of the literature on this topic an article in The Lancet (one of the three top medical journals of the time) dated May 1977 and titled: “Migraine and the Blood Brain Barrier: a hypothesis” That was nearly 50 years ago. In some ways we’ve come a long way since then, and in others related to this topic, not very far.
Why and how the brain manages its borders
The BBB exists to both limit molecular access to the brain, as well as to preserve brain specific chemicals to that location. It is formed by the endothelial cells lining the blood vessel, and surrounding them are high-resistance, tight junctions from glial cells surrounding the capillaries of the brain microvasculature. The resistance to casual penetration across the confines of the BBB is as high as any membrane barrier in all of biology. It is also the largest interface of the brain with the rest of the body, with a total suface area of 15-25 square meters.
In the above capillary, the red endothelium would represent the typical vascular interface anywhere else in the body. Brain capillaries are densely fortified!
This tight and efficient barrier comes with both pros and cons:
Pros:
-it acts as a selective filter, preventing toxins, pathogens, and other harmful substances from entering the brain and causing damage.
-it allows essential nutrients to enter the brain while filtering out waste products, ensuring optimal brain function.
-it regulates the flow of fluids and electrolytes, preventing brain swelling and maintaining proper brain volume.
-it maintains the separate pools of neurotransmitters in the central and peripheral nervous systems, preventing interference between different signaling pathways.
-it regulates the entry of immune cells into the brain, preventing excessive inflammation and damage to brain tissue.
-maintain a stable chemical and ionic environment within the brain, which is crucial for proper neuronal function.
-it will allow caffeine to cross into the brain. There are folks who confess the need for a steady caffeine blood levels for day to day function, and for them this is a lifesaving component of BBB flexibility. 😉
Cons:
-from a therapy perspective, a number of useful drugs do not effectively cross the blood brain barrier. This includes biologics, antibody based therapy and some chemotherapy or antiviral drugs,. Molecules that are large or not soluble in lipids have a harder time getting across the BBB. Many of the migraine active meds don’t cross well, but since they exert much of their benefit before crossing the the BBB at the endothelial level, they can still have a positive impact. The triptan drugs, calcium channel blockers and some some CGRP meds are examples of this.
-when the BBB is impaired, the previouly stated ‘pro’ advantages can be negated. Dysfunction of selective filtering, fluid and electrolyte balance, immune regulation and the rest of those “pros” can allow the expression of root causes of injury that may, in combination, be experienced as a migraine headache.
Blood brain barrier disruption and disease expression
Historically in the research world, the BBB is considered to be either intact, or disrupted-one or the other. Significant disruption of the BBB can occur with strokes, septic encephalopathy, multiple sclerosis, Alzheimer’s, seizures or traumatic brain injury. Recent history has demonstrated that the COVID-19 virus could cause direct damage to the BBB. And there is evidence that repetitive attacks of migraine with aura can result in infarct like lesions on CT, which suggests potential breakdown of or damage to the BBB.
In reality, the blood brain barrier, like any biological entity, functions on a spectrum of efficiency. Dysfunction within the BBB can alter many cell membrane functions, like receptor density, transporter and signaling activity, enzyme concentrations, changes in electrical potentials. level of glucose transport, immune cell traffic, solute leakage across the barrier and levels of pro-inflammatory cytokines. Just because an interface isn’t fully disrupted doesn’t mean that it’s function isn’t meaningfully altered. I would venture that everyone with migraine headaches likely has some low grade and recurring or chronic alteration of fully normal BBB function.
While our ability to measure this is still inexact, at any given time the BBB’s efficiency at brain protection is some fraction of the 100% ‘ideal.’ Is 93% effective enough to function well, or will 81% get the job done? Does clinical disease become apparent after one year, or five or 10 at 75% BBB impairment? We don’t really know. We do know that in the case of a migraine, headache pain is the brain’s cry for help. We should listen closely and look carefully for the all of the clues that could help solve its suffering.
Alzheimer’s and the blood brain barrier
Alzheimer’s is an interesting version of this situation. As a practical example of BBB injury, let’s consider a protein regulating BBB permeability called apolipoprotein E (APOE), which is a cholesterol and lipid carrier. The APOE gene is polymorphic, where combinations of two single nucleotide polymorphisms result in three different versions, or alleles (ε2, ε3, and ε4.) The APOE ε4 allele is associated with greater leakage in the BBB, as well as, a higher risk for Alzheimer’s type dementia. Chronic brain barrier leakage results in cumulative damage. Those who carry APOE4 homozygotes (two copies) have a lifetime risk of developing Alzheimer's dementia that can reach 60% by age 85. They make up only ~2% of the overall population, but they contribute to a much larger share of Alzheimer’s cases at an estimated 15%. Alzheimer’s may be a model example of how over time microscopic breaching of the BBB can accelerate brain damage and aging. Those with migraine have a higher incidence of dementia, including Alzheimer’s. We don’t know for sure that is a causal link, although some degree of BBB injury may be a contributing factor in both cases.
BBB injury and migraine headaches
Let’s apply what we just learned above about APOE and the BBB. A study in 20181 showed that ApoE protein levels can be significantly higher during migraine attacks than during the attack-free period, and that ApoE protein levels are also significantly increased in the “migraine with aura” group during the attack-free period compared to healthy controls or patients with tension type headaches. This study discusses how ApoE might play an important role in the pathophysiology of the BBB and its effect on both migraine and Alzheimer’s, and how it could potentially act as a diagnostic biomarker of migraine.
If your gene set has one or two APOE ε4 alleles you should address and minimize as many BBB provocatuers as you can identify. APOE gene testing can be obtained direct-to-consumer from many sources, like 23andMe, RxHomeTest, Blueprint Genetics, Life Extension, Labcorp, Quest Diagnostics or PrecivityAD.
Protecting your blood brain barrier is another good reason to keep the impact of your total inflammatory load to a minimum. Distant inflammatory conditions such as irritable bowel syndrome (IBS) or celiac have been linked to depression and psychiatric disorders and can present clinically with seizures, headaches, and cognitive impairment. These are due in part to gut sourced inflammatory changes that can injure the blood-brain barrier. We will address this source of potential inflammation in an upcoming post about how impaired gut barrier function can affect migraines.
Practical considerations for the BBB and migraine
Here are several factors that can adversely affect the blood brain barrier. Plan to address the ones that may apply to you:
Alcohol use depletes Vitamin B1 (thiamine). B1 is essential to repair the blood-brain barrier. If you enjoy adult beverages, even if you are only a ‘social user’ at a glass of wine per day, consider supplementing thiamine with its more absorbable form, called benfotiamine, dosed at 300 mg/day.
Diabetes: long-term elevated blood sugar levels trigger oxidative stress and inflammation, which damages the BBB's structure and function. There are multiple downstream implications from this for blood flow, insulin utilization, damaged proteins, oxygen transport and general brain permiability. If you have any neurological disorder, including migraines, then diabetic evaluation and management is paramount. Consider the HbA1c test described below to stratify your potential risk.
Smoking can signficantly raise the level of MMP-9, an enzyme associated with disruption of the blood-brain barrier. Smoking cessation has many health benefits and resisting migraine may be among them. Interestingly, the seizure drug Depakote (valproic acid) can significantly lower MMP-9 levels. This may be one reason it is used for both seizures and migraines. One might want to consider it as a pharmaceutical option for migraneurs who continue to smoke (forbid, but known to happen…).
Gut dysbiosis and reduced levels of short chain fatty acids (SCFAs). I’ll cover this in more detail in an upcoming post.
Genetic methylation deficits are implicated in BBB dysfunction and are linked to both vascular disease as well as cognitive decline, including conditions like Alzheimer's disease. When fully methylated, vitamins B12, B5, and B9 (folate) help maintain blood-brain barrier integrity. Methylation deficits are also an aggrvating factor for migraines, and there’s no doubt that there is some overlap between these two. For more information on this, read:
-FAQ Episode 39: Is there a relationship between Migraine and Alzheimer's type dementia?
-FAQ Episode 48: Four simple lab results everyone with migraine should know.
Electromagnetic fields (EMFs) are generated by electronic devices such as cell phones, Wi-Fi routers, and microwaves. EMFs activate VGCC (voltage-gated calcium channel) receptors in your cells, which leads to an influx of calcium ions. This surge in calcium catalyzes the production of peroxynitrite, a potent and inflammatory oxidant that damages cell membranes like those enclosing the blood brain barrier. Minimize screen time and keep screens at a distance. Avoid using a device when it is nearly discharged and it is in the initial stage of being recharged, especially right by your bed at night.
Excess Linoleic acid intake — This omega-6 fat is found in vegetable oils and commonly found in ultraprocessed foods. A diet high in LA, especially if the ratio of linoleic acid to omega-3 fatty acids is high, can impact the brain's ability to manage pain and inflammation, contributing to migraine. Some studies suggest that reducing LA intake and increasing omega-3 intake might help to alleviate migraine headaches. Processed carbs in a box or cellophane bag are the most common offenders to minimize.
Lab work related to BBB health and integrity
There are several basic lab tests for inflammation that can assist to highlight underlying conditions that can affect the BBB, including:
-highly sensitive CRP (c-reactive protein): a general indicator of whole body inflammation. It may not give the specifics of ‘why’, but an elevated number could alert you to search out the root cause(s).
-homocysteine level: a proxy for inherited B vitamin methylation deficits. Excess homocysteine on its own can be pro-inflammatory to blood vessel linings. Normal levels should be less than 10. A level over 12 merits a trial of methyl B vitamin supplementation as well as considering a reduction of red meat intake. See comments and links on this (above.)
-fibrinogen: elevated levels can indicate inflammation inside blood vessels, as well as being a marker for bleeding disoders or liver disease. I’m considering a future follow up FAQ on the specifics of fibrinogen elevation, its implications for brain, circulation and migraine, as well as related therapy.
-HbA1c: lets you know if you have early or undiagnosed adult diabetes, which is a very pro-inflammatory condition.
It doesn’t take much imagination to understand that a breach of the blood brain barrier can affect any and all brain functions. When you have a migraine, it is a sign that other critical brain functions could also be affected, both now and in the future. If your remedial efforts assist your migraines, as is our hope, you can also rest assured that you’ve done your brain health a favor in ways we probably won’t fully understand for years to come.
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Serum apolipoprotein E may be a novel biomarker of migraine Naoki Yuasa, et.al. PLOS Published: January 22, 2018 https://doi.org/10.1371/journal.pone.0190620