Serial Systemic Immune Inflammation Indices: Markers of Acute Migraine Events or Indicators of Persistent Inflammatory Status?

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Tissa Wijeratne, Melanie J. Murphy, Chanith Wijeratne, Paolo Martelletti, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5209065/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jan, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted 10 You are reading this latest preprint version Abstract Background Migraine is the most common complex neurological disorder, affecting over a billion people worldwide. Neurogenic inflammation has long been recognized as a key factor in the pathophysiology of migraine though little research has been directed to investigating whether inflammation is greatest in migraine with aura or without, and whether inflammation is a permanent state in migraine or whether is an event related transitory state. Thus, the primary aim of this single-centre, retrospective study was to explore the potential clinical utility of the systemic immune-inflammatory indices as a measure of duration and severity of inflammation derived from relative blood cell counts in migraine patients within an acute inpatient setting. Specifically, we assessed the role of serial white blood cell counts to calculate Serial Systemic Immune-Inflammatory Indices (SSIIi) (calculated using the formula: neutrophil count x platelet count/lymphocyte count) between aura (N = 67) and no-aura (N = 119) migraine patients at time of admission to a tertiary care centre in Melbourne, Australia, and at 24 hours post admission versus stable in-community migraineur controls (N = 20) Main Body: We conducted a retrospective analysis of medical records from patients presenting with migraine at Western Health over an 18-month period. Patients were categorized as having migraine with aura (MA) or without aura (MO) according to ICHD-3 criteria. Baseline demographics and brain imaging findings were evaluated for each group. Patients who had at least two sets of white blood cell counts drawn within 24 hours during their admission were included in the study. A mixed-design ANOVA showed a significant main effect of SSIIi between patients with migraine with aura (MA) and migraine without aura (MO) during acute inpatient presentation, in comparison to a convenience sample of outpatients with migraine (MA and MO) with similar blood measures. Conclusion SSIIi levels were significantly lower in patients with migraine with aura (MA), who also showed a greater, though non-significant, decrease between the two measurements compared to those with migraine without aura (MO) and controls, whose SSIIi levels remained consistently higher. The control group displayed similar findings to MO inpatients, suggesting persistent systemic inflammation in a subset of migraine patients regardless of the acuity of presentation. Further studies are needed to evaluate the role of systemic inflammation in migraine pathophysiology, chronicity, and progression. Migraine inflammation Serial Systemic Immune-Inflammatory Indices (SSIIi) cortical spreading depression aura Figures Figure 1 Introduction Migraine is a highly debilitating neurological disorder that affects over a billion people worldwide, making it a significant public health concern[ 1 – 3 ]. It ranks as the second leading cause of disability globally, particularly impacting individuals under the age of fifty, and remains the leading cause of disability among women[ 4 ]. Approximately 15% of the global population suffers from migraine, with about one-third of these individuals experiencing aura during some or all of their attacks[ 5 , 6 ]. The pathobiology of migraine is complex, involving intricate interactions between neurons, vasculature, glial cells, and neurogenic inflammation[ 7 , 8 ]. However, despite the profound impact of migraine on individuals and healthcare systems, the diagnosis remains clinical, with no objective biomarkers or definitive tests available to aid in diagnosis[ 9 , 10 ]. This lack of biomarkers, coupled with the phenotypic overlap between migraine and other primary and secondary headache disorders, contributes to its underdiagnosis, making it one of the most commonly underdiagnosed medical conditions worldwide[ 3 , 11 , 12 ]. Systemic inflammation and its role in migraine has long been debated [ 13 – 16 ]. However, what has not been ascertained is whether inflammation associated with migraine is a transitory response initiated by episodes of cortical spreading depression as in migraine with aura (MA) or in all migraine i.e. both with and without aura, (MO), or whether inflammation is a more persistent