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Among the world's 20 most disabling health problems, the migraine headache ranks 20th (and 9th in women), affecting up to 8% of men and 18% of women in the United States. The headaches are characterized by painful, disabling and recurring symptoms initiated by a variety of environmental triggers. There is a strong genetic association. Select comorbidities associated with migraine include anxiety, depression, dysmenorrhea and fatigue. Depression has been reported to occur more than twice as often in migraine sufferers, and the combination is seen with far greater frequency in women.



BB, a 40-year-old female, presented with a 20-year history of common migraine (no prodrome), depression, anxiety and fatigue. At the time of her first office visit, she reported having approximately four to six migraines each week. Headaches were worse around the time of her menses, and were also triggered by jogging. BB took eletriptan hydrobromide, a serotonin receptor agonist, and ibuprofen frequently to manage the migraine headaches. They could last up to three days without medication, but resolved within a few hours with medication. She was not taking medication for depression or anxiety.


BB, 40岁女性,已患常见的偏头痛20年,无前驱症状,伴有抑郁、焦虑和疲劳。第一次就诊时主诉每周偏头痛发作4到6次,月经期间头痛加剧,慢跑也会引发头痛。偏头痛发作时,BB经常服用依立取坦氢溴酸盐(血清素受体诱导剂)和布洛芬来缓解头痛。如果不服用药物,疼痛最多持续三天,但服用药物之后,几个小时内疼痛便会消失。她并未服用任何治疗抑郁或焦虑的药物。

BB reported having mild environmental allergies, for which she received allergy shots as a child. She also experienced significant bloating with her menses. She denied any gastrointestinal complaints. She used an etonogestrel/ethinyl estradiol vaginal ring for birth control. She reported that it did not alter her headache pattern. BB ate a standard American diet (SAD) which is characterized by high intake of red meat, sugary desserts and drinks, high-fat foods, dairy products, eggs and refined grains. Her physical exam was unremarkable. A standard battery of laboratory testing previously ordered included a complete blood count, comprehensive metabolic panel, and thyroid and iron studies that all showed results within normal limits.



1.Food-specific IgG4 antibodies: Food reactions, including those involving IgG antibodies, have been identified as an etiologic factor in migraine headaches.

2.Plasma amino acids: Amino acid insufficiencies have been identified in depression.

3.Urinary organic acids: Neurotransmitter metabolites and functional indicators of nutrient insufficiency may be assessed in an organic acids panel. Imbalances in urinary neurotransmitter metabolites and nutrients such as B12 and folic acid have been associated with depression.









Multiple food-specific IgG4 antibodies

Intestinal hyperpermeability

Multiple amino acid deficiencies resulting in:

Low total-body serotonin turnover

Low-normal catecholamine turnover











Elimination/Rotation Diet:

Eliminate all foods with IgG4 levels of +4 and +5 for one month

Foods with +1 to +3 reactions should be consumed no more often than twice per week

Reintroduction phase: after one month of avoidance, rotate IgG4 +4 and +5 foods into diet no more than twice per week

Lactobacillus and Bifidobacterium species 20 billion CFU, 1 capsule PO QD

Glutamine 5000 mg, l tsp PO BID 

Custom amino acids (10 g per 1 tsp):

Start with 0.25 tsp PO QAM and increase dose by 0.25 tsp until reaching 1.5 tsp QAM Fish oil, l capsule PO BID

Women's specific multivitamin and mineral supplement taken as directed


•    连续一个月排除所有IgG4在+4、+5水平的食物

•    反应在+1、+3水平的食物应该限制在每周摄入不超过两次

•    再引入阶段:排除饮食一个月之后,交替食用IgG4 +4、+5的食物,并且限制在一周不超过两次

•    乳酸菌和双歧杆菌200亿CFU,QD

•    谷氨酰胺5000mg, BID

•    定制氨基酸(10g/匙),起初,每天上午1/4匙, 以后慢慢增加,每次增加1/4匙, 直到1.5匙

•    鱼油1粒,BID

•    按需补充女性多种维生素和矿物质

Treatment plan rationale: Given that various foods can trigger migraine, it was determined that the numerous IgG4 reactions identified (Figure 1) warranted removal or, in the case of milder reactions, significantly reduced exposure. Thus, an elimination/rotation diet based on the laboratory results was initiated. The number of positive reactions was strongly suggestive of intestinal hyperpermeability, so nutrients involved in reducing inflammation and healing the GI tract were introduced, including probiotics, glutamine and fish oil. A customized amino acid blend based on BB's laboratory findings (Figure 2) was also implemented to ensure adequate availability of the essential amino acids necessary for their ubiquitous role in metabolism and, particularly, neurotransmitter production. A multivitamin and mineral supplement designed for women (e.g. increased calcium, magnesium, B vitamins) was introduced to support overall metabolic function.




