Category Archives: Research

Lawrence Robbins, MD

Abstract

To expand the current description of refractory migraine, the World Headache Society advocates the use of both simple and complex definitions. Simple would be for the general use of patients and support groups, and complex for research and clinical purposes. These definitions include the roles of preventive and abortive medications, non-medication treatments, medication overuse headache (MOH), and a refractory scale to rate severity.  The complex definition provides criteria for the categorization of responses to both abortives and preventives based on the availability of migraine treatments in different countries. It is suggested that refractoriness is defined as failure of adequate trials of at least 3 classes of preventives or 2 classes of abortives.  For countries with limited access to both preventive and abortive therapies, the patient should have failed at least half of the available preventive classes, or all of the classes of the available abortive therapies. The rationale behind the definitions is discussed in the subsequent sections.

A. Introduction

When an individual has persistent headaches that fail to improve after a trial of the standard treatments, the term “refractory migraine” is often used in clinical practice.¹   This term was coined by Reisman in 1952.² Since then, a number of definitions for refractory migraines have been proposed.^3,4,5,6,7 However, the current definition is appropriate primarily for countries where there is a wide array of treatments available, including onabotulinumtoxinA and CGRP medications. There is no mention in the current definitions of abortive approaches. Moreover, the role of medication overuse headache (MOH) is unclear in current definitions. There is no scale to separate milder patients from the more severe refractory migraineurs. It is also noted that current definitions focus on refractory chronic migraine. We have chosen to define refractory migraine.

This paper outlines the proposed definition of refractory migraine and the rationale behind the definition. In addition, other topics such as abortive medications, MOH, and a refractory scale have been included. To expand the current definition of refractory migraine, we would like to suggest both simple and complex definitions. Simple would be for easy general use, and complex for research and headache specialists. In the future, a panel of headache experts from the regional directorates of the World Headache Society will publish a consensus document.

B. Objectives for a revised definition

 To standardize terminology and agree on working definitions in order to:
– provide a clear definition of refractory migraines for:

1. Headache specialists
2. Researchers in headache medicine
3. All clinicians and allied healthcare professionals
4. Patients and caregivers
5. Policy makers and patient advocacy groups

– classify headaches in terms of severity and disability across the lifespan (pediatric, adult, elderly)
-to include responses to abortives as well as preventive therapies

C. Definition of Refractory Migraine

Simple definition:
The migraines have not been adequately controlled by medications or non-medication approaches.

Note: This definition is drafted for the general use of patients, primary caregivers and patient advocate groups.

Complex definition:
The migraines have not been adequately controlled by medications or non-medication approaches (non-pharmacological). ^8,9    

The migraines may be refractory to preventives, abortives, or to both. Not all patients have required preventive medications. If they have only been taking abortives, but these have failed, they do have refractory migraine (but just to abortive therapies). In addition, MOH will have been addressed prior to designating the patient as having refractory migraine.

Migraine is defined according to the International Classification of Headache Disorders-3.  In addition, migraine mimics and secondary migraines have been excluded,  as discussed in the World Headaches Society’s WHIS-MCH1 Classification Group 1, Syndrome of Migraine.

Note: This definition is drafted for the use of clinicians, allied medical professionals, and researchers in the field of headache medicine.

 Explanatory Notes

 2.1 Non- medication approaches

 Non-medication approaches have failed to achieve adequate relief. Not all patients are able to utilize most of the non-medication therapies, but attention to the usual lifestyle changes should have been attempted. At least one of the following measures should have been utilized: meditation, biofeedback, other relaxation approaches, psychotherapy, yoga, acupuncture, massage, physical therapy, and others.^10,11,12

 2.2 Preventive medications or preventive injections

For patients who have had access to almost all migraine medications, including OnabotulinumtoxinA and CGRP monoclonal antibodies:      

The preventive approaches have failed to reduce the impact of the migraines by at least 50%, as evidenced by a headache diary.^13,14 The patient should have failed on at least 3 classes of migraine preventives.

Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks or discontinuation due to adverse effects or ineligibility due to co-morbidities. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinumtoxinA and/or a CGRP preventive (injection or oral).

Preventive medications: For patients with limited access to certain migraine medications

The preventive approaches have failed to reduce the impact of the migraines by at least 50%.  The patient should have failed on at least half the classes of migraine preventives that are available. Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks, or discontinuation due to adverse effects. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinum toxin A and/or a CGRP preventive (injection or oral), or trials of non-medication therapies such as non-invasive neuromodulation, acupuncture, yoga or CBT.

 2.3 Abortive therapies

Abortive therapies: For patients who have access to almost all abortives, including gepants

The abortives have not provided consistent relief at least 50% of the time (trial in at least 4 consecutive headaches). Relief is defined as pain-freedom (or “near” pain-freedom) at 2 hours, after medication overuse headache has been addressed. ^15,16,18 Alternatively the medication may have been discontinued due to intolerable adverse effects. The patient should have utilized simple analgesics (paracetamol and NSAIDs) and at least 2 of the following categories: triptans, gepants, DHE, or injectables (ketorolac, etc).

Abortive therapies: For patients with limited access to certain abortive medications.    

Refractoriness may be defined as non-responsiveness to all of the available classes of abortive therapies.

NOTE: It is important to note if the patient is refractory to preventives, abortives, or both preventives and abortives.

 2.4 The Role of Medication Overuse Headache (MOH)

Medication overuse headache (MOH): The patient should have been assessed for MOH. MOH is defined according to ICHD-3 with the modifications as follows:

1. It is important that MOH not be conflated or confused with medication overuse (MO)
2. To determine whether MOH is truly present, a careful history regarding the offending medication must be obtained. Based on the history and assessment of headache diaries, it should be more likely than not that the offending medication is actually triggering more migraines. Ideally, the subsequent medication should be withdrawn, and the effect on the patient’s migraines observed. This is not always possible.
3. After observing the results of the offending medication having been discontinued, a definite determination of MOH may be made. If it is determined that the patient is most likely is suffering from MOH, the designation of refractory migraine will be withheld until the MOH situation is resolved.

2.5 Refractory Migraine Rating Scale:

It is useful to separate patients into mild, moderate, and severe refractory. This is helpful for research purposes. In addition, our clinical approach and expectations are different for a patient with mild refractory migraine versus severe refractory migraine.^18,19

Refractory Rating Scale for adult patients, age 20+:  The scale consists of eight items, with 10 possible points. Points are added if the patient is:

After totaling the points, the scale helps clinicians to categorize patients as follows:
2 to 4 points= mild refractory migraine
5 to 7 points= moderate refractory migraine
8 to 10 points= severe refractory migraine.

Refractory Migraine Rating Scale for Adolescents, ages 11 to 19:

 The point system for the adolescent patient would be as follows:

With this scale, a total of 8 points would be possible, ranking as such:

   2 to 4 points = mild refractory migraine.
   5 to 6 points = moderate refractory migraine.                         
   7 to 8 points = severe refractory migraine.

Future Perspectives and Conclusion

This is a continuous work in progress. We have attempted to revise and add to existing refractory definitions. Our primary changes include: including abortives in a refractory definition, separating a simple from a more complex definition, adding a section that applies to patients with limited access to more advanced approaches, adding to the existing MOH definition, and adding a refractory rating scale for adults and adolescents.

In the future, we may use biomarkers to identify refractory patients, but until then we must use our clinical criteria.

Key points

Committee Chair: Dr. Lawrence Robbins

Members: Dr. Pravin Thomas, Dr. Paul Emmanuel Yambao

Permission has been obtained from the co-authors to reproduce this article on Refractory Headache definition in the SPS newsletter.  Dr. Thomas is the founder (and directs) of the WHS, and Dr. Robbins is a Vice President. The permission comes from Dr. Pravin Thomas. 