state. Thus we have utilized the Systemic Immune-Inflammation Index (SIIi) that was initially developed as a unitary measure of chronic inflammation in the context of colorectal cancer in 2014 by Hu et al[ 17 ] as a means of profiling systemic inflammation in migraineurs using reanalysis of typical and rapid routine blood tests. The SIIi is calculated using routine peripheral blood cell counts of the relative numbers of lymphocytes, neutrophils, and platelets. It is defined as the platelet count (P) multiplied by the neutrophil count (N), divided by the lymphocyte count (L) (SIIi = P × N / L) to provide a measure of the balance between innate immune activity (as indicated by neutrophil (last < 24 hrs in blood) and platelet (8–10 days counts) and adaptive immune activity (as indicated by lymphocyte counts). Hu et al.,[ 17 ] in their seminal work, identified an optimal cutoff point for the Systemic Immune-Inflammation Index (SIIi) of 330 × 10⁹, which effectively stratified patients with hepatocellular carcinoma (HCC) into high (≥ 330) and low SIIi (< 330) groups within their training cohort. These numbers were achieved via rigorous univariate and multivariate analyses, and consequently Hu proposed that SIIi was an independent predictor for both overall survival and relapse-free survival as the area under the curve (AUC) for SIIi in predicting survival and recurrence was found to be superior to other conventional clinical indices. Early Serial measurements of SIIi has since been explored for its prognostic value in other conditions, including hepatocellular carcinoma (HCC)[ 17 ] and Post-COVID Neurological Syndrome [ 18 , 19 ]. Given the established role of inflammation in migraine pathophysiology, we have now sought to investigate whether serial measures of SSIIi in a cohort of hospitalized migraine patients can offer clinical insights into the temporal trajectory of inflammatory processes underlying Migraine with Aura and Migraine without Aura, i.e. whether inflammation is a transient process during migraine attacks or an indication of more persistent neuroinflammatory processes. Our study represents a novel approach to understanding migraine, leveraging the SSIIi as a tool to potentially improve diagnostic accuracy, track disease progression, and tailor therapeutic interventions based on an individual’s inflammatory response profile. We have chosen to focus on patients with migraine with no other confounding inflammatory conditions (i.e. patients with raised traditional inflammatory markers such as CRP were excluded from the study). This approach may enhance the clinical utility of SSIIi as a potential biomarker for persistent maladaptive neuroinflammation regulation in migraine patients and contribute to more targeted treatment strategies in the future. Methods and Participants This retrospective study analyzed data from the electronic health records of a patient cohort admitted to Western Health hospital, Melbourne, Australia, over an 18-month period, specifically for the acute management of a migraine attack. Western Health serves a culturally and linguistically diverse (CALD) population of approximately 1.2 million people, representing 166 languages, providing a unique context for understanding migraine across different demographic groups. Demographic data, including age, gender, and country of origin, were collected alongside relevant clinical information such as cardiovascular risk factors and the presence of atrial fibrillation. Patients were classified as having migraine with aura (MA) or without aura (MO) based on the International Classification of Headache Disorders-3 (ICHD-3) criteria. This classification allowed us to explore potential differences in systemic immune-inflammatory responses between these two subtypes of migraine. To be included in the study, patients had to have at least two sets of white blood cell counts (neutrophil counts, platelet counts, and lymphocyte counts) recorded 24 hours apart during their hospital admission. These measurements were necessary for calculating the Serial Systemic Immune-Inflammatory Indices (SSIIi), calculated using the following formula: Neutrophil count x platelet count (indication of innate immune activity) Lymphocyte count (indicative of adaptive immune activity) Patients whose admissions were complicated by conditions that could independently elevate systemic inflammatory markers were excluded to ensure that the inflammatory indices being measured were related to the migraine itself rather than confounding factors. Exclusion criteria were patients with raised traditional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), or those with acute infections comorbid with their migraine at the time of emergency room admission, were excluded from this analysis. Control sample comprised stable migraineurs (in accordance with ICHD-3 criteria) in the community. They had two blood tests completed 24 hours apart. 