Migraine remains a poorly understood disease, and with this the management traditionally is frequently unsatisfactory. Migraine headaches are characterized by a throbbing or pounding pain, and are classically located on one side of the head, although they can occur all over. The pain is usually severe, and is usually accompanied by sensitivity to bright lights, sounds as well as nausea and vomiting. The pain may last for hours or even days.

Some migraines are preceded by an “aura” 10-30 minutes before the headache. Typically, auras can be flashing lights, cracked glass visual change, motor/ speech difficulty, weakness of an arm or leg, or it can be sensory such as with tingling of the face or hands.

The pain is thought to be caused by abnormal dilatation of the blood vessels. The preceding aura is thought to be vascular constriction of the vessels before they dilate. This constriction leads to a lower blood flow through the affected part of the brain, and that the transient ischaemia causes the aura.

Certain foods that are “vasoactive” such as red wine, chocolate and aged cheese are well-known triggers. In women, hormonal changes at the times of menstruation can be a trigger. Sometimes it can be weather changes, or glare while driving, and the triggers can be obvious, but sometimes they can be very difficult to determine.

Migraine is about inflammation. Genetic information points to the involvement of transient receptor potential (TRP) channels in pain mechanism. TRPA1, an ion channel on the trigeminal (and most other sensory) nerves is the major oxidative threat sensor. It is activated by various irritants and agents releasing the pro-migraine peptide, calcitonin gene-related peptide through this nerve pathway. TRPA1 agonists release chemicals that cause vascular dilation.

Successful management of migraine is really about “turning off” the processes that are driving the inflammation. Other research at Griffith University has been looking for methylation defects in young women with migraine. In most (and perhaps all) there appears to be a defect in the gene methylation pathway so most can have their migraine reduced/ removed using appropriate B12 supplementation. Some cannot tolerate the folic acid which is combined with the B12 in most tablets. Sometimes the B12 needs to be changed to a different form, and some need IM B 12. Vitamin B2 (riboflavin) has been known for some time to reduce the frequency of migraine, especially in children, and B2 looks as though it is important in the methylation pathway in enabling vitamin B12 function.

At present, we know there are over 30 different mutations of the MTHFR gene, and we usually only test for 2 of them at present, but it seems highly likely we will have a saliva test that will give us a lot more answers in the near future. Not all migraine patients have the known defects, and we just don’t know what percentage of patients with migraine have one of the mutations, and there is also the possibility that it is an as yet unclassified mutation that underlies all these. It is not uncommon for people to have multiple mutations of the same gene, and I personally suspect this will turn out to be the answer. Given the improvement in frequency and severity of migraine with appropriate vitamin treatment  I believe all migraine patients should at least be considered for this management for at least a trial of a few months, especially if there is evidence in tests of methylation problem in other areas, eg elevated homocysteine (over 9 in adults).

Methylation problems with the associated elevated homocysteine appear to cause increased inflammation in vessels, leading to a higher likelihood of migraine which can then be triggered by a variety of things as mentioned above. Spinal problems are very common triggers, and with the increasing use of computers and tablets etc, I expect the frequency of people with migraine to increase.

Inflammation can also come from the gut with the foods we eat (where intolerance exists and the body sees this as a threat), from stress, as well as environmental factors. Various food intolerances appear commonly in people with methylation defects. When trying to sort migraines out, all possible causes that can trigger TLRs have to be assessed, and preferably, vitamin and homocysteine levels checked before supplements are started.

TLR Receptors (Toll-like receptors) are threat response receptors in our body that are activated by threats to the body, whether this be trauma, inflammation, food we are intolerant of etc- this then provokes an immune response which producing cytokines, interleukins and similar substances.

When a person eats food they are intolerant of, the innate immune receptors –Toll-Like Receptors (TLRs), are triggered, and as you keep eating this food you increase levels of inflammatory response. When these triggers are not turned off, when we continue to eat foods we are intolerant of, they provoke the responses that people with food intolerance experience, such as gut reactions, chronic fatigue etc etc.

You make this worse with stress, and even climate change etc etc increases the level of inflammation with increased cytokine and interleukin production. There is a blurring of boundaries in the various problems identified. For example, there may be a problem in the spine causing various symptoms, including triggering migraine, but so far, it looks as though the methylation defect is necessary to have migraine in the first place, and as there are no guidelines for this, it means we have to work through each person individually.

Cytokines are a diverse group of soluble proteins, peptides, or glycoproteins which act as hormonal regulators or signalling molecules at nano- to- picomolar concentrations and help in cell signaling. They are regulators of host responses to infection, immune responses, inflammation, and trauma.   Some of them are proinflammatory; these are necessary to initiate an inflammatory response necessary to recruit granulocytes, and later on, lymphocytes, to fight disease. Excessive inflammation, however, can result in certain diseases. Other cytokines are anti-inflammatory and serve to reduce inflammation and promote healing once the injury/infection/foreign body has been destroyed. (Source Wikipedia)

To complicate this is the research that implicates PFOs (Patent Foramen Ovale) as a cause of migraine “auras” in a number of adults (and it may be it is the same for kids), and again PFOs cause an inflammatory response , and when there is an aura (as described below) we may be looking at emboli (little TIAs or strokes). There are not restricted to the brain as other vessels can be affected. The biggest problem I can see is the potential for dementia if this is not identified if present. Once the brain is damaged, it cannot repair itself. It does not mean though, that if you have auras you have a PFO and will get dementia. At present, the current thinking is that they are both common, and that a percentage of people with migraine who also have PFOs, which puts them in the risk for vascular disease, and should be assessed correctly. At present, as the knowledge is expanding we must review these periodically to see where the understanding of the condition has progressed and whether changed are required in management. We also believe now, that if we can eliminate the migraines, especially the auras, we probably need to do no further investigation at present.

The link between migraine and PFO was identified some years ago. Getting accurate trials has been very difficult to achieve, but when the patient selection criteria are correct, we are able to provide an 85% cure rate from migraine with the closure of the PFO. The other factors discussed above also need to be addressed.

Around 20 to 25% of the population in general have foramen ovales that do not close at birth, but only a small percentage of patients with a PFO suffer with migraine and certainly not all migraine sufferers have a PFO. PFO is more common in migraine patients than in the general population- approximately 40 to 60% of people with migraine with auras have PFOs.

Approximately 40% of all strokes have no obvious cause, and this is more common in the under 60’s. In this group there is a higher percentage of PFO.  The risk is higher if there is any medical condition that raises the pressure in the right side of the heart eg lung disease, pulmonary hypertension, pulmonary embolus, Obstructive Sleep Apnoea, DVT, cancer or any severe acute or chronic illness. The presence of an atrial septal aneurysm (mobile atrial septum)  associated with a PFO or atrial septal defect also increases the risk of TIA/ stroke to 5% yearly.

Dr  Ross Sharpe at the Gold Coast is a leading cardiologist in PFO closure, probably with the best results in Australia. He agrees that the elevation of homocysteine is part of the equation through the MTHFR gene polymorphism amongst others but what exactly is the mechanism of cellular pathophysiology we just don’t know yet.

For the present, only a few people need to be referred for PFO assessment. Those who should be referred for assessment for a PFO include:

  1. The severe migraine with aura non responsive or intolerant to usual therapy.
  2. Blindness, hemiplegia or other significant neurological events would be a strong indicator for assessment (especially those whose employment is at risk or these events would place them or others in physical danger ie commercial pilots and divers).
  3. Anyone who we feel may have had a TIA (mini-stroke). Generally neurological symptoms lasting more than 20 mins in a migraine event could be TIA
  4. Migraine or anyone with unexplained changes in the brain MRI (or CT Spect)
  5. Migraine with aura who feel they have cognitive decline
  6. Severe migraine variants eg vestibular, abdominal
  7. The other masquerader is multiple sclerosis. If it’s obviously MS so be it but some just don’t behave clinically like it and the follow up MRIs don’t fit.

PFOs cannot be reliably diagnosed on an echocardiogram, the test most doctors use. They may need a Transcranial Doppler (CTD) which are done by Dr Ross Sharpe, a cardiologist on the Gold Coast with a special interest in this problem. The actual PFOs are often very small, and may be only the size of a pinhead so there are no functional problems occurring in the heart.

If you do need to see Dr Sharpe, the trans cranial Doppler test (CTD) can be in the rooms on the day they have the consult. If the TCD meets the criteria then he will do an echocardiogram to make sure there is no major structural problem. If not already done he will arrange an MRI to ascertain what damage has already been caused.

What is Patent Foramen Ovale (PFO)?

  • The septum is the muscular wall separating the heart into the left and right sides.
  • The atrial septum is the wall separating the atria (the two upper chambers).
  • The ventricular septum is the wall separating the ventricles (the two lower chambers).

The foramen ovale is a small hole located in the atrial septum that is used during foetal circulation to speed up the travel of blood through the heart. When in the uterus,a baby does not use it’s own lungs for oxygen-rich blood, it relies on the mother to provide oxygen rich blood from the placenta through the umbilical cord to the foetus. Therefore, blood can travel from the veins to the right side of the baby’s heart and cross to the left side of the heart through the foramen ovale and skip the trip to the baby’s lungs.

Normally the foramen ovale closes at birth when increased blood pressure on the left side of the heart forces the opening to close. If the atrial septum does not close properly, it is called a patent foramen ovale.

This type of defect generally works like a flap valve, only opening during certain conditions when there is more pressure inside the chest. This increased pressure occurs when people strain while having a bowel movement, cough, or sneeze.

If the pressure is great enough, blood may travel from the right atrium to the left atrium. If there is a clot or particles in the blood traveling in the right side of the heart, it can cross the PFO, enter the left atrium, and travel out of the heart and to the brain (causing a stroke ) or to other arteries blocking blood flow, potentially causing heart attacks or even blocking vessels to the abdominal organs.

Gore Helex Septal Occluder


This diagram is an example of one of the closures available:  Gore Helex Septal Occluder being inserted for PFO repair


  1. http://my.clevelandclinic.org/heart/disorders/congenital/pfo.aspx
  2. http://www.pfoandmigraine.com.au/
  3. http://onlinelibrary.wiley.com/store/10.1111/bph.12512/asset/bph12512.pdf;jsessionid=731213BFC38026DF699B2DBF27975B35.f03t02?v=1&t=hyxksbg8&s=3a852a23e800d3870463944f1686f38ea0493c03

This is available for download as a PDF file on our downloads page.

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