References

1. D’Antona, L., Matharu, M. Identifying and managing refractory migraine: barriers and opportunities?. J Headache Pain 20, 89 (2019). https://doi.org/10.1186/s10194-019-1040-x
2. Reisman EE Jr (1952) The use of experimental suppositories in treating refractory migraine. Am Pract Dig Treat 3(4):308–310
3. Sacco, S., Braschinsky, M., Ducros, A. et al. European headache federation consensus on the definition of resistant and refractory migraine. J Headache Pain 21, 76 (2020). https://doi.org/10.1186/s10194-020-01130-5
4. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D (2006) Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia 26:1168–1170
5. Martelletti P, Katsarava Z, Lampl C, Magis D, Bendtsen L, Negro A, Russell MB, Mitsikostas DD, Jensen RH (2014) Refractory chronic migraine: a consensus statement on clinical definition from the European headache federation. J Headache Pain 15:47
6. Schulman EA, Lake AE 3rd, Goadsby PJ, Peterlin BL, Siegel SE, Markley HG, Lipton RB (2008) Defining refractory migraine and refractory chronic migraine: proposed criteria from the refractory headache special interest section of the American headache society. Headache 48:778–782
7. Wöber C, Wessely P, Austrian Consensus Group on Refractory Chronic Migraine (2014) Comment on: Martelletti et al. Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J H
8. Guidelines /ICHD – International Headache Society (ihs-headache.org)
9. Classification of Head, Neck, and Face Pains First Edition (WHS-MCH1): Position paper of the WHS Classification Committee (headachemedicineconnections.com)
10. Grazzi L, Toppo C, D’Amico D, Leonardi M, Martelletti P, Raggi A, Guastafierro E. Non-Pharmacological Approaches to Headaches: Non-Invasive Neuromodulation, Nutraceuticals, and Behavioral Approaches. Int J Environ Res Public Health. 2021 Feb 5;18(4):1503. doi: 10.3390/ijerph18041503. PMID: 33562487; PMCID: PMC7914516
11. Wu Q, Liu P, Liao C, Tan L. Effectiveness of yoga therapy for migraine: a meta-analysis of randomized controlled studies. J Clin Neurosci. 2022. https://doi.org/10.1016/j.jocn.2022.01.018.
12. Ou MQ, Fan WH, Sun FR, Jie WX, Lin MJ, Cai YJ, Liang SY, Yu YS, Li MH, Cui LL, Zhou HH. A Systematic Review and Meta-analysis of the Therapeutic Effect of Acupuncture on Migraine. Front Neurol. 2020 Jun 30;11:596. doi: 10.3389/fneur.2020.00596. PMID: 32714268; PMCID: PMC7344239.
13. Silberstein SD. Preventive Migraine Treatment. Continuum (Minneap Minn). 2015 Aug;21(4 Headache):973-89. doi: 10.1212/CON.0000000000000199. PMID: 26252585; PMCID: PMC4640499.
14. Baos V, Ester F, Castellanos A, Nocea G, Caloto MT, Gerth WC; I-Max Study Group. Use of a structured migraine diary improves patient and physician communication about migraine disability and treatment outcomes. Int J Clin Pract. 2005 Mar;59(3):281-6. doi: 10.1111/j.1742-1241.2005.00469.x. PMID: 15857323.
15. Silberstein SD, Newman LC, Marmura MJ, Nahas SJ, Farr SJ. Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain. Curr Med Res Opin. 2013 Jul;29(7):861-7. doi: 10.1185/03007995.2013.787980. Epub 2013 May 22. PMID: 23514092.
16. Tfelt-Hansen P, Diener HC. Pain freedom after 2 hours should be the primary outcome in controlled trials treating migraine attacks. Cephalalgia. 2020 Oct;40(12):1331-1335. doi: 10.1177/0333102420941827. Epub 2020 Jul 13. PMID: 32660268.
17. VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. 2021;325(23):2357–2369. doi:10.1001/jama.2021.7939A
18. Sacco, S., Lampl, C., Amin, F.M. et al. European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure. J Headache Pain 23, 133 (2022). https://doi.org/10.1186/s10194-022-01502-z
19. Robbins L. Refractory chronic migraine: long-term follow-up using a refractory rating scale. J Headache Pain. 2012 Apr;13(3):225-9. doi: 10.1007/s10194-012-0423-z. Epub 2012 Feb 25. PMID: 22367626; PMCID: PMC3311833.
20. Robbins L. Refractory Chronic Migraine: Mild, Moderate, or Severe. Pract Pain Manag. 2019;19(4).
21. Safiri, Saeida,b; Pourfathi, Hojjatc; Eagan, Arielled,e; Mansournia, Mohammad Alif; Khodayari, Mohammad Taghig; Sullman, Mark J.M.h,i; Kaufman, Jayj; Collins, Garyk,l; Dai, Haijiangm; Bragazzi, Nicola Luigim; Kolahi, Ali-Asgharn,*. Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019. PAIN: February 2022 – Volume 163 – Issue 2 – p e293-e309 doi: 10.1097/j.pain.0000000000002275

Lawrence Robbins, MD

 Evolutionary Medicine is a growing, vital, fascinating and relevant area. I use it daily in my practice, to explain to patients (such as the evolutionary reason for anxiety, why we have so much neck and back pain, why we suffer pain and mortality with childbirth etc…) it should be taught in our medical, nursing, and physician assistant (PA) schools. We could avoid problems by studying evolution.  How best to use antibiotics, and how avoiding blocking certain compounds that are crucial for 400 million years such as CGRP, which certain migraine drugs block, are two examples of how understanding evolution could benefit patients. We ignore evolution “at our peril”.

A Bit O’ History

• Darwin thought along evolutionary lines: ERASMUS DARWIN, that is… (1790) Erasmus was the grandfather of Charles. Lamarcke (about 1805) built on his ideas. Lamarcke had the right idea (but thought an acquired trait during one’s life could be directly inherited… he believed in “spontaneous generation”)
• Later in 1858, Charles wrote “On the Origin of Species”. He was hurried along because of Alfred Wallace; they admired each other. Similar to Rosalind Franklin of DNA discovery, Wallace has been unfairly forgotten.

Early objections to evolution (my main thesis as an undergrad) were mainly along religious grounds, and also that early proof was lacking. Although The religious arguments persisted, within 15 years evolution was scientifically accepted.

Why Study Evolution?

• Goal of medicine is to improve health and prolong life.
• Evolutionary medicine goals include to:
  • Help develop safer treatments, such as our new CGRP meds to prevent migraine which are possibly dangerous.
  • Change modern behaviors. Historically, we had a healthier diet, and constantly exercised, for 99% of our human existence.
  • Learn to use medications in healthier ways, such as how to manage antibiotics.
  • Help clinicians explain to patients the evolutionary reason for their conditions, such as anxiety, depression.

Proximate vs. Evolutionary

• Proximate explanation = the nuts and bolts, such as neurochemistry, physiology, etc.
• Evolutionary = WHY something came about
• Proximate = a mechanical explanation
• Evolution = the engineering design
• Ontogeny = proximate (mechanical, “nuts and bolts”) development of an organism from fertility to egg to adult
• Phylogeny = evolution and history of a species

Natural Selection

• Natural selection (NS) depends upon variation.
• NS operates mainly at the level of the gene.
• NS involves phenotypic variations driving genotype and phenotype changes over generations.
• Within a population, variation leads to some individuals being better suited to the environment than others. This results in adaptive changes.
• Natural selection is going on today; as little as 8,000 years ago, nobody had the genes to digest lactase; now, the genes for lactase are present in over 70% of Northern Europeans. Even by Roman times those genes were becoming more common.

Asking the Right Question

• The right question (Nesse/Williams): Why are we so vulnerable to various diseases?
• The wrong question: what evolutionary advantage does each disease have? (yes, they may have advantages, but often they do not).
• Albert Einstein said, if given 60 minutes to solve a problem, he will take 55 minutes to come up with the right question.
• Jonas Salk: “Solutions… they come through asking the right question, because the answer pre-exists”…

6 Principles of Evolutionary Medicine

• Randolph Nesse pioneered much of this thinking: (Nesse and Williams):
  1. MISMATCH: our environment has changed, we are adapted for a radically different (ancient) environment.
  2. TRADE-OFFS: many (most) aspects of human anatomy and physiology involve trade-offs.
  3. EVOLUTION cares about reproduction and propagating one’s genes; it DOES NOT CARE about: health, happiness, longevity (except for possibly the “grandmother hypothesis: nurture and epigenetics”).
  4. PATHOGENS can replicate much faster than humans; hours versus our 18+ years. Pathogens will usually win the evolutionary arms race.
  5. DEFENSES: many symptoms are often defenses, not diseases (fever, nausea/vomiting, cough, diarrhea).
  6. NATURAL SELECTION and evolution are LIMITED; there are constraints on what selection can do; evolution tinkers, it does not invent.

