Experimental and Clinical Investigation of Cytokines in Migraine: A Narrative Review.

The role of neuroinflammation in the pathophysiology of migraines is increasingly being recognized, and cytokines, which are important endogenous substances involved in immune and inflammatory responses, have also received attention. This review examines the current literature on neuroinflammation in the pathogenesis of migraine. Elevated TNF-α, IL-1ß, and IL-6 levels have been identified in non-invasive mouse models with cortical spreading depolarization (CSD). Various mouse models to induce migraine attack-like symptoms also demonstrated elevated inflammatory cytokines and findings suggesting differences between episodic and chronic migraines and between males and females. While studies on human blood during migraine attacks have reported no change in TNF-α levels and often inconsistent results for IL-1ß and IL-6 levels, serial analysis of cytokines in jugular venous blood during migraine attacks revealed consistently increased IL-1ß, IL-6, and TNF-α. In a study on the interictal period, researchers reported higher levels of TNF-α and IL-6 compared to controls and no change regarding IL-1ß levels. Saliva-based tests suggest that IL-1ß might be useful in discriminating against migraine. Patients with migraine may benefit from a cytokine perspective on the pathogenesis of migraine, as there have been several encouraging reports suggesting new therapeutic avenues.

Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine.

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α, are known to be increased. Additionally, animal models of headache have demonstrated that immunological responses associated with cytokines are involved in the pathogenesis of migraine. Furthermore, these inflammatory mediators might alter the function of tight junctions in brain vascular endothelial cells in animal models, but not in human patients. Based on clinical findings showing elevated IL-1ß, and experimental findings involving IL-1ß and both the peripheral trigeminal ganglion and central trigeminal vascular pathways, regulation of the Il-1ß/IL-1 receptor type 1 axis might lead to new treatments for migraine. However, the integrity of the blood-brain barrier is not expected to be affected during attacks in patients with migraine.

Pathological analysis of children with childhood central nervous system infection based on changes in chemokines and interleukin-17 family cytokines in cerebrospinal fluid.

BACKGROUND: In this study, the pathologies of acute meningitis and encephalopathy were investigated, and biomarkers useful as prognostic indices were searched for. METHODS: The subjects were 31 children with meningitis, 30 with encephalopathy, and 12 with convulsions following gastroenteritis. Control group consisted of 24 children with non-central nervous system infection. Cerebrospinal fluid cytokine analysis was performed. RESULTS: Chemokines significantly increased in the bacterial meningitis group compared with those in viral meningitis and encephalopathy groups. On comparison of interleukin(IL)-17, it increased in cases with status epilepticus in influenza-associated encephalopathy group. In the rotavirus encephalopathy and convulsions following gastroenteritis groups, IL-17 particularly increased in the convulsions following gastroenteritis group. IL-8 increased in all cases irrespective of the causative virus. CONCLUSIONS: In the encephalopathy group, IL-8 may serve as a neurological prognostic index. IL-17 was increased in the convulsions following gastroenteritis group, particularly in cases with status epilepticus, suggesting its involvement as a convulsion-related factor.

Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) levels in the cerebrospinal fluid of children with influenza-associated encephalopathy.

INTRODUCTION: To search for an index of neurologic prognosis of children with influenza-associated encephalopathy (IAE), involvement of angiogenesis-related growth factors in the pathology was investigated. PATIENTS AND METHODS: The subjects were 11 IAE patients, 6 patients with bacterial meningitis (BM), and 24 patients with non-central nervous system infection as a control group admitted to our hospital. The correlation between the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) levels in cerebrospinal fluid and the relationship with an index of inflammatory marker, interleukin (IL)-6, were investigated. Using the Pediatric Cerebral Performance Categories (PCPC) score as a prognostic indicator, we evaluated the association between the biomarkers and neurologic prognosis. RESULT: PDGF significantly increased in the IAE group compared with that in the BM group. Cerebrospinal fluid VEGF and PDGF increased in all IAE and BM patients compared with that in the control group, and VEGF and PDGF were positively correlated in the 2 groups. No correlation was found between the cerebrospinal fluid VEGF and PDGF levels and IL-6 level in the IAE group, whereas a correlation was found in the BM group. All these factors increased in patients with poor neurologic prognosis. DISCUSSION: It is possible that the disease state of IAE can be evaluated based on vascular endothelial disorder-related markers.

Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy.

No biomarker has been established as a prognostic indicator of acute encephalopathy associated with various etiological factors. In this study, we examined useful prognostic biomarkers in patients with acute encephalopathy associated with respiratory syncytial virus (RSV) infection. The subjects were 11 children with RSV-associated encephalopathy admitted to our hospital. We measured the levels of interleukin (IL)-6, brain-derived neurotrophic factor (BDNF) and nitrogen oxide (NO)x in cerebrospinal fluid collected on the day of admission. Using the pediatric cerebral performance categories (PCPC) score as a prognostic indicator, we evaluated the association between the biomarkers and neurologic prognosis. Concerning neurologic prognosis, sequelae were noted in more than 50% of the subjects. There was no association between prognosis and age/sex. Increases in the levels of all biomarkers were observed in all subjects. IL-6 and BDNF levels were correlated with PCPC score, but not with NOx. Of the biomarkers investigated, the IL-6 and BDNF levels in cerebrospinal fluid were shown to be correlated with neurologic prognosis. Because many patients with this disease had severe sequelae, assessment should be conducted by early evaluation of the biomarkers examined in this study with respect to the clinical course.

Altered serum levels of platelet-derived growth factor receptor ß and cluster of differentiation 13 suggest a role for pericytes in West syndrome.

BACKGROUND: Pericytes play a role in the maintenance of the blood-brain barrier and neuroinflammation, attracting attention as to whether they are also involved in the pathogenesis of epilepsy.This study aimed to explore the relationship between West syndrome and pericytes. METHODS: Eighteen Japanese pediatric West syndrome patients and nine controls aged 2 years or younger were retrospectively enrolled in this study. We assessed theserumlevels of pericyte markers, serum PDGFRß (platelet-derived growth factor receptorß),CD13 (aminopeptidase N), and 27 cytokines in 17 pediatric patients with West syndrome and the control group. RESULTS: Patients with West syndrome exhibited significantly increased CD13 and decreased PDGFRß levels, compared with controls but not serum cytokine levels. These values did not differ significantly between symptomatic and idiopathic West syndrome. CONCLUSION: Pericytes might be implicated in the pathogenesis of West syndrome.

Experimental and Clinical Evidence of the Effectiveness of Riboflavin on Migraines.

Riboflavin, a water-soluble member of the B-vitamin family, plays a vital role in producing energy in mitochondria and reducing inflammation and oxidative stress. Migraine pathogenesis includes neuroinflammation, oxidative stress, and mitochondrial dysfunction. Therefore, riboflavin is increasingly being recognized for its preventive effects on migraines. However, there is no concrete evidence supporting its use because the link between riboflavin and migraines and the underlying mechanisms remains obscure. This review explored the current experimental and clinical evidence of conditions involved in migraine pathogenesis and discussed the role of riboflavin in inhibiting these conditions. Experimental research has demonstrated elevated levels of various oxidative stress markers and pro-inflammatory cytokines in migraines, and riboflavin's role in reducing these marker levels. Furthermore, clinical research in migraineurs showed increased marker levels and observed riboflavin's effectiveness in reducing migraines. These findings suggest that inflammation and oxidative stress are associated with migraine pathogenesis, and riboflavin may have neuroprotective effects through its clinically useful anti-inflammatory and anti-oxidative stress properties. Riboflavin's safety and efficacy suggests its usefulness in migraine prophylaxis; however, insufficient evidence necessitates further study.

Orthostatic Headache in Children Including Postural Tachycardia Syndrome and Orthostatic Hypotension: A Near-Infrared Spectroscopy Study.

BACKGROUND AND AIM: Although head and/or neck pain attributed to orthostatic hypotension is included in international guidelines, its mechanisms and relevance remain unknown. This study examined the term's relevance and aimed to elucidate the associated clinical features. METHODS: An active stand test was performed to evaluate fluctuations in systemic and cerebral circulation in children and adolescents reporting complaints in the absence of a confirmed organic disorder. The subjects were categorized based on orthostatic headache presence/absence, and their characteristics and test results were compared. RESULTS: Postural tachycardia syndrome was observed in 50.0% of children with, and 55.1% without, orthostatic headache. For orthostatic hypotension, the respective values were 31.3% and 30.6%. A history of migraine was more prevalent in children with orthostatic headaches (64.1% vs. 28.6%; p < 0.01). The observed decrease in the cerebral oxygenated hemoglobin level was larger in children with orthostatic headaches (Left: 6.3 (3.2-9.4) vs. 4.1 (0.8-6.1); p < 0.01, Right: 5.3 (3.1-8.6) vs. 4.0 (0.8-5.9); p < 0.01). CONCLUSION: Fluctuations in cerebral blood flow were associated with orthostatic headaches in children, suggesting that the headaches are due to impaired intracranial homeostasis. As orthostatic headache can have multiple causes, the term "head and/or neck pain attributed to orthostatic (postural) hypotension" should be replaced with a more inclusive term.

Effectiveness of low-dose riboflavin as a prophylactic agent in pediatric migraine.

BACKGROUND: Riboflavin may prevent migraine episodes; however, there is limited evidence of its effectiveness in pediatric populations. This study investigated the effectiveness of riboflavin and clinical predictors of response in children with migraines. METHODS: We retrospectively reviewed data from 68 Japanese children with migraines, of whom 52 also exhibited another type of headache. Patients received 10 or 40 mg/day of riboflavin. We evaluated the average migraine frequency per month as a baseline and after 3 months of riboflavin therapy to determine the effectiveness and clinical predictors of response. RESULTS: The frequency of migraine episodes was significantly lower at 3 months than at baseline (median, [interquartile range], 5.2 (3-7) vs. 4.0 (2-5); p < 0.01). Twenty-five patients (36.7%) showed 50% or greater reduction in episode frequency (responders), while 18 (26.5%) showed a 25%-50% reduction. We compared responders (n = 25) and non-responders (n = 43) and found no significant differences in sex, familial history, riboflavin dose, migraine type (i.e., presence or absence of aura), age at headache onset, or age at consultation. However, non-responders were more likely to have co-morbid non-migraine headaches (odds ratio, 4.11; 95% confidence interval [CI], 1.27-13.33; p = 0.02); this variable was also significant in a multivariate analysis (adjusted odds ratio, 3.8; 95% CI, 1.16-12.6; p = 0.03). Of the co-morbid headache types, only tension headaches were significant (odds ratio, 0.176; 95% CI, 0.04-0.73; p = 0.013). No adverse effects of riboflavin were identified. CONCLUSIONS: Low-dose riboflavin is safe and modestly effective for migraines in children. It may be especially beneficial for children without other co-morbid headache types.

Clinical Features and Burden Scores in Japanese Pediatric Migraines With Brainstem Aura, Hemiplegic Migraine, and Retinal Migraine.

BACKGROUND: Migraines are a broad spectrum of disorders classified by the type of aura with some requiring attentive treatment. Vasoconstrictors, including triptans, should be avoided in the acute phase of migraines with brainstem aura, in hemiplegic migraine, and in retinal migraine. This study investigated the characteristics and burden of these migraines. METHODS: Medical charts of 278 Japanese pediatric patients with migraines were retrospectively reviewed. Migraine burden of migraines with brainstem aura, hemiplegic migraines, and retinal migraine was assessed using the Headache Impact Test-6™ (HIT-6) and the Pediatric Migraine Disability Assessment scale (PedMIDAS). RESULTS: Of 278 patients screened, 12 (4.3%) patients with migraines with brainstem aura (n = 5), hemiplegic migraines (n = 2), and retinal migraine (n = 5) were enrolled in the study. All patients had migraine with/without typical aura, whereas some patients had coexisting migraine with another type of headache (chronic tension-type headache in 3 patients, and 1 each with frequent episodic tension-type headache, headache owing to medication overuse, and chronic migraine). Migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients with coexisting headaches had higher HIT-6 or PedMIDAS scores, whereas migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients without coexisting headache did not show high HIT-6 or PedMIDAS scores. CONCLUSION: All migraines with brainstem aura, hemiplegic migraines, and retinal migraine patients experienced migraine with or without typical aura, and some patients having other coexisting headaches also had high PedMIDAS and HIT-6 scores. PedMIDAS and HIT-6 should not be considered diagnostic indicators of migraines with brainstem aura, hemiplegic migraines, or retinal migraine. In clinical practice for headaches in children, careful history taking and proactive assessment of the aura are needed for accurate diagnosis of migraines with brainstem aura, hemiplegic migraines, and retinal migraine.

