Migraine Questions

Our Reddit Session on Migraine: Your Questions Answered

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Our Reddit Session on Migraine: Your Questions Answered

Thanks to those who joined our recent Reddit discussion, moderated by Roman Rothaermel Mable co-founder and CEO, Dr Tom Kent co-founder and CTO, Dr Kumeren Govender and Dr Tom Lovejoy from our Mable medical team, and Chris Eijsbouts from our science team. We were quite pleased at the chance to connect with so many of you, to answer some of your top-of-mind questions on migraine and more. 

If you were unable to attend, or if you’d like a refresher on some of the topics discussed, here’s a recap! 

Topic: Migraine 

Q: How is DNA related to migraine treatment? 

A:  It's common for people with migraines to find they don't respond well to drugs that may have worked well for others. In fact, about 75% of patients taking oral preventative treatments abandon use after 6 months (and many even earlier, see Fig. 3 in this paper for a good illustration). Among those with migraine who use acute treatments, most people surveyed would seek an alternative. In other words, people who experience migraine may frequently switch medications, in a continual quest to find the right fit for their unique needs.

To individualize your treatment, Mable collects personal DNA to aid in drug selection. Mable connects you with clinicians who we’ve advised to exclude specific treatments that may not be a good fit for you personally, whether due to potential side effects, lack of efficacy in people with your genetic makeup, or other factors. 

DNA encodes for the enzymes that metabolize migraine treatments; a variation in your DNA may cause abnormal metabolism of a particular drug. For example, amitryptyline, a preventative migraine treatment, is metabolized by the genes CYP2C19 and CYP2D6. We look for a variation in these genes, a clue that tells us you may metabolize this treatment differently than other people. These variations are surprisingly common — check out this recent Stanford study. If we discover such a variation, we may note "avoid use" or "change starting dose," as generally agreed upon by large research initiatives such as the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium.

Q: I’ve noticed that my most stressful days can be a critical source of migraine episodes, especially when the stress actually starts to go away. I expect stress to be a leading trigger or at least a major contributor to my migraine…but a headache when the stress is decreasing? Why would that happen? 

A: According to a December 2021 study published in The Journal of Headache and Pain, 80% of people with migraine self-reported stress as a major trigger! So, you are absolutely right that stressful days can be a significant source of migraine episodes. But interestingly, it’s often a change in baseline or routine activity that can trigger an attack, and that change can come both when stress is increasing…or decreasing. 

Q: Is there a significant link between gut microbiome, DNS, migraines (or cluster headaches), and food allergies/intolerance? 

A: Great question! Unfortunately, so far, no one knows for sure. Many diets may appear to help people avoid migraine attacks and improve migraine symptoms; however, there’s no consensus on the best diet for an individual patient. Our advice: keep a food and drink log to monitor potential triggers, and try to follow US dietary guidelines.

As every individual is unique, it's difficult to propose a one-size-fits-all approach. Many people avoid dairy, for example, but if you do, you must ensure that you ingest calcium and protein from other sources. 

You may want to consider Mable, where individualized and holistic care is as much a part of treatment as medication. We hope to help individuals to manage their behavioral and environmental factors, while offering a pharmacological approach tailored to each person.

Q: My partner is struggling with a long-lasting case of dizziness (it can occur months at a time). Doctors we've consulted believe it may be migraine-related. Topamax doesn't seem to help at all. Are there other viable options to address this issue with vertigo?

A: Sorry to hear about your partner’s dizziness and vertigo, which are particularly difficult symptoms to live with. Migraine with aura is often linked with vertigo (the false sensation that you’re spinning or moving), and of course your doctor has likely also reviewed with you potential other causes as well. Because it's unusual for dizziness to persist for months, we would hesitate to offer specific medical advice on Reddit!