Mismatch with the Environment

• Ten to twelve thousand years ago we began to cultivate agriculture.
• We morphed from hunter-gatherers (H-G) — more accurately called “forager-gatherer-fisher-hunters” — to agriculture-based societies.
• Changes in our environment include:
  • agriculture
  • a move towards dense, urban populations
  • artificial light, less sunlight, & light at night
  • Houses
  • Reading
  • Pollution
  • sterile food/water
  • solo sleeping
  • bottle feeding
  • Antibiotics
  • other medicines
  • sleep changes (less sleep)
  • steady food with less food insecurity and less fasting
  • heating and cooling
  • long-term marriage
  • birth control
  • mass media and social media
  • louder sounds
  • change in diet to high starches (beginning 14,000 years ago): led to many problems
• Approximately 50% of diseases are strongly influenced by environmental changes (mismatch with our previous environment)

Evolution and Migraine

• Migraines increased as we moved to more northern latitudes. Low vitamin D levels and the TRPM8 gene play a role. TRPM8 is linked to decreased sensitivity to both cold and migraine.
• Migraine due to mismatch with our modern environment, including increased light, sound, stress, immune response (possibly tied into ridding ourselves of worms/parasites), lack of exercise, urban density (and an increase in infections), poor sleep, changes in diet, pollution, electronics and social media, etc…
• Migraine may have occasional evolutionary advantages such as an enhanced immune response could be helpful in fighting certain infections. it is speculated that the rates of mating and fecundity among migraineurs may be increased, and more research is needed. In the past most people died of infections. If one is laid up with a migraine when a virus sweeps through, the migraine may enhance survival.
• Why migraine is much more common in women is unclear. Migraine often decreases during pregnancy, offering a small evolutionary incentive for more pregnancies.
• Hunting/fishing were often done more by men; migraine may pose disadvantages for these activities.
• Women did more of the foraging; migraine may not have as much of an effect on foraging, although this is unclear.
• Why does migraine only affect humans? It may be that our ancient human brainstem has difficulty coping with a newer cortex that is vastly enlarged. Higher cortical functions may add to our continued vulnerability to migraine.
• Migraine could be a defense mechanism against excessive stress, noise, or light.
  • Migraineurs have an enhanced sensitivity to smells; this may be protective from toxins or viruses entering the CNS. Vomiting from a migraine may remove toxins.
  • Women with migraine (probably) have a lower incidence of Type 2 diabetes.                                                                                    
  • Activating the trigeminal nuclear complex could be protective to the migraineur.

• If a migraineur has 100 migraines in a year, and just one protects from harm, the trade-off may be worthwhile. Evolutionarily, the cost of migraine may be inexpensive.
• Headache and pain are adaptive. Being still in bed may help with repairing damaged tissues.
• As mentioned, mismatch with our modern environment, with radical changes over 12,000 years, is a primary driver for the increase in migraines.
  • Cultural changes (social media etc.) also may play a role.
  • The elimination (past 140 years) of worms/parasites in our GI systems has led to an increase in autoimmune illnesses. Migraine is probably (somewhat) autoimmune.

Migraine, Evolution, and our CGRP Therapies-

• CGRP monoclonal antibodies to prevent migraine were introduced 2018. They are effective, but these have many short term adverse effects (in the 1st 3.5 years, 50,000 adverse events reported to the FDA, and 7,000 serious ones).
  • We do not yet know long term effects. CGRP has been in animals for at least 350 million years and is ubiquitous throughout our body. Blocking CGRP for years (or decades) ignores all of it’s numerous evolutionary advantages. If we paid attention to evolution, we may not have pursued the avenue of blocking CGRP.
  • We ignore evolution at our peril!

Further reading and YouTube viewing on Evolutionary Medicine:

There are excellent books, but I recommend searching YouTube: many outstanding talks on evolution and medicine

• Books: Why We Get Sick by Nesse and Williams, Human Errors by Lents, Good Reasons for Bad Feelings by Nesse, Evolution and Medicine by Perlman
• Robert Sapolsky is a marvelous author and speaker (many talks on YouTube: he was Scientist of the Year (U.S.) and has a newer book out, “Behave” that incorporates evolution and behavior
• Principles of Evolutionary Medicine by Gluckman et al., Evolutionary Psychiatry by Brune, The Third Chimpanzee by Diamond, Chaos and Life by Bird, The Evolution of the Human Head by Lieberman, Evolution In Health and Disease by Stearns et al, The Lives of the Brain by Allen, Sapiens by Harari, The Riddled Chain by McKee, Evolutionary Medicine and Health by Trevathan et al.

YouTube

• An excellent lecture is “An Evolutionary Model of Depression” by Markus Rantala
• YouTube: There are hundreds of excellent lectures and discussions.
  • Randolph Nesse has a plethora of videos and interviews; Yale Medicine and Steven Stearns has a series of excellent videos; Nathan Lentz is outstanding; Robert Sapolsky as mentioned above, and many others.

Evolutionary Psychiatry (EP)

• Anxiety and the “Smoke Detector Principle”
  • At the watering hole on the Savannah, if the chance of getting eaten is even 1 out of a thousand, it is worthwhile to run away every time; this is “adaptive”
  • However, if we start having panic attacks for no reason, this is “maladaptive”… the margins between adaptive and maladaptive can be blurry… and it all depends on the context in which the behavior occurs.
• The stress response is a product of millions of years of selection. The system is usually adjusted and turned off due to its costs. These adjustments include a minimized immune response during stress along with an increased metabolism.
• Even in fish, timid fish survive predation more than bold ones…
• Even now, evolution is occurring: red squirrels around Chicago are disappearing, as they are bolder than the grey squirrels, and don’t run away from cars. The timid grey squirrels are surviving
• Many behaviors are observed in humans and primates, and all the way back to fish or even fruit flies! Many animal behaviors do not change from genus to genus.
  • When emotions become maladaptive, they become a “psychiatric illness”
  • Anxiety costs energy, due to catecholamine release and cortisol depletion. Energy (or the lack of) and ATP governs much of animal behaviors and evolution.
  • Chronic stress and anxiety become maladaptive, with deleterious effects.
  • Phobias can be viewed as maladaptive forms of what would be healthy adaptive thoughts in a different environment. Phobias arise out of a perceived danger from attack, trauma, or predation. What might be a reasonable response in a context 2 million years ago is unreasonable now. We are unlikely to have problems from snakes, spiders or sharks, but these phobias persist…

• Adolescent behavior of pushing, attention seeking, impulsivity, and aggressiveness can be an advantage for mating and reproduction. Remember, evolution cares not for how happy you are, or how long you live. Evolution cares most about propagating genes.
• Risk taking can also help in food acquisition.
  • Male risk taking (peaks in adolescence) succeeds evolutionarily. It leads to more reproduction, but also contributes to many earlier deaths.
  • At age 20 (and most other ages), for every 100 women who die, on average 350 men die, partly due to risky behaviors. This number varies between countries. These risky behaviors lead to more procreation (which is the purpose of evolution), but also leads to death. Men are also more vulnerable to certain diseases. Men are 2 to 3 times more likely to die of cancer or heart disease. An increase in procreating, but dying earlier, is a classic trade-off.
• ADHD could possibly have adaptive survival benefits. In the forest, it could conceivably be beneficial to be unfocused and constantly looking around. However, it is more likely that ADHD is not very beneficial, but rather it is one of many illnesses that evolution simply cannot delete out of our genome. Schizophrenia is another such illness. One percent of people are schizophrenic in almost every country. Schizophrenia results in no evolutionary advantage for survival.
• Certain personality disorder (PD) traits (aggressiveness, salesmanship, paranoia, alpha behaviors, and the “charming- seductive” behaviors) can result in increased mating and reproduction. This is part of the reason why PDs persist. The other reason that these genes persist is the plethora of different genes involved in PD pathology. Evolution has no easy way to delete these genes.
• DEPRESSION: The different symptoms can be adaptive — if fighting an alpha male, submissive and depressed behavior may enable immediate survival. Low mood may allow an organism to recover from an infection more easily by not moving about. Depressed people may show little movements of the eye and mouth region, avoid eye contact, speak softly, and remain socially inactive. These all have advantages in certain contexts.
• In a situation where appeasement is necessary, and inferiority or defeat is present: the non-verbal behaviors of depression may lower aggression by others. Catatonia may be an extreme example of ancient defense mechanisms.
• Dominance, submission, and social hierarchy are inherent in most primates (and other animals, going back 400 million years). The winner and loser in a clash ideally both remain within the group. In ancestral environments, exclusion would have meant death.
• Human life is dependent on a complex web of interactions with other humans, more than in other primate species.

• Why do women have more depression than men? Outside of the proximate “nuts and bolts” explanations, evolutionary sex differences play a role. Women (more than men) depend upon social support. Women have had less ability (for several reasons) to leave a bad relationship/marital situation, with depression as a consequence. This may go back to ancestral times.
• Many theories as to why we become depressed have been put forward.
  • Early work focused on infant attachment.
  • Negative life events may trigger low mood or depression, and also loss of social status. Hunter-gatherer societies experience the low mood but not nearly as much of the depression. Depression is rampant in Western societies.
  • These theories are outlined in the excellent book by Randolph Nesse, MD: Good Reasons for Bad Feelings (2019)
• Depression is much more prevalent in Western societies
  • Depression (and anxiety) has increased from 2008 to the present; probably mismatch with the environment (social media, smartphones, pollution, etc.) and world stresses (pandemics, politics, war)
• As mentioned, little depression is observed among various hunter-gatherer societies, and also among the Amish.

 EP — Depression, Inflammation and evolution

• Inflammation plays a role in depression; our “modern’ diet plays some role in this…
• Western society has more inflammation than hunter-gatherer societies
• Our lifestyle and subsequent mismatch with the modern environment are factors
• GI worms/parasites downregulate our neuroimmune response; since ridding ourselves of these in the past 120 years, inflammation has skyrocketed!
• A “depression symptomatic” approach fits into evolutionary thought: the idea is that depression is a description of a number of different symptoms but not a “disease” itself. There is some evidence that simply asking about “low mood” is just as accurate for diagnosing depression as using DSM-5 criteria. A MDD diagnosis is not that helpful in guiding specific treatments.
  • The “depressive symptomatic” approach evaluates the varying symptoms, each of which can be treated. The symptoms influence each other in a feedback loop: for instance, insomnia causes fatigue, which increases low mood, which then exacerbates insomnia.
  • If we perturb one part of this system, the system will read just itself into a new homeostasis: if we decrease the insomnia, the fatigue is lessened, and then the depression may be better.
• Each particular symptom could be adaptive in an evolutionary sense; the symptom becomes maladaptive if it is pathologic and causes undue distress, such as panic attacks. Adaptive vs. maladaptive varies depending upon the environment and context in which it occurs.
• Sadness/emotional pain could be adaptive in that they lead to avoidance of actions that may result in more losses.
• Crying elicits empathy and support from other group members. Exclusion, real or threatened, from a group may lead to depression. Loss of social status or hierarchy triggers depression.
• Fatigue helps conserve energy and may be adaptive.
• Seasonal affective disorder (SAD) may help to conserve energy in winter. In winter if a primate hunkers down, possibly due to low mood, and does not go out in the cold, energy is conserved.

EP and Mania

• Mania may represent the pathologic extreme of dominance behaviors. Dominance and risky behaviors may lead to increased mating and reproduction (the goal of evolution).
  • Mania could also be a compensatory mechanism to view the world as less threatening.
• Hypomania/hypersexuality = may result in increased mating.
• Mixed states: one theory — mania is generated more from the cognitive/cortex level, and appeasement/depressive behaviors from the reptilian (older) brain.
• In dysphoric mania, evolutionarily the mania could offset that pervasive hypervigilant fear that is so often present.

EP, cont…

• Selection favors traits that promote fitness in our social environment such as: cooperation, reciprocal altruism, the ability to interpret actions of others, and also to detect freeloaders within the clan.
• Altruistic behavior lowers group stress, increasing survival of all group members.
  • What may look altruistic may actually be survival of the individual (the famous Wild Kingdom Wildebeest episode)
• An increase in cortical neurons, and acquisition of language, resulted in more complex group behaviors.
• Human behavior also involves mating choice, kin selection, social group living, etc. For more on human behavior, check out Robert Sapolsky’s books (particularly his book “Behave”) and YouTube talks.
• Schizophrenia and bipolar share many genes, spread throughout the genome. Autism and schizophrenia also share similar genes.
• The multitude of genes, spread throughout, is one reason evolution cannot easily delete “bad” genes. Mutations also play a role in creating “new” psychiatric illness. When many genes are involved it renders it impossible to cure these illnesses through any type of “gene therapy”.
  • There are exceptions, where a cure is conceivable, such as Huntington’s (a specific CAG repeat)
• For men, appeasement and submission do NOT pay off with increased mating. However, they may enhance survival. The differences in male vs. female depression may go back millions of years.
• For men, social status = crucial towards mating and reproduction. Higher social status = more mating.
• Lack of social support from elderly kin leads to increased risk for depression.
• We are clannish by nature: “The oddity effect”: animals don’t associate or align with phenotypically different individuals. This goes back to fish, birds, mammals and even plankton! Clannish nature may contribute to “otherism”, and possibly racism as well.
• This may be the origination of human bullying (“appearance-based bullying”), and helps to explain xenophobia.
• Within a group, those that look the most like the group tend to be the worst bulliers.

 Vasovagal syncope is probably adaptive. It is paradoxical: fainting in the face of perceived danger. The syncope could be adaptive in certain dangerous situations, so as to survive as a younger adolescent. In primates, when fighting a stronger alpha male, it is adaptive to faint and then have a chance at survival.

• Vasovagal syncope is observed in adolescents of other primate species.
• Humans are sensitive to early stress or trauma. As with most behaviors, this is true for other species as well. Even fish are sensitive to early stresses! In primates the effects of stress begins in utero (if mom is stressed, cortisol changes result and this greatly affects the fetus). The vital amygdala-prefrontal cortex connectome is greatly influenced in utero and in the first year of life.
• Aggressive and alpha behavior can be learned (as demonstrated by fish: the fish that lost the battle with an alpha fish, then was allowed to watch the alpha fish interact with others, subsequently learns to act like an alpha fish).
• Taking an ethological (observing behavior in various species) approach, depression may be observed in most species.
• These species include primates, voles, rats, and (There is an excellent YouTube talk on this: An Evolutionary Model of Depression, by Markus Rantala)
• The pelvis changes that resulted from going bipedal contribute to our difficulty with childbirth. Human mothers have more childbirth pain than other species. Human infant and/or mother mortality has been 10 to 20%. The baby has to rotate and flip. Our large skull size also contributes to the childbirth difficulties. We are born relatively immature, as compared to other primates, partly due to our large head: we are born earlier than is ideal.

The CGRP Monoclonal Antibodies for Migraine Are a Prime Example

Lawrence Robbins, M.D.

This letter is in response to an excellent July, 2020 article “Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile” (Boldig and Butala) in the International Journal of Neurology and Neurotherapy. (1) There are a plethora of adverse effects (AEs) from the CGRP monoclonals (mAbs) that were not identified in the Phase 3 trials. Unfortunately we frequently encounter this with new drugs. It often takes several years to identify an accurate picture of the adverse effect profile.