Granzyme A Participates in the Pathogenesis of Infection-Associated Acute Encephalopathy.

OBJECTIVE: The present study aimed to determine whether granzymes are implicated in the pathogenesis of infection-associated acute encephalopathy (AE). METHODS: We investigated granzyme and cytokine levels in the cerebrospinal fluid of patients with acute encephalopathy or complex febrile seizures (cFS). A total of 24 acute encephalopathy patients and 22 complex febrile seizures patients were included in the present study. Levels of granzymes A and B were measured using enzyme-linked immunosorbent assay, and levels of tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), interleukin 1ß (IL-1ß), IL-1 receptor antagonist (IL-1RA), IL-4, IL-6, IL-8, and IL-10 were assessed using the Bio-Plex suspension array system. RESULTS: Cerebrospinal fluid levels of granzyme A were significantly higher, and those of TNF-α and IL-1RA were significantly lower in the AE group than in the cFS group; however, no significant differences in the levels of granzyme B, IFN-γ, IL-1ß, IL-4, IL-6, IL-8, and IL-10 were observed between the 2 groups. In addition, no significant differences in granzyme A, granzyme B, or cytokine levels were observed between acute encephalopathy patients with and those without neurologic sequelae. CONCLUSIONS: Our findings indicate the involvement of granzyme A in the pathogenesis of acute encephalopathy.

Spinal Fluid Cytokine Levels and Single-Photon Emission Computed Tomography Findings in Complex Febrile Seizures.

In this study, the authors assessed cerebrospinal fluid cytokine levels and single-photon emission computed tomography (SPECT) findings in complex febrile seizures. This study included 23 Japanese patients with complex febrile seizures. Twenty patients underwent SPECT and 12 underwent analysis of cerebrospinal fluid cytokine levels (interleukin [IL]-6, interleukin-10, interleukin-17, interleukin-1ß, tumor necrosis factor-α, and interferon-γ); 9 patients underwent both studies. Cerebrospinal fluid cytokine levels were compared between the current complex febrile seizure patients and 30 patients with acute encephalopathy. In 17 of 20 patients, SPECT findings revealed areas of hypoperfusion, including the frontal (5), occipital (4), and lobular (4) regions, overlapping with other areas. Relative to patients with acute encephalopathy, those with complex febrile seizures exhibited significantly lower cerebrospinal fluid interleukin-6, interleukin-1ß, tumor necrosis factor-α, and interleukin-10 levels and significantly higher interleukin-17 levels. As patients with complex febrile seizures frequently exhibit abnormal SPECT findings, cerebrospinal fluid interleukin-17 levels might provide a valid biomarker to discriminate complex febrile seizures and acute encephalopathy, regardless of SPECT findings.

Serial Analysis of Multiple Serum Cytokine Responses to Adrenocorticotropic Hormone Therapy in Patients With West Syndrome.

Adrenocorticotropic hormone (ACTH) therapy is effective for West syndrome; however, the underlying mechanism of action remains unknown. This study explored this mechanism in 5 Japanese patients with West syndrome, injected with ACTH for 28 days. Serum samples were obtained before and 30, 120, and 720 minutes after ACTH injection divided into an "early" (1-4 days) and a "late" (10-28 days) group. Responses to ACTH over time were analyzed by measuring the levels of 27 cytokines. In the early group, serum levels of interleukins-5, -9, and -17, basic fibroblast growth factor, interferon (IFN-γ), IFN-γ-inducible protein 10, chemokine ligand (CCL) 3 and 4, and platelet-derived growth factor were higher in all patients before ACTH administration than in the 720-minute time point. In the late group, no definite trend was observed except for decreased CCL2 levels after ACTH administration. These changes may correlate with mechanisms underlying the anticonvulsant effects of ACTH.