BB reported that migraine episodes were reduced in intensity and frequency. She had not required medication for the previous three weeks, and did not report any medication withdrawal symptoms. When she did experience a headache, she noted that they were triggered when some of the reactive foods were reintroduced, so she avoided these foods with rare exception. She also noted a change in the pain pattern of her headaches. Previously, they started behind her eyes but, after a month of treatment, they were, as she described them, more diffuse, with the pain spanning her forehead.


Two-month follow-up plan

Continue supplements

Continue to avoid all migraine trigger foods identified on reintroduction

phase of elimination diet (primarily eggs and dairy)

Add anti-inflammatory plant sterol


•    继续补充营养

•    继续避免食用可以引发偏头痛的食物

•    排除饮食(主要是鸡蛋和乳制品)

•    添加抗炎植物甾醇

Treatment plan rationale: A plant sterol was introduced with the hypothesis that it could reduce the inflammatory response and, in so doing, minimize migraine reaction to IgG4-positive foods.



BB reported feeling more energetic and happy. She stated that she could "feel the positive effects of the amino acids on mood and energy." She found her mood to be much more even, without the big swings between anxiety and depression she experienced in the past. The frequency of migraine attacks was reduced to once per month, accompanying her menses. When she did experience one, it was reduced in intensity and didn't always require medication. She also reported some improvement in bloating and cramps during menses. Previously, she got migraine attacks "all the time" and took medication at least weekly. She did continue to get occasional exertion-induced migraines during exercise, which required eletriptan. She admitted that the rotation diet (especially avoidance of eggs and dairy) was difficult, but it was a significant factor in minimizing migraine attacks, even those associated with her menstrual cycle and exercise. She believed that, if she could fully comply with the diet, she would reduce the incidence of migraines even further.



Three-month follow-up plan

Continue treatment as directed

Avoid reactive foods

Counseling given on identifying occult food exposure


•    按计划继续治疗

•    避免食用敏感食物

•    咨询关于食物的隐形接触


Migraine pathogenesis is believed to involve dysfunction of monoaminergic sensory control systems in the brainstem and thalamus, resulting in increased sensitivity to environmental and sensory input. The monoaminergic system includes the aromatic amino acid-derived neurotransmitters dopamine, epinephrine, norepinephrine and serotonin. Dopamine, epinephrine and norepinephrine are referred to as catecholamines, and serotonin is an indoleamine. A variety of sensory and environmental triggers including light, sounds, exertion, chemicals, foods and hormonal shifts may all lead to migraine attacks. A significant genetic association has also been identified.



The role of foods in triggering migraine headaches is well recognized. Dietary triggers have generally been attributed to specific characteristics such as, tyramine, nitrates or MSG. The majority of studies use migraine frequency to identify specific food triggers. However, newer research has implicated immune reactions to foods as a cause of migraine, as was occurring with this patient. BB's baseline food-specific IgG4 antibody assay revealed many positive findings, including severe reactions to casein, milk and egg white, and mild-to-moderate reactions to numerous other foods (Figure 1). Not surprisingly, an individualized oligoantigenic diet that involved the removal or rotation of reactive foods significantly reduced the incidence and severity of BB's episodes. Oligoantigenic or hypoallergenic diets have shown remarkable success in resolving migraines. A case control study of elimination diets based on IgG response to foods successfully controlled migraines without the need for medications.


The high number of food reactions shown in Figure 1 also suggested intestinal hyperpermeability. Left untreated, larger food peptides are allowed to penetrate the epithelial barrier and form IgG4 antibody/antigen complexes. These complexes may be capable of triggering an inflammatory response, which in the case of BB, resulted in migraine attacks. In addition to an oligoantigenic diet, treatment for the intestinal lining was important for BB, and included glutamine, probiotics, fish oil, amino acids, vitamins and minerals.





BB presented with migraine, depression, anxiety and fatigue. The latter three are recognized migraine comorbidities. Monoaminergic dysfunction may be a common pathogenic mechanism in all of these complaints. Serotonin or catecholamine modulation is used for treatment in depression, anxiety, dysmenorrhea and migraines.


BB's fasting plasma specimen (Figure 2) revealed a general pattern of low essential and non-essential amino acids, including the aromatic amino acids tryptophan and tyrosine. Phenylalanine, also an aromatic amino acid, was in the second quintile, and therefore on the lower side of a normal finding. The aromatic amino acids are substrates for the monoaminergic neurotransmitters. Urinary organic acid testing demonstrated that the catecholamine metabolites vanilmandelate (VMA) and homovanillate (HVA) were low-normal. 5-Hydroxyindoleacetate (5-HIAA), the serotonin metabolite, was low (Figure 3).



图2 :氨基酸平衡分析(单位:μmol/L)



The low to low-normal levels of amino acids, including tryptophan, tyrosine and phenylalanine, were consistent with impaired production of serotonin and the catecholamines and their breakdown products, 5-HIAA, VMA and HVA. Low levels of these amino acids, neurotransmitters and their breakdown products have been found in both depression and migraines. Low whole blood serotonin may also be associated with rebound migraine. The low tryptophan and low 5-HIAA suggested that BB's available serotonin pool was also low. With treatment, tryptophan and 5-HIAA normalized (Figures 5 and 6), suggesting that tryptophan levels and serotonin synthesis in the CNS improved.


While tryptophan normalization alone could have resulted in improved mood, the patient dramatically reduced her dosage of eletriptan hydrobromide, the serotonin receptor agonist. This change supports the hypothesis that endogenous serotonin production also normalized. Increases in tyrosine , while not enough to be within normal limits, would have increased norepinephrine and dopamine levels and thereby increased VMA and HVA , also contributing to the patient's clinical improvement. It is possible that the small amount of tyrosine being produced from supplementation was being shunted toward production of the catecholamines, and thus was still low in plasma. Regardless, the remaining low amino acids indicated that supplementation was still required for this patient.


Follow-up IgG4 food antibody production was significantly lower after treatment, both in the number of foods and in the severity of reaction . After three months of treatment, only a moderate reaction to egg and a mild reaction to milk and casein were noted. It is likely that BB was being exposed to small amounts of egg and milk, and therefore generating a slight antibody response. This corroborated her suspicion that occult exposure to dairy and eggs continued to trigger migraine. Since the rest of the reactions were resolved, the intestinal permeability was likely improved.




Laboratory follow-up improvements paralleled those seen clinically. At three months, BB reported increased energy, significantly decreased anxiety and depression, and considerably reduced migraine attacks. Her use of migraine medications was significantly lessened. With poor serotonin synthesis and reliance on eletriptan hydrobromide, BB would have been at risk of developing rebound headaches, which are a difficult-to-treat but relatively common finding with chronic migraine.` Complying with the rotation diet was difficult for BB, but she experienced its value in her clinical improvement and was therefore committed to avoiding her known trigger foods.








More than 65 million individuals suffer from either migraine, depression or both conditions in the United States today.However, both conditions are underdiagnosed and undertreated, and therefore the true incidence is likely much higher. The debility of both conditions is also high.For instance, in one study, a full 91% of migraineurs report functional impairment and 53% report severe impairment resulting from their headaches.While migraine medications may be helpful in relieving symptoms after the onset of an attack, regular, frequent use may lead to medication overuse headaches, a challenging-to-treat and painful condition.Antidepressant medication may similarly be quite helpful, although side effects limit tolerance and are the number one reason for cessation. Moreover, while medication is palliative (and likely necessary), it fails to address the underlying causes of the illnesses, and therefore lasting efficacy may be unobtainable.



In this case, laboratory testing uncovered a number of IgG4 food-specific antibodies and amino acid and neurotransmitter imbalances that appeared to be causal factors of migraine, depression and other comorbidities in this patient.The treatment of the patient, which involved removal of the offending foods along with the addition of amino acids and other nutrients, led to a significant reduction in the intensity and frequency of migraine headaches as well as corresponding improvement in mood, energy, and overall quality of life. Medication use was reduced by approximately 75%.


作者:Cass Nelson-Dooley, MS; Stephanie Kaplan, ND; J.Alexander Bralley, PhD; Kara Fitzgerald, ND 

医生:Stephanie Kaplan, ND