The package insert (PI) for the CGRP mAbs, as with many of the new drugs, identifies few AEs. The reasons for this include:  1. trial investigators did not use a checklist of AEs (a checklist is almost never utilized during drug trials) 2. as with most drug trials, the studies were powered for efficacy but would need many more patients to accurately assess AEs 3. the studies do not extend long enough in order to identify the true adverse effect profile and 4. adverse effects become “disaggregated”.  For instance, one person may say they have malaise while another may state they suffer from fatigue. This adverse effect is disaggregated and subsequently not included in the PI. After the study is completed these effects may be reaggregated, but that method is not accurate.

To accurately assess AEs post-approval, we must examine multiple lines of evidence. The FDA/FAERS website is an important source of information. Unfortunately, the side effects listed are adverse events, not necessarily adverse effects. As of January 2021, (2.5 years post-launch) there were 40,378 adverse events catalogued from the four CGRP mAbs.  On the FDA website, serious adverse events include those that are life threatening, or that resulted in hospitalization. 5,562 serious adverse events were listed. These numbers are staggering, particularly considering that the vast majority of adverse effects, even serious ones, go unreported.  Erenumab resulted in the bulk of the adverse events. This is most likely because erenumab was the first to market and has been the CGRP mAb most widely utilized. Save for constipation, I do not believe that erenumab is necessarily more likely to produce adverse effects than are the other 3 mAbs. 

After the launch of the drug, another line of evidence is the available post-approval studies and case reports.  One of the observational studies concluded that adverse effects resulted in 33% of erenumab discontinuations (2). Another study described 63.3% of patients as having reported an adverse effect, but they concluded that the CGRP monoclonal antibodies were well tolerated. (3)

We published a study of 119 chronic migraine patients who had utilized one of the CGRP monoclonals. (4) We incorporated a checklist of 19 possible adverse effects. The patients were initially asked about adverse effects by posing the question, “Have you experienced any issues, problems, or side effects from the injection?” Subsequently the patients were interviewed regarding each possible adverse effect, utilizing the checklist. A determination was made, between the patient and researcher, as to whether the adverse effect was truly due to the use of the monoclonal. 66% of the patients identified at least one additional adverse effect via the use of a carefully chosen checklist. 18 patients had one additional adverse effect. 56 patients identified 2 to 8 additional adverse effects.

An additional line of evidence is the opinion of high prescribers of the drug. This is gleaned from chat boards of headache providers, private correspondence, and discussions during conferences. Some headache providers feel that the CGRP monoclonals are safe and adverse effects are infrequently encountered. Others believe, as I do, that the mAbs result in a number of deleterious effects.  There is no consensus at this time.

In addition to headache provider comments, the CGRP patient chat boards provide valuable insight into adverse effects. We assessed 2,800 patient comments regarding adverse effects. We judged 490 to be highly believable. The list of common adverse effects, as identified by the highly believable comments, aligns well with our other lines of evidence.

 After assessing the various post-approval lines of evidence, there are signals that the following adverse effects may result from the use of CGRP monoclonals: constipation, anxiety, injection site reactions, weight gain or loss, worsening hypertension, increased headache, insomnia, depression, hair loss, joint pain, fatigue, irritability, muscle pain or cramps, nausea, rash, sexual dysfunction, and tachycardia (or other heart irregularities).  Most likely there are others as well.  In addition, there have been cases of reversible cerebral vasoconstriction syndrome and stroke. Angina and myocardial infarction have also been reported. Thomas Moore, a leading expert in the acquisition of adverse effects of drugs, published a review of the CGRP monoclonals in the online journal QuarterWatch. QuarterWatch utilizes various resources, including FDA reports and published post-approval studies. (5) The report cites the “sheer number of case reports,” and concludes that “…it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.”

This discussion has revolved around short-term adverse effects. Long-term effects, which are unknown at this time, remain a serious concern. CGRP has been important in various species for 400 million years. We ignore evolution at our peril. There are a multitude of beneficial effects partially mediated by CGRP. These include protecting our cardiac and cerebrovascular systems through vasodilatory effects(particularly during stressful conditions), resisting the onset of hypertension, decreasing oxidative stress in the aorta, improving circulation in the face of heart disease (including heart failure), aiding with wound healing, burns, and tissue repair, minimizing the effects of sepsis, aiding in the healing of GI ulcers, protecting the GI mucosa, affecting GI motility, contributing to flushing and thermoregulation, aiding with cold hypersensitivity, regulating bone metabolism, protecting the kidneys in certain pathologic conditions, playing a role in regulating insulin release, affecting metabolism and body weight, and helping to mediate the adrenal glucocorticoid response to acute stress in the mature fetus. (6) The hypothalamic-pituitary-adrenal axis may be affected by CGRP, and this has not been adequately studied. If these mAbs are to be used in adolescents, we must first study the hormonal effects.

 The package inserts often do not reflect the reality of the AE profile. I believe that the FDA should overhaul the guidelines as to how adverse events are acquired in formal studies. This situation has been harmful to patients. This is not unique to the mAbs. We should work towards improving the early identification of an accurate adverse effect profile. Certain adverse effects, such as sexual adverse effects, or depression, are missed in formal studies.

The CGRP monoclonal antibodies have been beneficial for many migraineurs. The efficacy of these mAbs rivals that of onabotulinumtoxinA. However, CGRP plays a crucial role in many physiological processes. There is evidence for a multitude of deleterious effects that result from blocking CGRP. Long-term effects are completely unknown. We should be cautious and judicious in our use of the CGRP monoclonal antibodies.

Disclosure: L. Robbins is a speaker for Abbott Labs, Teva, and Amgen.

References

1. Boldis K, Butala, N (2020) Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile. International Journal of Neurology and Neurotherapy 7:101: DOI:10.23937/2378-3001/1410101
2. Robblee J, Devick K, et al. (2020) Real-World Patient Experience with Erenumab for the Preventive Treatment of Migraine.  Headache 60:9, p. 2014-2025. https://doi.org/10.1111/head.13951
3. Alex A, Vaugh C., Rayhill M (2020) Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study. Headache 60:10, p. 2454-2462. https://doi.org/10.1111/head13956
4. Robbins L, Phenicie B, (2020) CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practical Pain Management 20:2, p. 48-52.  (online at practicalpainmanagement.com, March/April, 2020)
5. Moore T. (2019) Aimovig, Ajovy, and Emgality. QuarterWatch Reports 24:16, p. 2-4.
6. Robbins L (2018) CGRP Antagonists: Physiologic Effects and Serious Side Effects (Letter). Headache 58:9, p. 1469-1471.

Lawrence Robbins, MD

 INTRODUCTION

Migraine often results in disability and diminished quality of life. Despite this, our species remains particularly vulnerable to migraine. Why is this so?  Evolution may provide answers. The study of evolution and disease is not simply an academic exercise. In studying the history of our species, and those that preceded us, we may be able to develop safer and more effective treatments. We ignore evolution at our peril.

Chaos theory is a subset of nonlinear dynamics. Nature has been able to utilize chaotic dynamics in the brain, heart, and elsewhere (Korn, & Faure, 2003). Chaotic dynamics provide advantages over stochastic (random) or reductive (simple, linear) systems. Neurons and neuron clusters effectively utilize chaos. One hallmark of chaos is the extreme sensitivity to initial conditions (Bird, 2003). This leads to the classic butterfly effect, where a tiny perturbation in the beginning results in enormous changes down the line. Initial conditions played a significant role in the development of Homo sapiens (Bird, 2003). If we travelled back in time, and changed even the tiniest initial traits, today’s human would appear significantly different. 

Chaotic dynamics may play several roles in migraine pathophysiology. For instance, a tiny initial change in blood flow, such as occurs due to a patent foramen ovale (PFO), could eventually lead to the initiation of a migraine. The complex electrical wiring of the brain involves chaotic dynamics (Korn et al., 2003).  Chaos, migraine, and evolution are intimately interwoven. This paper outlines some of their connections. 

CHAOS AND THE NERVOUS SYSTEM

Chaos is a math-based subset of non-linear dynamics. Chaos improves the adaptability, efficiency, and versatility of neuronal systems.  A number of biological systems are governed somewhat by chaotic dynamics.  These systems include the ion flow and electrical activity of the brain, the beating of the heart, blood glucose levels, and glycolysis. Several studies have demonstrated chaos at the cellular level in the brain (Schweighofer, Doya, et al., 2004). By evaluating the flow of ions through the energy barriers of the channel protein, maps reveal the chaotic controls. Algorithms and numerical solutions have been constructed revealing when the transition to chaotic dynamics occurs (Landau, Sompolinsky, 2018). Characteristics of chaotic systems include, most importantly, an exquisite sensitivity to initial conditions.  Chaos is deterministic and predictable solely from one point to the next, but not beyond that point. The initial conditions are then reset after each point.

When compared to reductive or stochastic systems, chaotic systems save energy and are more adaptable.  Chaotic dynamics are involved in governing cortical spreading depression (CSD) (Pietrobon, Moskowitz, 2014). Chaos has been demonstrated to play a role in K+, Ca+, and Na+ movements. The flow of ions about the cell has been determined to be a combination of randomness, reductive(linear) movements, and chaotic processes. A small initial change in K+ efflux, or Ca+ influx, will result in a large effect downstream. Clusters of neurons, as well as single neurons, fire in a variety of patterns. These range from regular oscillating patterns to bursts, and everything in between. Neuronal systems undergo transitions that carry them between diverse states (Vreeswijk, Sompolinsky, 1998). Chaotic dynamics partially govern both individual neurons, as well as groups of neurons.

CHAOS AND MIGRAINE

Tiny CNS perturbations may be brought about by the usual migraine triggers such as weather, stress, or hormonal changes. Through chaotic dynamics this may result in plasma protein extravasation (PPE) and cortical spreading depression, both of which are vital processes in the pathophysiology of migraine (Kernick, 2005). Medications affecting CSD may influence the neuronal membrane through chaotic controls. A small number of patients with patent foramen ovale (PFO) have experienced resolution of their migraines after PFO closure. The usual explanation for the PFO induction of migraine is via microemboli. It is also possible that chaotic dynamics play a role.  A small change in blood flow downstream (the heart) may induce a significant change in CNS dynamics upstream.

Chronic migraine pathophysiology involves wind-up and central sensitization(CS) . These are possibly controlled by chaotic dynamics. Thalamic recruitment involved in expansion of the pain area is likely governed by chaotic dynamics. Thalamic-cortical circuits involve chaotic dynamics. The pathological shift of homeostasis observed in chronic CS, with a loss of brainstem inhibition, may actually reflect a loss of chaotic control (Vreeswijk,et al.,1998). This is similar to the loss of control in the heart, resulting in arrhythmia.  The brainstem periaqueductal grey (PAG)—important in migraine—has been shown to be under chaotic control thru P/Q- type Ca+ channels. Migraine physiology incorporates a combination of genetic and environmental factors.  Trigger factors that affect migraine include stress, weather, and hormonal   changes.   These may affect the delicate balance between interneuronal nonlinear, reductive, and stochastic dynamics.  This may lead to chronic migraine. When a system is forced or stressed, nonlinear dynamics may be affected. 

New onset daily persistent headache (NDPH) may result from a perturbation of neuronal dynamics. Emotional, infectious, or other stresses may influence the delicate balance between nonlinear dynamics and stochastic or reductive dynamics. This could lead to chronic head pain.

Calcium and sodium efflux occur with CSD. Potassium and P/Q calcium channels are also involved. This complex system is unlikely to be governed primarily by random or linear kinetics. Chaotic controls have been demonstrated to be involved with these ionic movements (Pietrobon, et al., 2014). Chaotic dynamics could explain some of the properties of CSD. The initiation of CSD may be brought about by a miniscule change in potassium levels. This tiny effect may activate receptors and result in a large change downstream. The result is CSD and oligemia. With the potassium efflux partially under chaotic control, the chaos probably helps to regulate the increased cortical hyperactivity inherent in the brain of some migraineurs.

The trigeminal nucleus caudalis, vital in migraine pathophysiology, may be activated by a tiny initial stimulus. Through chaotic dynamics, this may result in the release of pro-inflammatory peptides and a release of glutamate. CSD leads to increased plasma protein extravasation. Only chaotic dynamics may explain how this may be possible. The medications that affect CSD (amitriptyline, topiramate, sodium valproate) may influence chaotic dynamics via membrane effects. When nonlinear dynamics are involved, it possibly takes less drug to produce an effect. The periaqueductal gray matter is involved in a number of CNS processes, including migraine. There is evidence that the periaqueductal gray is partially controlled by chaotic dynamics (Schweighofer, et al., 2004).

The loss of chaotic dynamics may lead to a pathological shift of homeostasis. The loss of brainstem inhibitory activity may actually reflect a lessening of chaotic control, eventually leading to a migraine. Similar loss of chaotic dynamics may explain certain arrhythmias and epileptic seizures.

The primary excitatory neurotransmitter in the brain is glutamate.  Along with calcium, glutamate is crucial in the feedback process. Glutamate is directly involved in bi-directional communications between neurons and astrocytes. It is likely that glutamate feedback processes are critical in the generation of complex bursting oscillations in astrocytes. These glutamate-mediated events are involved in migraine, epilepsy, and memory storage. The control of this feedback process may be partially enacted through chaotic dynamics. The cascade of magnesium binding to N-methyl-D-aspartate (NMDA) in the periphery about the brain, with subsequent calcium influx, is very sensitive to minute initial changes (Kernick, 2005).  This cascade is important in peripheral sensitization, which leads to migraine attacks. These magnesium and NMDA effects may be under chaotic control.

Brain-derived neurotrophic factor (BDNF) is a neurotropin that modulates neuronal membrane excitability. BDNF was used in one study to affect hippocampal neurons (Fujisawa, Yamada, Nishiyama, Ikegaya, 2004). Chaotic dynamics partially govern patterns of electrical activity in hippocampal neurons. The hippocampal electrical system is a deterministic one with a few degrees of freedom. Neuronal chaos may be sensitive to change by the application of small amounts of materials, such as BDNF, that influence temporal spiking. The application of BDNF to cultured hippocampal neurons enhanced spike timing and resulted in stereotyped firing patterns. It was felt that BDNF influenced chaos through effects on membrane levels of sodium (Fujisawa, et al., 2004).  BDNF enhanced membrane conductance and thus stabilized the membrane. The application of BDNF affected the switching between periodic and aperiodic neuronal oscillations. BDNF has been linked to modulation of neuroplasticity. The BDNF application decreased irregularity of firing patterns by modulating neuronal outputs as well as inputs. The result was a BDNF-induced chaos stabilization. This was the first experiment to demonstrate a pharmacological stabilization of chaos at the neuronal level (Fujisawa, et al., 2004).

CHAOS AND EVOLUTION

Chaos and evolution are intimately interconnected. There is a chaotic (non-linear) connection between phenotype and genotype. This complex relationship is constantly in flux. A single mutation may be inconsequential, or it may result in enormous changes that are unpredictable. This is typical for a non-linear system. With these unpredictable mutations, iterations over thousands of generations will usually result in evolutionary changes (McKee, 2000). It is debatable as to how much the environment plays a role, versus genetic changes that are generated internally.

The unpredictability of evolution is typical of non-linear systems. Most discussions of evolution predictors focus on random, stochastic processes (mutations, genetic drift, random environmental changes). A reductive system would behave in a much more orderly, predictable manner. However, these fixed reductive systems are limited, and non-linear dynamics allows for enhanced evolutionary adaptability. The behavior of evolutionary systems is extremely sensitive to initial conditions. This was demonstrated during the quaternary period. At the beginning of each interglacial, the initial circumstances determined the outcome of that period. Between interglacials there were differences that were unpredictable, due to the non-linear nature of the system (Bird, 2003).

