Science of Migraine

About 12% of the population suffers from migraines. In addition to high rates of migraine-related disability, migraineurs are at a higher risk than the general population of additional disability related to depression, anxiety, irritable bowel syndrome, fibromyalgia, and other conditions.

Fibromyalgia is a disorder of the central nervous system with increased brain excitability. It often manifests itself not only with muscle pains, but also fatigue, memory problems, and sleep and mood disturbances. Various studies estimate that anywhere from 2% to 8% of the general adult population suffers from fibromyalgia. Just like with migraine, women are more often affected than men. The likelihood of coexisting fibromyalgia increases with increasing frequency and severity of migraine attacks.

Both migraine and fibromyalgia have been individually linked with increased risk of suicide. However, it is not clear that the risk is more than additive.

A study just published in Neurology, reports that patients with migraine and coexisting fibromyalgia have a higher risk of suicidal ideation and suicide attempts compared with migraine patients without fibromyalgia.

The study looked at 1,318 patients who attended a headache clinic. Of these patients, 133 or 10% were found to also have fibromyalgia. Patients with both conditions had more frequent, more severe, and longer-lasting migraine attacks as well as higher use of abortive medications.

Compared with migraine patients who did not have fibromyalgia, those with fibromyalgia were more likely to report suicidal ideation (58% vs 24%) and suicide attempts (18% vs 6%).

This report suggests that migraine and fibromyalgia may magnify the risk of suicide compared with the risk of the individual conditions. However, because this data comes from a specialty headache clinic, many patients were severely affected by their migraines, with more than 35% having chronic migraine. It is likely that the results would be less dramatic among migraine sufferers in the general population. Almost half of the estimated 35 million migraine sufferers in the US do not consult a physician. Most of them suffer from milder migraines than those who do consult a doctor.

This study suggests that patients with migraine should be evaluated for other chronic pain conditions and for their mental health well-being. In particular, patients with chronic migraine should be screened for other painful conditions and mental illness. And patients with fibromyalgia should also be evaluated for migraine and potential suicide ideation. Patients often do not appear depressed, but simple questions can detect depression, which can lead to effective treatment. Our initial evaluation at the New York Headache Center includes two questions which are highly indicative of depression: 1. Have you been bothered a lot in the last month by feeling sad, down, or depressed? 2. Have you been bothered a lot in the last month by a loss of interest or pleasure in your daily activities?

Antidepressants have been proven to be effective for the prevention of migraines even in the absence of depression and are the best choice for people suffering from both conditions. Prozac, Lexapro and other SSRI antidepressants do not help migraines or pain, but SNRIs such as Effexor, Cymbalta, and Savella or tricyclics such as Elavil, Pamelor, and Vivactil do relieve pain and depression.

Magnesium deficiency is common in both migraines and fibromyalgia and we recommend an oral supplement to all patients. Some patients do not absorb magnesium and respond very well to monthly intravenous infusions of magnesium. Both their migraines improve as do fibromyalgia symptoms.

One interesting difference between migraines and fibromyalgia is the response to Botox. Botox is proven to be highly effective for the prevention of migraines and it works very well to relax spastic muscles. However, Botox appears to be ineffective for the treatment of muscle spasm in fibromyalgia. It is possibly explained by the fact that Botox interferes with the function of acetylcholine, a neurotransmitter involved in contracting healthy muscles. In fibromyalgia, studies suggests a deficit in acetylcholine, so further blocking it would be ineffective or even make the muscle pain worse (which I’ve seen in a few patients).

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MRI scans of migraine sufferers are almost always normal. Occasionally we see white spots on the MRI, which can be also found in people with high blood pressure, dementia, and sometimes in perfectly healthy people (see my previous post on this).