For example, your partner may be taking Topamax, probably the most widely prescribed medication for preventing migraines. Topamax can work well for people bothered by light during migraine (photophobia or photosensitization). If dizziness is due to migraine, it may improve over time with this drug, as preventatives take up to three months at optimal dose to have full effect. However, conversely, Topamax can also have many side effects that affect the brain and nerves and may actually be the source of dizziness, drowsiness, fatigue, and so on. 

The good news is, there are many other preventative medications which don't typically cause dizziness and vertigo symptoms; these other options may be worth exploring, with your physician’s help.

Q:  I'm curious about scintillating scotoma and its relation to intense migraines.

A: Scintillating scotoma is a fascinating symptom, very likely linked to visual aura. It’s no doubt difficult to explain it to someone who hasn't experienced it!

Aura is believed to be caused by a wave of abnormal nerve networks firing across the surface of the brain. This effect is known as cortical spreading depression (CSD). CSD is also thought to cause the trigeminal nerve, which normally receives information from the skin of the face and the surface of the eyes, to behave differently. CSD may even cause the normally super-controlled Blood-Brain-Barrier to lose some of its structural integrity. It's likely that such effects correlate with the intensity of migraine symptoms!

Fortunately, many available treatment options — acute and preventative, pharmacological and non-pharmacological — can help to address the imbalance. And of course, your physician should check to assure that there’s been no visual field change.

Topic: How Mable Works

Q: What does Mable do with my DNA after testing?

A: Mable does not retain your DNA sample after processing it and ensuring we've retained the data for a short time period in the unlikely event it may require reprocessing due to contamination or issues during extraction/sequencing. Your data is securely stored on our platform (in an encrypted and e-identified form) and shared only with the service providers we rely on for processing. Beyond that, our data is stored in the US and is not shared with any third party (for example, for research efforts) without your explicit consent .

Q:  Does your approach consider rarer types of migraine, such as hemiplegic migraines? 

A: Rarer types that cause one-sided weakness (such as hemiplegic migraines) will be identified as a neurological condition for further medical evidence. At this point in time, we are not accepting individuals who present with "red-flag" symptoms.

However, over time, we certainly hope to offer individualized holistic migraine treatment to all people who live with migraine. We’re passionate about providing you with resources on non-pharmacological treatments, so stay connected via the Mable blog!

Q: Does Mable’s ability to better treat migraines depend on the migraine types and markers you employ? Are there specific types you're initially focused on? Does early consultation help your team identify whether an individual might benefit from your approach?

A: This question about the importance of migraine subtypes in personalized treatment touches upon one of our research interests. Mounting evidence indicates that migraine with and without aura have distinct genetic architectures (check out the largest genetic study of migraine risk to date). We’re actively collecting data for subtyping that will help us explore this area further. Currently, we focus on treating migraine with and without aura -- although, as mentioned, we do screen to see if individuals have any "red flags" that may warrant more immediate medical attention!

Q: How did you arrive at the single nucleotide polymorphisms (SNPs) you’re using to determine what treatment is likely to work for each individual? What validations show that they’re really predictive? 

A: At the moment, with our patent pending, we’re not at liberty to disclose full technical details. Some SNPs that we look at underlie previously established pharmacogenetic recommendations, based on studies using a variety of outcomes (e.g. drug discontinuation or variation of serum concentrations by genotype). (CPIC lists such studies for amitriptyline on p. 26 here).

A growing number of pharmacogenetic studies are being conducted, so it's very likely that additional genetic associations will be discovered in the near future. Part of our internal research focuses on finding more of them, allowing even more refined predictions for our members over time.

Q:  How much of the variance of migraine incidence do these loci explain? And, what percentage of migraine sufferers do you expect will have a genotype allowing for more targeted therapy? Your site references a big increase in treatment efficacy for patients who’ve been on ineffective therapy – how would this compare to patients changing medicines in a standard setting, with no DNA testing?