2.1 Sample Size An initial cohort of 232 patients with an age range of 18–88 was utilised in this study, with number of patients and mean (SD) age for patient group shown in Table 1 below. The study predominantly included female participants, representing 85.5% of the total sample. The patient cohort was diverse in terms of birth origin, with most participants born in Australia, followed by individuals from South Africa, Europe, Africa, the Middle East, Central and South America, and North America. A convenience sample of migraineurs (MA and MO, N = 20) were selected from an outpatient migraine cohort for control comparisons. Table 1 Mean and Standard Deviation of Age of Patients in the Migraine and Control Groups N M SD Migraine without aura (MO) 132 40.04 13.41 Migraine with aura (MA) 79 41.89 11.85 Control 20 43.65 10.67 A priori power analysis using G*Power (version 3.1.9.6) for Mixed-design ANOVA at a power of .80, with small effect (0.2) and alpha of 0.01 indicated that a sample of 93 would be sufficient to detect significant effect for SSIIi changes over time and between the groups, thus indicating that the final sample for the analysis was appropriately powered. 2.2 Statistical Analysis Data were analysed using JASP (2024; Version 0.18.3). After data screening and removal of outliers defined as cases falling above or below 1.5 times the upper or lower interquartile range, respectively, the data for a total of 206 patients were included in the analyses (N = 119 with MO, N = 67 with MA and N = 20 control). Mixed-design ANOVA with Migraine Dx (MA, MO or Control) as the between subjects factor and Time (Admission [Time 1] versus 24 hours Post Admission [Time 2] or equivalent timeframe for controls ) as the within subjects factor was employed to examine changes in SSIIi for the three groups over two time points at an alpha of 0.05 level of significance, followed by post hoc tests with Holm’s Correction when appropriate. Results As depicted in Fig. 1 , the MO and control cohorts presented with similar SSII indices, which remained stable over the 24-hour time period during which samples were collected. In contrast, the SSIIi of MA patients were slightly lower than both MO and control groups at Time 1 and decreased notably by Time 2. The baseline SSIIi for all groups indicated markedly elevated levels of inflammation, which persisted for the MO and control groups across time. Mixed-design ANOVA revealed no significant effect for Time, F(1, 203) = 1.83, p = 0.18, or SSIIi × Time interaction effect, F(2, 203) = 0.90, p = 0.41. However, a significant difference between Migraine Dx groups was observed, with a small effect size, F(2, 203) = 2.69, p = 0.07, η² p = 0.03. Post hoc tests showed that the overall SSIIi for MA patients was lower than that for MO patients, but not controls; whose SSIIi did not differ from either the MA or MO groups. Discussion Our study demonstrated that the initial Serial Systemic Immune-Inflammatory Indices (SSIIi) values were significantly elevated in patients with both migraine with aura (MA) and migraine without aura (MO), compared to historical levels observed in patients with hepatocellular carcinoma (HCC) by HU et al[ 17 ], but not when compared to same age controls processed at same institute. These findings support previous studies that indicate that a systemic inflammatory response plays a role in both acute exacerbation of migraine, as well as in the case of migraine in the community from the clinic cohort. Indeed, the therapeutic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) [ 20 – 24 ] and corticosteroids [ 25 – 27 ] in treating certain migraine patients further supports the role of inflammation in migraine, and suggests SSiii as a useful simple, universally available, and low-cost snapshot of both innate and adaptive immune system activity associated with immune responses at time of hospitalization and then again after pain levels had been reduced. Thus making SSIIi a potentially useful tool in understanding and managing migraine. Previous research has shown increased platelet-leukocyte interactions and platelet activation in migraine patients, suggesting a vascular-inflammatory component to migraine pathobiology[ 14 , 28 – 39 ]. Indeed a platelet hypothesis of migraine dates back as early as 1978[ 40 , 41 ], More recent studies [ 14 , 28 , 29 , 31 , 40 , 42 ] have continued to explore hematological parameters