Migraine and histamine intolerance, with a link to MS

Migraine case management requires assessment of multiple contributing causes, and there is mounting evidence that histamine intolerance contributes to migraine and other neuroinflammatory disorders. A study just published in the Journal of the Neurological Sciences presents evidence that treating insufficient DAO activity (diamine oxidase, the enteric enzyme that breaks down histamine) can be an effective therapy for migraine. The authors state:

"Histamine has been considered as a chemical mediator of migraine. The degradation is done in two different pathways. One of the enzymes that allow this process is the diamino-oxidase (DAO)... The aim of this study is to identify the prevalence of the deficit in the activity of DAO in patients with migraine, and test the supplementation of this enzyme in a randomized controlled double- blind trial."

They randomized patients with four to fourteen migraine attacks per month between to receive either placebo or DAO three times per day during one month. Their outcome measures included reduction in hours of pain and the use of other migraine medication. DAO supplementation was effective for migraine in their study subjects:

"We studied 137 patients with migraine, and find the deficit of DAO activity (<80 HDU/ml) in 119 (87%). One hundred patients were randomized and included in the intention- to-treat analysis. Between run-in and first month of treatment, the mean number of hours of pain decreased in both groups but with significant difference in the final control in the group treated with DAO compared with placebo. The use of the acute antimigraine drug was significantly reduced in the DAO but not in placebo group. There were no adverse events in either group."

Since excess histamine can produce inflammation in the central nervous system and DAO 'digests' histamine (see earlier post titled Histamine intolerance), the authors' conclusion stands to reason:

"Deficit in the activity of DAO is very prevalent in population with migraine. The supplementation with the enzyme is effective and safe as a preventive therapy for migraine."

 Clinicians should be aware that neuroinflammation and loss of immune tolerance can affect more than one nervous system 'target' at a time. An interesting case report published in The Journal of Headache and Pain describes multiple sclerosis presenting as a worsening of migraine symptoms:

"Multiple sclerosis (MS) is a chronic autoimmune disease that targets myelinated axons in the central nervous system. Headache has been reported as a subtle symptom of the onset of MS, with a variable frequency of 1.6–28.5%; however, it remains unclear whether headache is a true symptom of MS onset. Here, we report the case of a female patient who had a history of migraine without aura and experienced worsening of migraine-headache symptoms as the initial manifestation of MS."

Subsequent to the initial presentation of migraine the patient developed typical full-blown MS neurological deficits (bilateral numbness of the lower legs, unsteady gait, difficulty in defecation, and urine retention for the past week, etc.). The diagnosis of MS was then confirmed by MRI. Interestingly...

"The cerebrospinal fluid (CSF) analysis performed after admission to exclude other possible infectious causes showed no white cells and normal glucose (70 mg/dL) and protein (26 mg/dL) levels. CSF tests were negative for virus isolation and for Gram stain and culture. No oligoclonal bands were found. Serum analyses for presence of rheumatoid factor (RF), antibodies against nuclear antigen, and anticardiolipin immunoglobulins G and M yielded negative results; in addition, the levels of the C3 (90.7 mg/dL) and C4 (18.5 mg/dL) complement were normal. Furthermore, the anti-HIV and rapid plasma reagin (RPR) tests were negative. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were <0.10 mg/dL."

Practitioners should notice that the above laboratory markers, including CRP and ESR, were normal in the presence of raging neuroinflammation. The authors advise clinical vigilance:

"To our knowledge, there is no description in the literature of patients presenting with worsening migraine symptoms without neurological signs as the first episode of MS. When the initial symptoms of MS are worsening migraines and changes in headache patterns, they may be discounted as a recurrent event and ignored. Our study suggests that it is important to consider the possibility of MS in patients with worsening migraine symptoms accompanied by episodes of focal deficit and to follow-up these patients regularly."

They comment on the role of stress in triggering inflammation:

"Many factors can trigger migraine attacks, such as changes in weather, drugs, alcohol, caffeine withdrawal, stress, fatigue, lack of sleep, hormonal therapy, diet, and hunger. In our case, none of the above-mentioned factors was found. We hypothesize that stress causes inflammation in general, and particularly in MS, because stress-related neuropeptides activate the excretion of inflammatory molecules by microglia and mast cells. Although no obvious stress was observed in our case, a hidden stress may have caused the acute MS attacks. As observed in our case, MS may be considered as one of the differential diagnoses of acute-migraine-like episodes."

Clinicians should bear in mind the authors' summary of findings:"We conclude that MS with periaqueductal grey matter involvement may present with worsening migraine. It is important to be cautious if any secondary causes exist, especially when the patient has a history of migraine without aura. MS should be one of the differential diagnoses in young women showing a change in headache pattern or poor clinical drug response to migraine treatment accompanied by episodes of focal neurological deficit. Failure to recognize MS may lead to inappropriate treatment and worse prognosis; early diagnosis in patients with MS is essential to improve their clinical outcomes and quality of life." In addition to the fact that histamine intolerance can contribute to migraine, a recent study published in the journal Fluids and Barriers of the CNS offers evidence that histamine levels are also increased in multiple sclerosis:

"Multiple sclerosis (MS) is a complex autoimmune disease with inflammation and demyelination within the central nervous system (CNS). Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis."

They found a significant association between histamine levels and MS:

"CSF histamine levels in MS patient samples were significantly higher (median: 35.6 pg/ml) than in controls (median: 5.5 pg/ml). In addition, histamine increased with age."

The tendency for histamine to increase with age is one of the reasons why we tend to have more inflammation and chronic symptoms as the years go by.This finding links histamine intolerance, migraine and multiple sclerosis. The authors conclude:

"Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system... This observation encourages a deeper investigation of the role of GM-CSF, granulocytes, macrophages and histamine in MS. Further, histamine may be investigated as diagnostic marker for MS and other inflammatory CNS diseases."

 Those who wish to dig deeper into the mechanism by which histamine contributes to autoimmune inflammatory diseases of the central nervous system including MS will appreciate a paper published in the European Journal of Immunology showing that two specific histamine receptors are involved in pathogenesis:

"Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)-H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1) R and H(2) R are propathogenic, while H(3) R and H(4) R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1) H(2) RKO and H(3) H(4) RKO mice and studied them for susceptibility to EAE."

In other words, they produced two sets of study subjects, one without H(1)and H(2) receptors, the other without H(3)and H(4) receptors and found that neuroinflammation was much less severe when the former pair were 'turned off':

"Compared with wild-type (WT) mice, H(1) H(2) RKO mice developed a less severe clinical disease course, whereas the disease course of H(3) H(4) RKO mice was more severe. H(1) H(2) RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3) H(4) RKO mice. Additionally, splenocytes from immunized H(1) H(2) RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17."

IL-17, of course, is a 'hallmark' autoimmune cytokine. The authors advance the reduction of histamine signalling as a 'disease-modifying therapy for MS:

"These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases."