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功能医学干预偏头痛案例分析

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.



在世界20大致残性健康问题中,偏头痛位于第20位(女性中位列第9)。在美国,超过8%的男性和18%的女性正深受其害。偏头痛的主要特点就是疼痛,是由多种环境因素引发的致残性循环症状。偏头痛和基因有着强烈的相关性,常见的与偏头痛相关的并存症状包括:焦虑、抑郁、痛经和疲劳等。据报道,抑郁的发病率超过偏头痛的两倍,而且抑郁型偏头痛在女性中的发病率远大于男性。


案例分析


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.


病史

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.


据BB自诉,她有轻微的环境性过敏反应,小时候打过脱敏针。此外,月经时伴有腹痛,无任何胃肠疾病,先前使用过依托孕烯/乙炔基雌二醇阴道环避孕,头痛症状并无改善。BB采用标准美国饮食,大量摄入牛羊肉、含糖甜品和饮料、高脂食物、乳制品、鸡蛋、精米精面。体格检查未见异常,先前预定的标准实验室检测包括全血记数、生化全项、甲状腺和铁指标均在正常范围之内。


初步检测结果

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.


1.食物特异性IgG4抗体:包括IgG抗体参与的所有食物反应,都是偏头痛的病因。

2.血浆氨基酸:抑郁患者体内氨基酸缺乏。

3.尿液有机酸:神经递质代谢产物和营养不足的功能性指标可通过有机酸来评估,尿液中神经递质代谢产物和营养素(比如B12、叶酸)失调都会导致抑郁。


初步评估

Dysmenorrhea

Depression

Anxiety

Fatigue

Multiple food-specific IgG4 antibodies

Intestinal hyperpermeability

Multiple amino acid deficiencies resulting in:

Low total-body serotonin turnover

Low-normal catecholamine turnover


痛经

抑郁

焦虑

疲劳

复合食物特异性IgG4抗体

肠道通透性过高

复合氨基酸缺乏导致:

血清素转化降低

儿茶酚胺转化降低


初步计划

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


排除饮食/循环饮食:

•    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.


治疗计划基本原理

假定不同食物都可以引发偏头痛,那么能够确定的是,利用大量的IgG4反应可以鉴别出必要的食物移除,或者基于更轻微的反应,也能够明显的减少和食物的接触。首先,根据检测结果采用排除饮食和轮替饮食。阳性结果的数量能够很好的体现肠道通透性过高,所以我们引进了几种可以降低炎症、治疗胃肠道疾病的营养素,包括益生菌、谷氨酰胺和鱼油。其次,根据BB的检测结果定制氨基酸混合物,确保必需氨基酸得到充分的利用,发挥氨基酸在代谢,尤其是神经递质合成方面的重要作用。最后,引入专门为女性设计的多种维生素和矿物质(比如钙、镁、维生素B等),维持机体的代谢功能。


第二个月随访

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.


BB偏头痛发作的强度和频率均得到缓解。前三周都未服用药物,也并没有表现出任何停药症状。当她头痛发作时,注意到再次食用某些食物可能是诱发头痛的主要因素,因此,一概停食这些食物。她还注意到头痛的模式也发生了改变,以前疼痛的发作部位位于眼部之后,经过一个月的治疗之后,疼痛开始扩散,现在蔓延到了前额。


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


第二个月的后续治疗计划

•    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.


治疗计划基本原理:应用植物甾醇目的在于减少炎症反应,降低对IgG4阳性食物的偏头痛反应。


第三个月随访

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.


BB说比起以前更有活力,也更开心了。她说:“我感受到了氨基酸给我的心情和精力所带来的积极的影响。”她的心情比之前更为平和,不像以前那样在焦虑和抑郁之间大起大落。偏头痛的发病频率降低到了一个月一次,和月经一样的周期。当偏头痛发作时,疼痛程度甚至比以前更低了,不需要服用药物。月经期间的腹部肿胀和小腹绞痛感也得到了改善。以前,她一直遭受偏头痛的折磨,至少每周都需要服用药物。现在只是偶尔在运动时会发作运动型偏头痛,需要服用依立曲坦缓解疼痛。


她认为,虽然循环饮食(尤其是避免食用鸡蛋和乳制品)很难实现,但是在缓解偏头痛,甚至是改善月经和运动方面是有效的。她相信,如果她可以完全坚持遵守轮替饮食的话,一定能够更好的降低偏头痛的发病率。


Three-month follow-up plan

Continue treatment as directed

Avoid reactive foods

Counseling given on identifying occult food exposure


第三个月的后续治疗计划

•    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


Discussion

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.


讨论

偏头痛的发病机理涉及到脑干和丘脑单胺能传感控制系统功能紊乱,导致该系统对环境和感觉输入的敏感性提高。单胺能系统包括芳香族氨基酸衍生出的神经递质多巴胺、肾上腺素、去甲肾上腺素和血清素。多巴胺、肾上腺素、去甲肾上腺素称为儿茶酚胺,血清素是一种吲哚胺。一系列的感觉和环境诱发因素包括:光照、声音、力、化学物质、食物和激素变化都可能会诱发偏头痛,此外,基因也和偏头痛有着重要的联系。


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.


我们对食物如何诱发偏头痛的机理认识非常深刻。饮食因素发挥作用要归因于几个具体特点,比如酪胺、硝酸盐和谷氨酸钠。大多数研究利用偏头痛发病率来确定特定食物诱发因子,然而,最新研究将免疫反应和食物联系起来,将其视为偏头痛的诱发因素。BB的食物特异性IgG4抗体基准试验显示出很多阳性的结果,包括和酪蛋白、牛奶和蛋白之间的剧烈反应,以及大量其它食物之间的轻微到中等的反应。所以,涉及反应性食物排除和交替的个人低抗原饮食,能够在很大程度上降低BB的发作机率及严重程度。基于食物的免疫球蛋白反应,排除饮食法的对照研究能够在不服用药物的情况下,有效控制偏头痛的发作。


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.


如图1所示,大量食物反应也表明小肠渗透性过高。如果不采取治疗,大的多肽能够渗透到上皮屏障,进而形成IgG4抗原抗体复合物。这些复合物可能会诱发炎症反应,在BB的案例中,炎症反应就是偏头痛。除了低抗原饮食,修复小肠内壁,以及营养补充如谷氨酰胺、益生菌、鱼油、氨基酸、维生素和矿物质等等,对于BB的治疗也十分重要。


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12.jpg

图1:IgG4抗体检测结果


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表现出偏头痛、抑郁、焦虑和疲劳,后三种症状被称为偏头痛并存病。单胺能功能紊乱可能是这些疾病共有的致病机理。我们利用血清素或儿茶酚胺调控来治疗抑郁、焦虑、痛经和偏头痛。


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显示了必需氨基酸和非必需氨基酸的检测结果,这些氨基酸包括:芳香族氨基酸色氨酸和酪氨酸。苯基丙氨酸也是一种芳香族氨基酸,排列在第五分之二的位置,因此不易被发现。芳香族氨基酸是单胺能神经递质的载体。图3尿液有机酸检测表明,儿茶酚胺代谢产物香草基扁桃酸和高香草酸浓度低于正常水平。血清素代谢产物5羟基吲哚乙酸也处于较低水平。


3.jpg

图2 :氨基酸平衡分析(单位:μmol/L)


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图3:尿液有机酸代谢分析(神经递质代谢标记)


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.


低于正常水平的氨基酸包括色氨酸、酪氨酸、苯基丙氨酸,都和血清素、儿茶酚胺,儿茶酚胺分解产物——5羟基吲哚乙酸、香草扁桃酸,高香草酸的合成受损保持一致。抑郁、偏头痛患者体内的这些氨基酸,神经递质,神经递质分解产物浓度均会降低。全血血清素水平低也可能和偏头痛复发有紧密联系。色氨酸和5羟基吲哚乙酸水平低表明,BB体内可用血清素总量同样低。经过治疗之后,色氨酸和5羟基吲哚乙酸水平恢复到正常值,这表明中枢神经系统的色氨酸水平和血清素合成均得到了提高。


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.


虽然色氨酸浓度恢复正常可以改善心情,但是患者大量减少血清素受体激动剂-依立曲坦氢溴酸盐的剂量,这个改变证实了内源性血清素产物也恢复了正常的假设。酪氨酸浓度升高,虽然超过了正常范围,但能够提高去甲肾上腺素和多巴胺的浓度,进而提高香草扁桃酸和高香草酸的浓度,对临床疗效有帮助。少量的酪氨酸有可能从营养补剂中获取,一部分的酪氨酸转移到儿茶酚胺的合成中,因此血浆中的浓度依然很低。不管怎样,剩余低浓度的氨基酸表明,营养补剂对病人的治疗依然很有必要。


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.


后续的免疫球蛋白G4食物抗体的合成在接受治疗之后显著减少(图4),不管是在食物数量方面,还是反应的严重程度方面。在为期三个月的治疗之后,病人只对鸡蛋有中等程度的反应,对牛奶和酪蛋白有轻微的反应。有可能BB会接触少量鸡蛋和牛奶,导致了轻微的抗体反应。

乳制品和鸡蛋的隐形接触能够引发偏头痛的猜想得到了证实。因为剩余反应都得到了解决,肠道通透性也将可能得到改善


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6.jpg图4:三个月后复查IgG4抗体检测结果


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.


后续试验改进和临床观察同步进行。三个月后,BB精力旺盛,焦虑、抑郁明显降低,偏头痛也很大程度上得到了改善。偏头痛药物的服用明显减少。由于血清素合成偏弱,依赖依立坦曲,BB面临着头痛复发的风险,这是一项很难治愈的问题,但相对来说慢性偏头痛是非常普遍的现象。对BB来说,循环饮食很难执行,但是她能感受到此项疗法带来的临床改善,并决定注意避免食用已知的诱发偏头痛的食物。

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图5:三个月后复查氨基酸平衡分析


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图6:三个月后复查尿液有机酸代谢分析

(神经递质代谢标记)


CONCLUSION

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.


结论

如今在美国超过了650万人正遭受着偏头痛和抑郁的折磨,其中一部分人同时得了这两种疾病。然而,这两种病至今还没有全面性的诊断和治疗方法。因此,发病率仍在增长,所带来的影响还是很大。比如有研究显示,有91%的偏头痛患者都存在功能性损伤,而53%的患者受损严重。虽然偏头痛的药物治疗在发病初期能有效缓解症状,但是定期频繁地服用也会造成药物乱用性头痛,这也是一种令人痛苦的,至今还无明确治疗方法的一种疾病。另外,抑郁时服用抗抑郁药相当有效,但是其副作用会降低人体的耐受力,这也是人们停止服药的首要原因。虽然药物能缓解症状(服用药物也是相当必要的),但是并不能从根本上治疗疾病。


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%.


在这种情况下,实验测试发现了一些IgG4食物特异性抗体、氨基酸与体内神经递质之间失衡的关系。这种失衡某种程度上导致了患者的偏头痛、抑郁症以及一些其它同时发作的疾病。关于疾病的治疗,患者在祛除一些特定的敏感食物,并添加氨基酸以及其它营养物质的状态下,其偏头痛的强度和发作频率都明显地减少了,而且情绪和体能提高了,生活质量也得到了改善,药物的使用率也降低了大约75%......


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

医生:Stephanie Kaplan, ND

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