such as neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) as potential markers of inflammation in migraine patients[ 35 , 43 – 45 ]. For instance, a Belgian outpatient study by Saricam involving 250 migraine patients and 215 healthy volunteers found that inflammatory markers such as NLR, LMR, and PLR were significantly higher in migraine patients compared to healthy controls, particularly those with aura[ 35 ]. Our findings of elevated SSIIi in both MA and MO are consistent with this body of work, suggesting a persistent immune-inflammatory response in migraine[ 14 , 35 , 43 – 48 ]. In our study, we observed a significant drop in SSIIi over time, particularly in the MA cohort, which may suggest that the initial immune-inflammatory response is more transient in patients with aura. Furthermore, it must be noted that both groups received treatment with acute analgesic, medication, usually NSAIDs, which could have influenced the observed second time point values in one group. This finding supports the notion that persistent, maladaptive immune-inflammatory processes may play a critical role in the pathobiology of migraine, a concept that can be further understood through the lens of psychoneuroimmunology (PNI)[ 49 – 57 ] that actually explores the interactions between neural, psychological, and immunologic processes and their impact on human health and behavior. Our observation that SSIIi values in MA and MO patients were approximately twice as high as those reported in HCC by Hu et al [ 17 ] patients but no different to episodic migraine controls highlights the potential relationship between neurological disorders and the immune system, particularly in the context of stress, inflammation, and mental health[ 51 , 54 – 57 ] . Limitations Our study has several limitations that must be acknowledged. Foremost among them being its single-center, retrospective design. Although we took considerable precautions to exclude other potential inflammatory biomarkers like ESR and CRP in either the ER admissions or outpatient control groups, the study's design inherently limits its generalizability. Ideally, a healthy, age-matched control group as well as control groups of migraine (Mo &MA) outpatients, measured at similar diurnal times to inpatient measures would have provided a more robust comparison. Despite these limitations, the finding that SSIIi (Systemic Inflammatory Index) remains elevated in both inpatient groups suggests persistent systemic inflammation, which SSIIi appears to capture effectively among these cohorts[ 58 ]. The study underscores the necessity for future research with more rigorous designs, including the incorporation of expanded test subsets, such as lymphocyte subtypes measured at similar times in the diurnal cycle and specific psychoneuroimmunology markers. As well as identification of specific drug treatments to better explore the biological mechanisms driving migraine pathobiology in millions of affected patients. Despite the limitations mentioned, this study suggests that SSIIi holds potential clinical utility as a simple, accessible tool for assessing systemic inflammation in migraine and other neurological patients, while highlighting the promise of SSIIi as a potential pathway for more personalized and timely interventions in migraine management. Future studies should include multi- center designs with better-matched control groups and larger sample sizes to confirm these preliminary findings. Additionally, research should focus on establishing standardized guidelines for the clinical application of SSIIi as a biomarker for systemic inflammation in migraine patients. Conclusion In conclusion, our study has shown that SSIIi values in patients with both MA and MO were not significantly elevated compared to community migraine controls, despite suggesting a robust systemic inflammatory response during acute migraine attacks as well among the control group. The observed decline in SSIIi over time, particularly in the MA group, indicates that this inflammatory response may be adaptive and potentially protective, a concept that aligns with the principles of stress related psychoneuroimmunological findings 45 . However, it is important to note that both groups received treatment with acute analgesics, including NSAIDs, which could have influenced the observed second time point values. Overall, our findings support the hypothesis that systemic inflammation plays a significant role in the pathophysiology of migraine, particularly during acute attacks that necessitate hospital emergency department visits. The SSIIi could have therapeutic implications, serving as a simple and universally accessible biomarker for monitoring inflammation in migraine patients. We propose that more comprehensive, controlled, multicentre studies are needed to further evaluate the role of immune-inflammatory factors in the pathobiology of migraine and to confirm the clinical utility of SSIIi in this context. Declarations Ethical approval Ethical approval was received from Western Health IRB, Australia with approval number QA2014/24. Author Contribution T.W and C.W wrote the main mansucript. M.M and L.K performed the statiscal analysis. All authors reviewed and edited the manuscript. All authors approved the final submission Acknowledgements The authors would like to thank the Health Information Unit, Western Health Australia for providing access to electronic data for the retrospective analysis and all the patients. Data Availability Data is provided within the manuscript or supplementary information files. Additional data can be provided as needed with a reasonable request through the corresponding author References Wijeratne T, Grisold W, Dodick D, Carroll W, World Brain (2019) Day 2019: migraine, the painful truth. Lancet Neurol 18:914. 10.1016/s1474-4422(19)30281-9 Wijeratne T, Tang HM, Crewther D, Crewther S (2019) Prevalence of Migraine in the Elderly: A Narrated Review. 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Psychoneuroendocrinology 33:18–29. 10.1016/j.psyneuen.2007.10.008 Dantzer R (2004) Innate immunity at the forefront of psychoneuroimmunology. Brain Behav Immun 18:1–6. 10.1016/j.bbi.2003.09.008 Dantzer R (2005) Somatization: a psychoneuroimmune perspective. Psychoneuroendocrinology 30:947–952. 10.1016/j.psyneuen.2005.03.011 Dantzer R (1997) Stress and immunity: what have we learned from psychoneuroimmunology? Acta Physiol Scand Suppl 640:43–46 Zaaqoq AM, Namas RA, Abdul-Malak O, Almahmoud K, Barclay D, Yin J, Zamora R, Rosengart MR, Billiar TR, Vodovotz Y (2019) Diurnal Variation in Systemic Acute Inflammation and Clinical Outcomes Following Severe Blunt Trauma. Front Immunol 10:2699. 10.3389/fimmu.2019.02699 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Jan, 2025 Read the published version in The Journal of Headache and Pain → Version 1 posted Editorial decision: Revision requested 22 Nov, 2024 Reviews received at journal 22 Nov, 2024 Reviewers agreed at journal 22 Nov, 2024 Reviews received at journal 21 Oct, 2024 Reviewers agreed at journal 20 Oct, 2024 Reviewers agreed at journal 09 Oct, 2024 Reviewers invited by journal 09 Oct, 2024 Editor assigned by journal 07 Oct, 2024 Submission checks completed at journal 07 Oct, 2024 First submitted to journal 05 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5209065","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":381455830,"identity":"a352f5bd-7db3-499a-90a7-1390d1a1cd5d","order_by":0,"name":"Tissa Wijeratne","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYDACZgjFw9gAYcgxSBDQwYOi5QADgzFhLSg8oJbEBkJa7NnZH3/4wXBYhrm99+Hnjzts0jfcbmB8XPGLQd7gAC6H8ZhJ9jAc5mHsOW4scfBMWu6GOweYDc/2MRhuwK2FDei62zyMM9IYJA62Hc7ddiOBTbKxh4ERtxb2xx//gLTMf8b842Db/3QzqBZ73FoYDKQhtrCxAW05kADW0vCDIRGnlsM8ZtIyBv+Bfkljszjblmy4/0Zis2Fjg0TyTBxa2PuPP/74piLN3rD9GPONyjY7eckZyQcfNvyxse3DoQUCDBgYDBvgPGCsMrYRih0gkEfl/iGsYxSMglEwCkYMAACCIVrp7TCDAgAAAABJRU5ErkJggg==","orcid":"","institution":"Migraine Foundation Australia","correspondingAuthor":true,"prefix":"","firstName":"Tissa","middleName":"","lastName":"Wijeratne","suffix":""},{"id":381455831,"identity":"64f784bb-e7b5-42c6-8f65-4757f110e8a0","order_by":1,"name":"Melanie J. Murphy","email":"","orcid":"","institution":"La Trobe University","correspondingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"J.","lastName":"Murphy","suffix":""},{"id":381455832,"identity":"d8b20e6f-66e2-4572-82b5-94b0ba68aeb8","order_by":2,"name":"Chanith Wijeratne","email":"","orcid":"","institution":"Migraine Foundation Australia","correspondingAuthor":false,"prefix":"","firstName":"Chanith","middleName":"","lastName":"Wijeratne","suffix":""},{"id":381455833,"identity":"fb1b46b8-46a3-4830-ab87-880fbb4270c3","order_by":3,"name":"Paolo Martelletti","email":"","orcid":"","institution":"Unitelma Sapienza University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Martelletti","suffix":""},{"id":381455834,"identity":"365defcf-f9d8-417e-b1ca-7646a9316301","order_by":4,"name":"Leila Karimi","email":"","orcid":"","institution":"RMIT University","correspondingAuthor":false,"prefix":"","firstName":"Leila","middleName":"","lastName":"Karimi","suffix":""},{"id":381455835,"identity":"b3921f1e-236d-4d68-b522-d475d5b0339c","order_by":5,"name":"Vasso Apostolopoulos","email":"","orcid":"","institution":"Victoria University","correspondingAuthor":false,"prefix":"","firstName":"Vasso","middleName":"","lastName":"Apostolopoulos","suffix":""},{"id":381455836,"identity":"32c93990-80f5-4df7-93fb-75cf6c622a55","order_by":6,"name":"Carmela Sales","email":"","orcid":"","institution":"Migraine Foundation Australia","correspondingAuthor":false,"prefix":"","firstName":"Carmela","middleName":"","lastName":"Sales","suffix":""},{"id":381455837,"identity":"01325d70-eda6-4443-9876-3364b019adfb","order_by":7,"name":"Nina Riddell","email":"","orcid":"","institution":"La Trobe University","correspondingAuthor":false,"prefix":"","firstName":"Nina","middleName":"","lastName":"Riddell","suffix":""},{"id":381455838,"identity":"1c0fff89-b593-4db0-8531-98dfac97553e","order_by":8,"name":"Sheila G. Crewther","email":"","orcid":"","institution":"La Trobe University","correspondingAuthor":false,"prefix":"","firstName":"Sheila","middleName":"G.","lastName":"Crewther","suffix":""}],"badges":[],"createdAt":"2024-10-05 13:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5209065/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5209065/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s10194-024-01929-6","type":"published","date":"2025-01-10T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70287346,"identity":"b931b2aa-9c1c-4fe9-99e3-050c27f4f97d","added_by":"auto","created_at":"2024-12-01 16:51:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27666,"visible":true,"origin":"","legend":"\u003cp\u003eMean (+/- Standard Error) Serial systemic immune-inflammatory indices (SSIIi) at Time 1 (baseline) compared to Time 2 (after 12-24 hours) for Migraine without aura (MO), Migraine with aura (MA) and community control migraine outpatients.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5209065/v1/f7acd8818635fcdd77abe176.jpg"},{"id":73694152,"identity":"1d4661de-6ef6-43c1-9c19-2f3f6b87af79","added_by":"auto","created_at":"2025-01-13 16:11:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":518852,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5209065/v1/085d31d4-86cd-4a76-b65d-02777dad9b33.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serial Systemic Immune Inflammation Indices: Markers of Acute Migraine Events or Indicators of Persistent Inflammatory Status?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMigraine is a highly debilitating neurological disorder that affects over a billion people worldwide, making it a significant public health concern[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It ranks as the second leading cause of disability globally, particularly impacting individuals under the age of fifty, and remains the leading cause of disability among women[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Approximately 15% of the global population suffers from migraine, with about one-third of these individuals experiencing aura during some or all of their attacks[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The pathobiology of migraine is complex, involving intricate interactions between neurons, vasculature, glial cells, and neurogenic inflammation[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, despite the profound impact of migraine on individuals and healthcare systems, the diagnosis remains clinical, with no objective biomarkers or definitive tests available to aid in diagnosis[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This lack of biomarkers, coupled with the phenotypic overlap between migraine and other primary and secondary headache disorders, contributes to its underdiagnosis, making it one of the most commonly underdiagnosed medical conditions worldwide[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSystemic inflammation and its role in migraine has long been debated [\u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, what has not been ascertained is whether inflammation associated with migraine is a transitory response initiated by episodes of cortical spreading depression as in migraine with aura (MA) or in all migraine i.e. both with and without aura, (MO), or whether inflammation is a more persistent state. Thus we have utilized the Systemic Immune-Inflammation Index (SIIi) that was initially developed as a unitary measure of chronic inflammation in the context of colorectal cancer in 2014 by Hu et al[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] as a means of profiling systemic inflammation in migraineurs using reanalysis of typical and rapid routine blood tests. The SIIi is calculated using routine peripheral blood cell counts of the relative numbers of lymphocytes, neutrophils, and platelets. It is defined as the platelet count (P) multiplied by the neutrophil count (N), divided by the lymphocyte count (L) (SIIi\u0026thinsp;=\u0026thinsp;P \u0026times; N / L) to provide a measure of the balance between innate immune activity (as indicated by neutrophil (last\u0026thinsp;\u0026lt;\u0026thinsp;24 hrs in blood) and platelet (8\u0026ndash;10 days counts) and adaptive immune activity (as indicated by lymphocyte counts).