Non-linear dynamics lead to a system that is not scaled. The tree of life is fractal, and follows non-linear dynamics. The branches of the tree are continuously being split, resulting in evolutionary changes.  If we travelled back 5 million years, and re-started the human evolutionary process, the result would be dramatically different. This is the nature of a non-linear system. A simpler stochastic reductive system would be predictable but limited. It has been demonstrated that, when many traits interact, chaotic dynamics may govern phenotypic evolution.   Ancient species in human evolution, such as Australopithecus and Homo habilis, may have diverged due to chaotic dynamics (McCann, Yodzis, 1994).

Natural selection utilizes chaotic dynamics, chance, and coincidence (McKee, 2000). Natural selection does not invent, it tends to mosey along and tinker. The chance mutation must be coincidentally beneficial because of some environmental change.  For instance, if our ancestors needed robust teeth due to changing climactic conditions, those who happened to have larger teeth would have prevailed. Chaotic dynamics oversees chance and coincidence in the evolutionary process.

 EVOLUTION AND MIGRAINE

 Examining evolutionary systems in relation to disease is much more than an academic exercise. The evolutionary history will give us a complete picture of a disease. Understanding the evolutionary foundation may help us in developing safe and effective treatments.

Illness can be considered through two frameworks: 1. a proximate view, and 2. an evolutionary lens. The proximate view considers the nuts and bolts of a disease: pathophysiology, treatment, biochemistry, etc. It’s vitally important to also consider the disease process using an evolutionary viewpoint (Perlman, 2013). One essential question is: “why have migraines persisted, and why are humans still so susceptible to migraine?” The proximate lens says that migraine is a physical trait that involves multiple physiologic systems. The evolutionary framework begs the question: “why does our DNA code for migraine?”

There are physiological trade-offs that permeate evolution. While sickle cell disease is devastating, the sickle cell gene does also protect against malaria. Cystic fibrosis also involves serious trade-offs. Heterozygotes for cystic fibrosis were less likely to suffer dehydration from illnesses such as cholera. Genes exist to propagate themselves, sometimes to the detriment of the organism (the “selfish gene”)(Dawkins, 2013). This is also the story of migraine. Evolutionary benefits from migraine are possible (Loder, 2002).  It is also possible that our species simply continues to be vulnerable to migraine, and the evolutionary benefits are few. There are multiple genes involved in migraine, and evolution does not easily remove “bad genes”(Loder, 2002).

 It’s likely that migraines in humans increased as a result of our migration to more northern latitudes (Vigano, Manica, Di Piero, Leonardi, 2019).  Low vitamin D levels may help explain the increase in prevalence of migraine farther north (Prakash, 2010). The TRPM8 gene involves a receptor that plays a part in cold sensation and thermoregulation. TRPM8 (the “T” variation) is also linked to an increased risk for migraine (Dussor, Cao, 2016).  People who carry the “T” variation are better adapted to cold environments, and this adaptation likely improved their survival and reproductive success. Migraine may have been a negative consequence from this cold adaptation: another trade-off. The TRPM8 and latitudinal studies were the first to link migraine, evolution, natural selection, and geography (Vigano, et al., 2019).

The reasons why migraine persists are varied. While there is no epidemiological data from past millenia, the prevalence of migraine may be increasing. An increased sensitivity to light, smells, and sound could be beneficial under certain conditions. Migraine may be advantageous in combating certain infections (Loder, 2002). This may occur through an enhanced immune response, or by an increase in blood flow. Only a small percentage of people never experience headache (7% of men, and 1% of women), signaling that there may be some evolutionary advantage of headache.

Certain genes that result in harmless “quirks” in one environment can have deadly outcomes in other venues. Our modern environment certainly contributes to migraine frequency. The environment has radically changed, after millions of years of evolution (Cochran, Harpending, 2009).  For the vast majority of human history, we were primarily hunting and gathering. Recently, only 10 to 12 thousand years ago, societies in Southwest Asia (the fertile crescent) began to cultivate plants and domesticate animals. Many factors may contribute to increased migraine frequency: changes in culture, living circumstances, agriculture and diet, environmental toxins, densely packed populations, infections (particularly viral), harsh indoor lighting, loud speakers, poor sleep, and increased stress (Loder, 2002).  When modern hunter-gatherer societies switch to our “western diet,” they suffer from heart disease and an increase in cancer (Milton, 2000).  One of many examples where a changing environment has an impact on disease involves the genes for heart disease. These genes may not have been particularly detrimental for Stone Age humans, due to short lifespans. But as lifespans have been significantly lengthened, these genes have become threatening. Phenotypic and adaptive plasticity are significant factors in humans adapting to the changing environment (Perlman, 2013).

While migraine is three times more common in women than in men, the evolutionary explanation for this is unclear. Men generally did most of the hunting and gathering, for which migraine could pose disadvantages. For child care, food preparation, and homekeeping, migraine may possibly offer small evolutionary advantages. Migraine commonly decreases during pregnancy, providing an evolutionary incentive for more pregnancies.

It’s likely that migraine only afflicts the human species. Our ancient human brainstem has obstacles in coping with a cortex that is recently enlarged. With excessive afferent input, our brainstem may be overwhelmed. Having higher cortical functions not found in other primates may contribute to our continued vulnerability to migraine.   

Migraine may function as a defense mechanism against excessive stress, noise, or light (Loder, 2002).  The elevated sense of smell may serve as a defense from toxins or viruses entering the CNS. Vomiting may help to remove toxins. Women migraineurs probably have a lower prevalence of type 2 diabetes, compared to those without migraine (Fagherazzi, El Fatouhi, Fournier, et al., 2019).  An activation of the trigeminal nuclear complex could be protective (Loder, 2002).  If migraine offers protections for an individual, then that individual’s genes may be propagated more successfully. If an ancestral human experienced 100 migraines during a year, and just one of those migraines protected the person from harm, the trade-off would have been worthwhile. In an evolutionary framework, the cost of migraine may be inexpensive.

There is a difference between a defense and a defect. Coughing is a defense, but becoming blue from hypoxia is not. We want to retain our natural defenses. The calcitonin gene-related peptide (CGRP) associated with migraine may be advantageous under stress (Kee, 2018). CGRP has existed in a variety of species for hundreds of millions of years. CGRP plays various roles in the body, some positive, some harmful (Kee, Kodji, Brain, 2018). Under stress, CGRP is beneficial for our cerebrovascular and cardiovascular systems. Disrupting this natural defense, as happens with our CGRP monoclonal antibodies that prevent migraine, may be harmful.  The CGRP story is one example of the danger in ignoring the evolutionary importance of a compound.       

Natural selection is dependent on reproduction. After the reproductive years, a particular trait could very well become detrimental, but that does not affect gene propagation. In order to understand a trait (or disease) such as migraine, we must consider all of the evolutionary processes. These include genetic drift, mutations, migration, non-random mating, and natural selection (Perlman, 2013). Sometimes, natural selection produces opposing effects, resulting in a heightened vulnerability to disease.

 It’s imperative to not only view individuals through an evolutionary lens, but to also consider the phylogeny of the species (Perlman, 2013). The relationships between humans have morphed in the past 12,000 years (Cochran, et al., 2009).  One primary factor driving phylogenetic changes is the increase in population density, resulting in most humans living in significantly smaller spaces. Culture, which influences our state of disease or health, may also contribute to an increase in headache prevalence.

Headache and pain are adaptive responses. Being still, or in bed, may help repair damaged tissues. Incomplete or inadequate natural selection is often cited as the cause for our flaws or disease, but it is more likely that many illnesses are the result of compromises and/or design flaws (Nesse, Williams, 2012).  For example, our esophagus crosses our trachea. Because of this, our airway must inconveniently be closed every time that we swallow, to prevent choking. Allergies, atherosclerosis, nearsightedness, and nausea in pregnancy are similar examples stemming from evolutionary compromises and design flaws (Nesse, 2005, 2012).

