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 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.

Involvement of Peripheral Monocytes with IL-1ß in the Pathogenesis of West Syndrome.

Neuroinflammation has been implicated in the pathogenesis of West syndrome (WS). Inflammatory cytokines, including interleukin-1ß(IL-1ß), have been reported to be associated with epilepsy. However, the assessment of cytokine changes in humans is not always simple or deterministic. This study aimed to elucidate the immunological mechanism of WS. We examined the intracellular cytokine profiles of peripheral blood cells collected from 13 patients with WS, using flow cytometry, and measured their serum cytokine levels. These were compared with those of 10 age-matched controls. We found that the WS group had significantly higher percentages of inter IL-1ß, interleukin-1 receptor antagonist (IL-1RA)-positive monocytes, and interferon gamma (IFN-γ) in their CD8+ T cells than the control group. Interestingly, the group with sequelae revealed significantly lower levels of intracellular IFN-γ and IL-6 in their CD8+ T and CD4+ T cells, respectively, than the group without sequelae. There was no correlation between the ratios of positive cells and the serum levels of a particular cytokine in the WS patients. These cytokines in the peripheral immune cells might be involved in the neuroinflammation of WS, even in the absence of infectious or immune disease. Overall, an immunological approach using flow cytometry analysis might be useful for immunological studies of epilepsy.

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.

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.

High mobility group box 1 and angiogenetic growth factor levels in children with central nerve system infections.

INTRODUCTION: To clarify the pathology of children with acute encephalopathy and other neurological disorders, the involvement of high-mobility group box 1 (HMGB1), which is a representative of danger-associated molecular patterns, and angiogenesis-related growth factors were investigated. PATIENTS AND METHODS: Participants were 12 children with acute encephalopathy (influenza, rotavirus, and others), 7 with bacterial meningitis, and 6 with epilepsy disease (West syndrome). Twenty-four patients with non-central nervous system (CNS) infections as a control group were admitted to our hospital. We examined the levels of HMGB1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and other cytokines in the serum and cerebrospinal fluid (CSF) of the subjects. RESULTS: Serum and CSF HMGB1 levels were significantly higher in the encephalopathy and meningitis groups than in the West syndrome and control groups. CSF HMGB1 levels correlated with those of interleukin-6 and -8. CSF HMGB1 and VEGF levels were correlated, and PDGF showed a positive relationship. CONCLUSION: HMGB1 and angiogenesis-related growth factors appear to play pivotal roles in the pathophysiology of CNS infections.

Complementary and Integrative Medicines as Prophylactic Agents for Pediatric Migraine: A Narrative Literature Review.

Complementary and integrative medicines (CIMs) are increasingly used as a preventive antimigraine therapy. In this review, we aimed to summarize the evidence for the efficacy and safety of eight CIMs (riboflavin, coenzyme Q10, magnesium, melatonin, polyunsaturated fatty acids, and combination therapy of feverfew, vitamin D, and ginkgolide B) in pediatric migraine prevention. The level of evidence for riboflavin was relatively high; it was investigated by many studies with five/seven studies demonstrating its efficacy. Five studies investigated the use of melatonin, with one reporting negative results. There was insufficient evidence on the effectiveness of coenzyme Q10, magnesium, and polyunsaturated fatty acids. Combination therapy showed positive potential; however, reports on the individual antimigraine effects of the CIMs were lacking. A definitive conclusion was not reached regarding the specific integrative drugs clinicians should choose for pediatric migraines, owing to low-quality evidence and a limited number of studies. Integrative medications are becoming more common for pediatric migraine prevention as they do not produce serious side effects, and underlying research data suggest their efficacy in preventing migraine. Additional studies are warranted to confirm the role of CIMs in treating patients with migraines.

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.

A Review on the Triggers of Pediatric Migraine with the Aim of Improving Headache Education.

Although migraines are common in children and adolescents, they have a robustly negative impact on the quality of life of individuals and their families. The current treatment guidelines outline the behavioral and lifestyle interventions to correct common causative factors, such as negative emotional states, lack of exercise and sleep, and obesity; however, the evidence of their effectiveness is insufficient. To create a plan for disseminating optimal pediatric headache education, we reviewed the current evidence for factors correlated with migraine. We assessed three triggers or risk factors for migraines in children and adolescents: stress, sleep poverty, and alimentation (including diet and obesity). While there is a gradual uptick in research supporting the association between migraine, stress, and sleep, the evidence for diet-related migraines is very limited. Unless obvious dietary triggers are defined, clinicians should counsel patients to eat a balanced diet and avoid skipping meals rather than randomly limiting certain foods. We concluded that there is not enough evidence to establish a headache education plan regarding behavioral and lifestyle interventions. Clinicians should advise patients to avoid certain triggers, such as stress and sleep disorders, and make a few conservative dietary changes.

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.

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.

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.

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.

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.

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.

Single-Photon Emission Computed Tomography Is an Ambiguous Imaging Method on Initial Diagnosis for Acute Encephalopathy.

The distinction between acute encephalopathy (AE) and convulsive disorders with pyrexia may be problematic. We analyzed the clinical and laboratory features in 127 children who were admitted for suspected AE. They were categorized into (1) definite acute encephalopathy group (DAEG; n = 17, abnormal findings on electroencephalography [EEG], magnetic resonance imaging, or single-photon emission computed tomography [SPECT] with prolonged impaired consciousness), (2) probable acute encephalopathy group (PAEG; n = 21, abnormal findings without prolonged impaired consciousness), and (3) nonacute encephalopathy group (NAEG; n = 89). Cerebrospinal fluid interleukin-6 (CSF IL-6), and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine phosphokinase levels were significantly higher in DAEG compared with NAEG but not PAEG. No significant differences were observed between DAEG and PAEG except for serum creatinine levels. In PAEG, an area of hypoperfusion was observed on SPECT images of nine patients with normal CSF IL-6 levels. AE was suspected in two PAEG patients who exhibited high CSF IL-6 levels and abnormal EEG findings without abnormal SPECT findings. All seven patients with severe neurological sequelae were categorized to DAEG. CSF IL-6 and serum AST, ALT, and creatine kinase levels may be valid predictors of typical AE; prolonged impaired consciousness is an important sign of AE. However, SPECT may not be suitable for initial diagnosis of AE.