\u003c/p\u003e \u003cp\u003eHu et al.,[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] in their seminal work, identified an optimal cutoff point for the Systemic Immune-Inflammation Index (SIIi) of 330 \u0026times; 10⁹, which effectively stratified patients with hepatocellular carcinoma (HCC) into high (\u0026ge;\u0026thinsp;330) and low SIIi (\u0026lt;\u0026thinsp;330) groups within their training cohort. These numbers were achieved via rigorous univariate and multivariate analyses, and consequently Hu proposed that SIIi was an independent predictor for both overall survival and relapse-free survival as the area under the curve (AUC) for SIIi in predicting survival and recurrence was found to be superior to other conventional clinical indices. Early Serial measurements of SIIi has since been explored for its prognostic value in other conditions, including hepatocellular carcinoma (HCC)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and Post-COVID Neurological Syndrome [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the established role of inflammation in migraine pathophysiology, we have now sought to investigate whether serial measures of SSIIi in a cohort of hospitalized migraine patients can offer clinical insights into the temporal trajectory of inflammatory processes underlying Migraine with Aura and Migraine without Aura, i.e. whether inflammation is a transient process during migraine attacks or an indication of more persistent neuroinflammatory processes. Our study represents a novel approach to understanding migraine, leveraging the SSIIi as a tool to potentially improve diagnostic accuracy, track disease progression, and tailor therapeutic interventions based on an individual\u0026rsquo;s inflammatory response profile.\u003c/p\u003e \u003cp\u003eWe have chosen to focus on patients with migraine with no other confounding inflammatory conditions (i.e. patients with raised traditional inflammatory markers such as CRP were excluded from the study). This approach may enhance the clinical utility of SSIIi as a potential biomarker for persistent maladaptive neuroinflammation regulation in migraine patients and contribute to more targeted treatment strategies in the future.\u003c/p\u003e"},{"header":"Methods and Participants","content":"\u003cp\u003eThis retrospective study analyzed data from the electronic health records of a patient cohort admitted to Western Health hospital, Melbourne, Australia, over an 18-month period, specifically for the acute management of a migraine attack. Western Health serves a culturally and linguistically diverse (CALD) population of approximately 1.2\u0026nbsp;million people, representing 166 languages, providing a unique context for understanding migraine across different demographic groups.\u003c/p\u003e \u003cp\u003eDemographic data, including age, gender, and country of origin, were collected alongside relevant clinical information such as cardiovascular risk factors and the presence of atrial fibrillation. Patients were classified as having migraine with aura (MA) or without aura (MO) based on the International Classification of Headache Disorders-3 (ICHD-3) criteria. This classification allowed us to explore potential differences in systemic immune-inflammatory responses between these two subtypes of migraine.\u003c/p\u003e \u003cp\u003eTo be included in the study, patients had to have at least two sets of white blood cell counts (neutrophil counts, platelet counts, and lymphocyte counts) recorded 24 hours apart during their hospital admission. These measurements were necessary for calculating the Serial Systemic Immune-Inflammatory Indices (SSIIi), calculated using the following formula:\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003eNeutrophil count x platelet count (indication of innate immune activity)\u003c/p\u003e \u003c/div\u003e\n\u003cp\u003eLymphocyte count (indicative of adaptive immune activity)\u003c/p\u003e\n\u003cp\u003ePatients whose admissions were complicated by conditions that could independently elevate systemic inflammatory markers were excluded to ensure that the inflammatory indices being measured were related to the migraine itself rather than confounding factors. Exclusion criteria were patients with raised traditional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), or those with acute infections comorbid with their migraine at the time of emergency room admission, were excluded from this analysis.