However, Mayo Clinic neurologists, led by Dr. Todd Schwedt reported being able to diagnose chronic migraines on the MRI scan. The accuracy of the diagnosis of those who had 15 or more headache days each month was fairly high – 84%. Patients with this frequency of attacks are considered to be suffering from chronic migraines. However, they could diagnose only 67% of those with episodic migraines (less than 15 headache days each month). The researchers used sophisticated software (FreeSurfer) that measured the surface area, thickness, and volume of 68 various brain regions and discovered that changes in 6 of these regions were predictive of migraine diagnosis. These 6 regions participate in pain processing in the brain and include the temporal lobe, superior temporal lobe, anterior cingulate cortex, entorhinal cortex, medial orbital frontal gyrus, and the pars triangularis. The software used in the study is freely available, but using it is time consuming and it is utilized only by researchers and not by any hospital or private MRI facilities.

Their findings confirmed what until now was an arbitrary decision by headache experts to divide migraines into episodic and chronic ones with a 15 day cutoff. Ahother study by Dr. Richard Lipton and his colleagues at the Montefiore headache clinic has found that those who have 10 or more headache days each month have many similar features compared to those who have less than 10.

This is not a purely academic question. Insurance companies will pay for Botox only if a patient has 15 or more headache days each month because this type of patients was used in clinical trials of Botox. However in practice we also see very good response to Botox in patients who have fewer than 15 days.

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Ehlers-Danlos syndrome is a group of inherited disorders that are notable for excessive joint mobility with some people also having lax or stretchy skin, at times heart problems, and other symptoms. Headaches appear to be also very common.

We see Ehlers-Danlos syndrome in many of our migraine patients and most of our headache specialist colleagues also notice this association. However, there are very few studies that confirm this observation. One such study was recently presented at the annual scientific meeting of the American Headache Society in Washington, DC. The research was performed at a cardiology clinic in Texas. They looked at the records of 139 patients who were referred to this clinic in a period of one year. Of these 139 patients with Ehlers-Danlos syndrome, 90% were women and the average age was 32. Out of 139 patients, 70% suffered from headaches – 32% had tension-type, 26% had migraines, 9% had chronic migraines and 2% had sinus headaches. These numbers are much higher than what is seen in the general population, confirming clinical observations by headache specialists.

One form of Ehlers-Danlos syndrome affects not only joints and ligaments, but also the heart. So, when see a migraine patients who also appears to have Ehlers-Danlos syndrome, we also ask about symptoms related to the heart and if they are present refer such patients to a cardiologist.

Another presentation at the same meeting described a 23-year-old woman with Ehlers-Danlos syndrome who suddenly developed headaches that would worsen on standing up and improve on lying down. This is typical of headaches due to low cerebrospinal fluid (CSF) pressure, which was confirmed by a spinal tap. The most common causes of low CSF pressure are a leak caused by a spinal tap done to diagnose a neurological disease or caused by a complication of epidural anesthesia. Spontaneous unprovoked leaks have also been reported. In this patient with Ehlers-Danlos syndrome the leak probably occurred because of the lax ligaments that surround the spinal canal and contain the CSF. The report describes the most accurate test to document such leaks, which is an MRI myelogram.

The treatment of CSF leaks begins with a blood patch procedure, but if it is ineffective, surgery is sometimes done to repair the leak. A recent report suggested that Botox could be effective for low spinal fluid pressure headaches.

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Chronic migraine sufferers appear to be more likely to have dryness of their eyes, according to a study by ophthalmologists at the University of Utah, which was published in the journal Headache. The researchers used sophisticated techniques to measure tear production, corneal sensitivity, dry eye questionnaire, and other tests. The results of these tests were compared in migraine sufferers and healthy control subjects.

A total of 19 chronic migraine patients and 30 control participants completed the study. The nerve fiber density was significantly lower in the corneas of migraine patients compared with controls. All migraine sufferers had symptoms consistent with a diagnosis of dry eye syndrome. The researchers plan to continue studying the interrelationships between migraine, corneal nerve architecture, and dry eye.

Similar findings in patients with episodic migraine were published by a group of Turkish doctors in the journal Cornea in 2012.

Migraine sufferers and their doctors should be aware of this correlation since irritation caused by dry eyes could potentially trigger a migraine. It is possible that some migraines can be prevented by using over-the-counter and prescription eye drops or, in severe cases, eye inserts (Lacrisert). High doses of omega-3 fatty acids have been reported to help dry eyes and omega-3 fatty acids have also been reported to relieve migraines.

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Chronic fatigue syndrome sufferers have endured years of neglect and sometimes ridicule. The condition has even been called “yuppie flu”. Informal surveys indicate that half of the doctors do not believe that this is a true physical disease. This is despite the fact that 1 to 2 million Americans have been diagnosed with this condition. In a previous post I mentioned that patients with chronic fatigue are much more likely to suffer from migraines – they occur in 84% of patients. Tension-type headaches were found in 81% and only 4% had no headaches at all.

There is an overwhelming amount of evidence that chronic fatigue syndrome is a physical condition and one of the names that has been used by doctors is Myalgic Encephalomyelitis. The Institute of Medicine recently issued a report, Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, which proposes a new name – Systemic Exertion Intolerance Disease, or SEID. The name indicates that the main characteristic of the disease is the fact that exertion of any kind – physical, cognitive, or emotional – can affect many different body organs and impair normal functioning and reduce quality of life. The report also states that to make this diagnosis, the symptoms have to be chronic, frequent and moderate or severe in intensity. The experts suggest that patients could be diagnosed with both SEID and Lyme disease, fibromyalgia, or another disease that causes fatigue. Currently, if a patient suffers from Lyme disease or another fatiguing condition, chronic fatigue is not added as a separate disease. The report also noted that the prognosis is not very good – many people continue to suffer from SEID for many years.

Fibromyalgia, another condition which was thought to be purely psychological, now has three medications approved to treat it (Lyrica, Cymbalta, and Savella), which has led more doctors treat it as a real disease. Unfortunately, there are no drugs approved for chronic fatigue or SEID.

Here are the specific diagnostic criteria for SEID established by the Institute of Medicine:
– Reduction or impairment in the ability to carry out normal daily activities, accompanied by profound fatigue
– Post-exertional malaise
– Unrefreshing sleep
In addition, diagnosis requires one of the following symptoms:
– Cognitive impairment
– Orthostatic intolerance (difficulty standing up and being in an upright position).

I would add that to make this diagnosis, other known potential causes of fatigue should be ruled out. These include thyroid disease, anemia, chronic infections (Lyme and other), vitamin B12 and other deficiencies. As mentioned in a previous post, the test for vitamin B12 is not very accurate. Many laboratories list normal levels being between 200 and 1,000. However, many patients with levels below 400, and some even with levels above 400 still have a deficiency. If a deficiency is strongly suspected, additional tests are needed – homocysteine and methylmalonic acid levels.

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A report by Taiwanese doctors just published in the journal Neurology suggests that having migraine headaches may double the risk of Bell’s palsy.

Several medical conditions, such as asthma, anxiety, depression, irritable bowel syndrome, epilepsy, and other occur with higher frequency in migraineurs, but until now, no one suspected an association between migraines and Bell’s palsy.

The researchers compared two groups of 136,704 people aged 18 years and older – one group with migraine and the other without. They followed these two groups for an average of 3 years.

During that time, 671 people in the migraine group and 365 of the non-migraine group developed Bell’s palsy.

This association persisted even after other factors such as sex, high blood pressure, and diabetes were taken into account.

The authors speculated that the inflammation and the blood vessel problems seen in both conditions may explain this association.

This study appears to be of purely academic interest since we do not know how to prevent Bell’s palsy. However, I decided to write about it because a couple of my colleagues (one in our office and at least one other on a doctors’ discussion board) reported seeing Bell’s palsy soon after administering Botox injections for chronic migraines. This report by Taiwanese doctors suggests that Bell’s palsy might have been not due to Botox, but rather a coincidence since Bell’s palsy is more common in migraine sufferers.

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Cyclic vomiting syndrome (CVS) is usually seen in children. The attacks of vomiting often stop as the child gets older, but then they usually go on to develop migraine headaches. A recent report in Headache describes three adults with CVS. The article also mentions a previous report which described another 17 adults with this syndrome.

CVS typically consists of recurrent stereotypical attacks of incapacitating nausea and vomiting, separated by symptom-free periods. Supporting evidence that helps diagnose this condition include personal or family history of migraine and other symptoms, such as headaches, motion sickness, and sensitivity to light.

Just like in children, CVS in adults is a diagnosis of exclusion, meaning that other causes of vomiting must be considered and ruled out. I mentioned in a previous post that one out of three children with CVS turned out to have another medical problem rather than migraine.

CVS in adults seems to respond well to an injection of sumatriptan (Imitrex). This allows for a quick relief of symptoms and makes this debilitating condition very manageable. Besides Imitrex injections, Zomig (zolmitriptan) nasal spray can sometimes be effective as well.

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The first time I heard of the potential benefit of stem cells for migraine headaches was last year from one of my patients. This 55-year-old woman had been having some improvement from intravenous magnesium and nerve blocks, while Botox was ineffective. However, she reported a dramatic improvement in her headaches after receiving an intravenous infusion of stem cells in Panama. The stem cells were obtained from a donated umbilical cord.

Stem cell research has been controversial because most of the early research used stem cells obtained from an aborted fetus. Since then, stem cells have been obtained from the bone marrow, umbilical cord, placenta, and artificial fertilization. Another rich source of stem cells is body’s fat tissue. Most of the stem cell procedures are not yet approved in the US. The main concern is that when you obtain stem cells from another person’s umbilical cord or placenta, there is a risk of transmitting an infection. There are relatively few stem cells in the bone marrow, placenta or the umbilical cord, which means that after isolating them, they need to be grown in a petri dish. This process involves adding various chemicals, which may not be safe, according to the FDA.

A group of doctors in Australia recently reported relief of migraines using stem cells from patients’ own fat. These doctors did not grow these cells, but infused them intravenously right after separating them from fat. The infused cells were not only stem cells, but so called stromal vascular fraction, which also includes cells that surround blood vessels. These four patients were given stem cell treatment for osteoarthritis and not migraines, but they noticed that their migraines and tension-type headaches improved.

Four women with long histories of chronic migraine or chronic tension-type headaches were given an infusion of cells isolated from fat, which was obtained by liposuction. Two of the four patients, aged 40 and 36 years, stopped having migraines after 1 month, for a period of 12 to 18 months. The third patient, aged 43 years, had a significant decrease in the frequency and severity of migraines with only seven migraines over 18 months. The fourth patient, aged 44 years, obtained a temporary decrease for a period of a month and was retreated 18 months later and was still free of migraines at the time the report was submitted one month later.

This case series is the first published evidence of the possible efficacy of stromal vascular fraction in the treatment of migraine and tension-type headaches.

It is not very surprising that stem cells can improve migraine headaches because stem cells are tested as a treatment for a variety of inflammatory diseases, such as multiple sclerosis, arthritis, and colitis. Inflammation is proven to be present during a migraine attack and this inflammation may attract stem cells. Many experts believe that stem cells may work for MS or other neurological disorders not by becoming brain cells, but by stimulating body’s own repair mechanisms.

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Parkinson’s disease (PD), parkinsonian symptoms, and restless leg syndrome (RLS) are more common in people who in middle age suffered from migraines with aura. Those suffering from migraine without aura in their midlife had increased risk of having symptoms of Parkinson’s and RLS, but not PD. These are the findings of a large study of residents of Reykjavik, Iceland who were born between 1907 and 1935. These residents had been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of PD, family history of PD, and RLS.

People who suffered from migraines, particularly migraine with aura, were in later life more likely than others to report parkinsonian symptoms and diagnosed to have PD. Women with migraine with aura were more likely than others to have a parent or sibling with PD. Late-life RLS was increased in those with headaches generally.

The authors concluded that there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism.

There are no proven ways to prevent PD, but eating more fruits and vegetables, high-fiber foods, fish, and omega-3 rich oils (or taking an omega-3 supplement, such as Omax3) and avoiding red meat and dairy may have some protective effect against PD.

Intensive research into the causes and treatment of Parkinson’s disease, supported by Michael J. Fox and Sergey Brin of Google among others, should lead to true breakthroughs in the next few years.

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Skipping meals, for some people, is a sure way to get a migraine headache. Even those who do not suffer from migraines can get a headache from not eating breakfast and lunch. However, fasting has remained popular for the treatment of various conditions. Migraine sufferers who suspect that some foods may be triggering their headaches are sometime advised to try an elimination diet. This diet often begins with a fast and then one type of food is introduced at a time to see if it triggers a negative reaction. Anecdotal reports describe relief of migraine headaches with fasting for periods of up to five days. Some programs recommend five-day fasts twice a year, while others are advocating five days each month. A 5:2 diet involves eating a normal amount of calories for five days and the following two days eating 1/4 of that amount. The problem is that some people will have worsening of their headaches in the first day or two. However, most patient reports that after having headaches for a day or two the head becomes very clear.

It is not clear if fasting helps various medical conditions, if indeed it does, which remains an open question. One potential mechanism may involve stem cells. Recent studies suggest that fasting causes proliferation of stem cells. The study was published in the journal Cell Stem Cell. The research was done in mice and showed that prolonged fasting protects against immune system damage and induce immune system regeneration. The researchers speculated that fasting induces stem cells from a dormant state to a state of proliferation.

One of the authors of the study said that “We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system. When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. ”

Fasting and induction of stem cells seems to reduce an enzyme which has been linked to aging, tumor progression and cancer. Fasting also protected against toxicity in a small human trial where patients fasted for 72 hours prior to chemotherapy.

“Chemotherapy causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy.”

So, how long do you need to fast to induce your stem cells and to get beneficial results? Some advocate suggest one or two days a week. Others promote twice yearly five-day fasts. The bottom line, we have no research on this topic.

Fasting may help protect against brain disease. Researchers at the National Institute on Aging have found evidence that fasting for one or two days a week can prevent the effects of Alzheimer and Parkinson’s disease. Research also found that cutting the daily intake to 500 calories a day for two days out of the seven can show clear beneficial effects for the brain. It is possible that fasting helps by inducing proliferation of stem cells in the brain.

Fasting cuts your risk of heart disease and diabetes:
Regularly going a day without food reduces your risk of heart disease and diabetes. Studies show that fasting releases a significant surge in human growth hormone, which is associated with speeding up metabolism and burning off fat. Shedding fat is known to cut the risk of heart disease and diabetes. Doctors are even starting to consider fasting as a treatment.

3. Fasting effectively treats cancer in human cells:
A study from the journal of aging found that cancer patients who included fasting into their therapy perceived fewer side effects from chemotherapy. All tests conducted so far show that fasting improves survival, slow tumor growth and limit the spread of tumors. The National Institute on Aging has also studied one type of breast cancer in detail to further understand the effects of fasting on cancer. As a result of fasting, the cancer cells tried to make new proteins and took other steps to keep growing and dividing. As a result of these steps, which in turn led to a number of other steps, damaging free radical molecules were created which broke down the cancer cells own DNA and caused their destruction! It’s cellular suicide, the cancer cell is trying to replace all of the stuff missing in the bloodstream that it needs to survive after a period of fasting, but can’t. In turn, it tries to create them and this leads to its own destruction.

This post contains direct quotes from

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