Another important evolutionary concept to consider is intrinsic vulnerability (Nesse, 2011). Different species have various levels of vulnerability to certain diseases. Humans mature rather slowly, with infrequent reproduction. This is a factor regarding enhanced vulnerability of our species to certain diseases. It’s difficult for us to rid ourselves of genes that cause harm. Migraine involves a multitude of factors and genes, and it’s not likely that natural selection would be capable of eliminating migraine.

To more wholly understand migraine, we should venture beyond the proximate and physiologic processes. The evolutionary foundations of migraine are vitally important to study. Examining migraine under an evolutionary lens may help us in evaluating the safety of new treatments, such as the CGRP monoclonal antibodies. We must pay attention to evolution.

CONCLUSION

Chaos, migraine, and evolution are intertwined. Chaotic dynamics are vital within the central nervous system. Chaos is important at the ionic, neuronal, and neuronal cluster levels. Chaos may be involved in the generation of CSD. Sensitization and wind-up, crucial components of migraine, probably incorporate chaotic dynamics.

Evolution and natural selection involve chaos, chance, and coincidence. The evolutionary result of thousands of generations depends exquisitely upon initial conditions, characteristic of chaotic dynamics.

For myriad reasons, our species remains remarkably vulnerable to migraine. To understand migraine, we have to look farther than simple physiologic and proximate processes. We cannot truly understand migraine without examining the evolutionary underpinnings. The safety of new migraine treatments should be evaluated under an evolutionary lens.

                                                               REFERENCES

Bird, R. (2003). Chaos and Life: complexity and order in evolution and thought. NY,NY: Columbia University Press.

Cochran G, Harpending H (2009). The 10,000 Year Explosion: How civilization accelerated human evolution. NY,NY: Basic Books.

Dawkins,R.  (2016). The Selfish Gene. Oxford, UK: Oxford University Press.

Dussor G, Cao,Y-Q. (2016). TRPM8 and migraine. Headache, 56, 1406-1417.

Fagherazzi G, El Fatouhi D, Fournier A. (2019). Associations between migraine and type 2 diabetes in women: findings from the E3N cohort study. JAMA, 76, 257-263.

Fujisawa S, Yamada M, Nishiyama N, Ikegaya N. (2004). BDNF boosts spike fidelity in chaotic neural oscillations. Biophysics J, 86, 1820-1828.

Kee Z, Kodji X, Brain SD. (2018). The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Frontiers in Physiology, 9, 1249.

Kernick D. (2005). Migraine—new perspectives from chaos theory. Cephalalgia, 25, 561-566.

Korn H, Faure P. (2003). Is there chaos in the brain? C.R. Biologies, 326, 787-840.

Landau ID, Sompolinsky H. (2018). Coherent chaos in a recurrent neural network with structured connectivity. Computational Biology, Retrieved May 20, 2020 from https://doi.org/10.1371/journal.pcbi.1006309

Loder E. (2002). What is the evolutionary advantage of migraine? Cephalalgia, 22, 624-632.

McCann K, Yodzis P. (1994). Non-linear dynamics and population disappearances. The American Naturalist, 144, 873-879.

McKee, J (2000). The Riddled Chain: chance, coincidence, and chaos in human evolution. Piscataway,NJ: Rutgers University Press.

Milton K. (2000). Hunter-gatherer diets: a different perspective. The American Journal of Clinical Nutrition, 71, 665-667.

Nesse,RM. (2005). Maladaptation and natural selection. The Quarterly Review of Biology, 80, 62-70.

Nesse,RM. (2011). Ten questions for evolutionary studies of disease vulnerability. Evolution Applications, 4, 264-277.

Nesse,RM, Williams GC. (2012). Why We Get Sick: the new science of Darwinian medicine. New York, New York: Vintage Books.

Perlman R. (2013). Evolution and Medicine. Oxford, UK: Oxford University Press.

Pietrobon D, Moskowitz MA. (2014). Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nature Review Neuroscience, 15, 379-393.

Schweighofer N, Doya K, et al. (2004). Chaos may enhance transmission in the inferior olive. Proceedings of the National Academy of Science, 101, 4655-4660.

Vigano A, Manica A, Di Piero V, Leonardi M. (2019). Did going north give us migraine? An evolutionary approach on understanding latitudinal differences in migraine epidemiology. Headache, 59, 632-634.

Vreeswijk C, Sompolinsky H. (1998). Chaos in neuronal networks with balanced excitatory and inhibitory activity. Science, 274, 1724-1726.

Lawrence Robbins,M.D.

Gepants are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. The preventive CGRP monoclonal antibodies(Aimovig, Emgality, Ajovy) are large molecules, delivered once per month as a SQ injection. Seven gepants have been developed since 2004. (1) Telcagepant was extensively studied, but withdrawn due to hepatotoxicity concerns. CGRP has many effects throughout the body. CGRP triggers a cascade of inflammatory mediators that feed into the trigeminovascular system. By blocking CGRP, the gepants stop the process prior to inflammation.

Regarding migraine, CGRP is an inflammatory compound. They will initially be utilized as migraine abortives, but eventually they will also be used to prevent migraine. The gepants may be helpful for 3 groups of migraineurs. They will be prescribed for a number of patients who found triptans (sumatriptan, rizatriptan, zolmitriptan, etc.) to be ineffective. In addition, gepants will be used for certain patients who cannot tolerate triptans. Finally, for those patients with significant cardiac or cerebrovascular risk factors, the gepants may be relatively safe, since they do not constrict cardiac or cranial arteries. While efficacy is modest, these are well tolerated medications.

The first gepant to come to market will be ubrogepant. Almost 2,700 patients participated in the ubrogepant ACHIEVE studies. (2,3) The doses have ranged from 25mg to 100mg. The t-max is 0.7 to 1.5 hours. Approximately 20% of patients who used the 50mg dose were pain free after 2 hours. While 25mg and 100mg tablets of ubrogepant were evaluated, it is likely that 50mg will be the primary dose. Ubrogepant was well tolerated, with 2% to 5% of patients reporting nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections. No serious adverse events were reported. The safety and tolerability were also explored in a 52 week extension study. Few adverse events, and no hepatotoxicity was reported. The effect of ubrogepant on the patient’s most bothersome migraine symptom was evaluated 2 hours post-dose. 39% of those treated with ubrogepant reported that their worst migraine symptom was resolved. The therapeutic gain for ubrogegepant (active drug vs. placebo) is relatively low, 6.4%-9.4%. In comparison, the therapeutic gain for sumatriptan is 16%-21%.

Rimegepant is another gepant, in development for abortive and preventive use. The dose is 75mg, with a t-max of 2 hours. In the 2 main trials, 19.4% of patients achieved pain freedom at 2 hours. (4) 37% of patients reported freedom from their most bothersome symptom. As with ubrogepant, no significant liver toxicity was reported. Adverse events were low, with nausea being reported by 1.4% of patients. The therapeutic gain for rimegepant is 5% to 7.6%.

A third gepant, atogepant, is currently being studied.

The gepants will be a useful alternative to triptans. Many patients find triptans to be ineffective. Some migraineurs cannot tolerate the adverse effects of the triptans. For certain patients with cardiovascular risk factors, triptans may not be completely safe. Gepants will be considered in these clinical settings. The initial (2 hour) efficacy rates are fairly low, but it appears that gepants may become more effective over 2 to 8 hours. During the trials, these were fairly well tolerated medications. It will take at least several years before we are able to accurately assess the true adverse effect profile of the gepants.

References

1. Olesen J, Diener H-C, Husstedt IW et al Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. 2004. N Eng J Med 350:1104-1110.

2. Allergan Announces Positive Top Line Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-phase-3-resul.

3. Allergan Announces Second Positive Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/News/News/Thomson-Reuters/Allergan-Announces-Second-Positive-Phase-3-Clinica.

4. Biohaven Announces Successful Achievement of Both Co-Primary regulatory Endpoints in Two Pivotal Phase 3 Trials of Rimegepant an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine Available at https://biohavenpharma.com/wp-content/uploads/2018/03/CONFIDENTIAL-BIOHAVEN-PRESS-RELEASE-FINAL-v2.pdf.