A: The variance explained on the basis of the genetic associations in the 2022 migraine genome-wide association studies (GWAS) is about 10-15%. Estimates from twin studies are much greater at 40-60%. We're hoping that future genetic association studies will close this gap, for example by considering the effects of rare genetic variation on migraine predisposition.

Interestingly, there is evidence that markers from such studies of migraine predisposition work to predict drug response. This interesting paper by Kogelman et al. predicts triptan response on the basis of migraine risk. Our loci of interest include those around well-known pharmacogenes (e.g. CYP450) which affect migraine drug metabolism without necessarily impacting one’s risk of having migraines.

Variation in these pharmacogenes is quite common. This overview from Stanford discusses the prevalence of genetic variation impacting drug response, which also goes beyond migraine.

In answer to that final question, we haven't come across a mention of the expected increase in efficacy from a non-genetically guided drug switch in the literature, but the historic drug response data we collect would allow us to calculate this.

Q: Exactly what have you found in DNA that links to migraine? Does this information enable you to determine exact types of migraines? And how far along are you with research to treatment?

A: A wealth of literature provides evidence linking your DNA (or mutations within it) to both the onset of migraine and your responses to treatments. At Mable, we’re focused on the latter, aiming to improve the often tedious process of pinpointing the right treatment for you. 

Therefore, we're not currently focused on investigating diagnostic genetic markers for migraine. Nevertheless, a whole field of study is dedicated to genetically predisposed migraine subtypes such as Familial Hemiplegic Migraine, a rare monogenic form of migraine (included in the review here), as well as migraine with and without aura (which evidence suggests are genetically distinct, but which are both influenced by a wide range of variants across the genome). In the future, we do hope to expand our DNA testing to encompass migraine diagnosis, but at this time we're focused on treatment.

Regarding treatment, a wealth of evidence supports the thinking that mutations in your DNA, particularly in regions and genes associated with drug metabolism, can significantly impact the efficacy of your medication and the side effects you experience (see these reviews by the Clinical Pharmacogenetics Consortium or the Dutch Pharmacogenetics Working Group). This is the case for a number of medications used to treat migraines. 

 If you carry a mutation in a gene involved in the metabolism of your migraine medication, you might find that your medication doesn't work very well to reduce your migraines, or that you experience more side effects than other people. Because of the wide array of possible medications used to treat migraine, it's often trial-and-error to find medication that works well for you with a tolerable level of side effects.

This is where Mable comes in: we look at hundreds of genetic markers to estimate whether a drug will have low efficacy or more side effects, then apply that information to help pinpoint a medication that should work well for you. We pair you with a physician who is aware of your information and can make informed treatment decisions for you.

Q: Has your team done any research on vestibular migraines? 

A: Vestibular migraine is unlike traditional migraine as the main symptom is dizziness — you may not even get a headache! Because vestibular migraine is a complex condition, we’re not yet able to provide treatment plans for this condition; however, we hope to explore this in the future. 

Q: My wife suffers from menstrual migraines that cause her to be completely down for about 3-4 days a month. Does your treatment work for this type? She currently has some success with sumatriptan.

A: We sympathize with migraine patients who experience head pain that essentially shuts you down. It’s our goal to help lessen the frequency and/or severity of your wife's migraine attacks. An individualized approach is key to addressing the unique needs of each person with migraine.

Mable uses DNA information to look at likely responses to medication, and our clinical team looks for contributing factors that lead to migraine, or the absence of protective factors. Many people living with migraine have a problem with certain nerves that supply blood vessels within the brain. Either pain is transmitted along these nerves, or the nerves release pain-causing chemicals, causing the headache symptoms associated with migraine.

Sumatriptan behaves like serotonin, a chemical messenger that sends signals between nerves in many different parts of the body. Serotonin (often called the “happy hormone”) has many different effects on the body. Its involvement in migraine is complex; research shows that it acts directly on blood vessels in the brain, upon nerves that control how pain is sensed, and via a broad network of nerves projecting from the base of the brain (the brainstem) into almost all areas of the brain. 

You may see sumatriptan referred to as a serotonin (5-HT1) agonist. Sumatriptan has three different modes of action:

  • Activates specific nerves that use serotonin
  • Prevents the release of pain-causing chemicals
  • Adjusts blood circulation in the brain

Combined, these mechanisms can reduce the level of pain that a person with migraine experiences, which has the potential to relieve migraine symptoms as soon as a migraine starts to appear. 

And newer forms of migraine analgesia or acute medication, such as CGRPs, provide alternative options to consider!

Topic: The Path Forward with Mable 

Q: If I already have my full-genome sequence data (not a subset), can I skip the "take a DNA test" step and simply share my genome with you?

A: Accepting data generated by third parties is definitely something we're looking to support in the future. As you probably know, a whole genome is a lot of data, and right now, our pipeline isn't set up to accept it. Feel free to message us with information on where you had your genome sequenced, and we'll look at accelerating that vendor in our pipeline roadmap.

Q: Is there enough info about how migraines/headaches happen to really decide on a targeted solution? Most doctors I've talked to always seem to say they don't really know how and why migraines happen. Also, how do newer migraine treatments affect your plans — for instance, Aimovig (first FDA-approved medication that blocks the CGRP receptor to help prevent migraine)?

A: This is precisely at the heart of what Mable stands for. A major problem in standard migraine care is that traditional clinical assessment rarely provides information about the individual sufficient enough to narrow down the scope of potentially suitable treatments. As a result, people often undergo a long trial-and-error process as they try to avoid side effects or find effective relief.

Mable helps physicians and patients bridge the gap between a traditional clinical assessment and the growing field of pharmacogenomics. The number one thing missing in standard migraine care are biomarkers. And monoclonal antibodies such as Aimovig are part of our offering.

Again, many thanks for your interest and curiosity in Mable’s mission. As always, we’re here to help! 

Note to our readers: In this blog, we’ve made some edits for clarity and brevity. You can check out the original full Reddit thread here.

Sources

Sources

  1. NIH/National Library of Medicine. Graph: Discontinuation up to 12 months. https://pubmed.ncbi.nlm.nih.gov/27837173/#&gid=article-figures&pid=figure-3-uid-2
  2. NIH/National Library of Medicine. Pharmacogenetics at Scale: An Analysis of the UK Biobank. https://pubmed.ncbi.nlm.nih.gov/33237584/
  3. PharmGKB. Annotation of DPWG Guideline for amitriptyline and CYP2D6. https://www.pharmgkb.org/guidelineAnnotation/PA166104982
  4. Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org/
  5. The Journal of Headache and Pain. Is there a causal relationship between stress and migraine? Current evidence and implications for management. https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-021-01369-6
  6. Dietary Guidelines for Americans. US Dietary Guidelines. https://www.dietaryguidelines.gov/
  7. Mable. The Mable Blog. https://www.trymable.com/blog
  8. Nature. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. https://www.nature.com/articles/s41588-021-00990-0
  9. Supplement to Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Tricyclic Antidepressants: 2016 Update. https://files.cpicpgx.org/data/guideline/publication/TCA/2016/TCA_Supplement_2016.pdf
  10. ResearchGate. Migraine polygenic risk score associates with efficacy of migraine-specific drugs. https://www.researchgate.net/publication/336804111_Migraine_polygenic_risk_score_associates_with_efficacy_of_migraine-specific_drugs
  11. The Journal of Headache and Pain. Advances in Genetics of Migraine. https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-019-1017-9
  12. Mable. The Mable Blog. https://www.trymable.com/blog/nurtec-rimegepant-migraine
  13. NIH/National Library of Medicine. Pharmacogenetics: a tool for identifying genetic factors in drug dependence  and response to treatment. https://pubmed.ncbi.nlm.nih.gov/22002450/

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