\u003c/p\u003e \u003cp\u003e Control sample comprised stable migraineurs (in accordance with ICHD-3 criteria) in the community. They had two blood tests completed 24 hours apart.\u003c/p\u003e\n\u003ch3\u003e2.1 Sample Size\u003c/h3\u003e\n\u003cp\u003eAn initial cohort of 232 patients with an age range of 18\u0026ndash;88 was utilised in this study, with number of patients and mean (SD) age for patient group shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e below. The study predominantly included female participants, representing 85.5% of the total sample. The patient cohort was diverse in terms of birth origin, with most participants born in Australia, followed by individuals from South Africa, Europe, Africa, the Middle East, Central and South America, and North America. A convenience sample of migraineurs (MA and MO, N\u0026thinsp;=\u0026thinsp;20) were selected from an outpatient migraine cohort for control comparisons.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean and Standard Deviation of Age of Patients in the Migraine and Control Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMigraine without aura (MO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMigraine with aura (MA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eA priori\u003c/em\u003e power analysis using G*Power (version 3.1.9.6) for Mixed-design ANOVA at a power of .80, with small effect (0.2) and alpha of 0.01 indicated that a sample of 93 would be sufficient to detect significant effect for SSIIi changes over time and between the groups, thus indicating that the final sample for the analysis was appropriately powered.\u003c/p\u003e\n\u003ch3\u003e2.2 Statistical Analysis\u003c/h3\u003e\n\u003cp\u003eData were analysed using JASP (2024; Version 0.18.3). After data screening and removal of outliers defined as cases falling above or below 1.5 times the upper or lower interquartile range, respectively, the data for a total of 206 patients were included in the analyses (N\u0026thinsp;=\u0026thinsp;119 with MO, N\u0026thinsp;=\u0026thinsp;67 with MA and N\u0026thinsp;=\u0026thinsp;20 control). Mixed-design ANOVA with Migraine Dx (MA, MO or Control) as the between subjects factor and Time (Admission [Time 1] versus 24 hours Post Admission [Time 2] or equivalent timeframe for controls ) as the within subjects factor was employed to examine changes in SSIIi for the three groups over two time points at an alpha of 0.05 level of significance, followed by post hoc tests with Holm\u0026rsquo;s Correction when appropriate.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAs depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the MO and control cohorts presented with similar SSII indices, which remained stable over the 24-hour time period during which samples were collected. In contrast, the SSIIi of MA patients were slightly lower than both MO and control groups at Time 1 and decreased notably by Time 2. The baseline SSIIi for all groups indicated markedly elevated levels of inflammation, which persisted for the MO and control groups across time. Mixed-design ANOVA revealed no significant effect for Time, F(1, 203) = 1.83, \u003cem\u003ep\u003c/em\u003e = 0.18, or SSIIi × Time interaction effect, F(2, 203) = 0.90, \u003cem\u003ep\u003c/em\u003e = 0.41. However, a significant difference between Migraine Dx groups was observed, with a small effect size, F(2, 203) = 2.69, p = 0.07, η²\u003csub\u003ep\u003c/sub\u003e = 0.03. Post hoc tests showed that the overall SSIIi for MA patients was lower than that for MO patients, but not controls; whose SSIIi did not differ from either the MA or MO groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \n\n "},{"header":"Discussion","content":"\u003cp\u003eOur study demonstrated that the initial Serial Systemic Immune-Inflammatory Indices (SSIIi) values were significantly elevated in patients with both migraine with aura (MA) and migraine without aura (MO), compared to historical levels observed in patients with hepatocellular carcinoma (HCC) by HU et al[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], but not when compared to same age controls processed at same institute. These findings support previous studies that indicate that a systemic inflammatory response plays a role in both acute exacerbation of migraine, as well as in the case of migraine in the community from the clinic cohort.\u003c/p\u003e\u003cp\u003eIndeed, the therapeutic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) [\u003cspan additionalcitationids=\"CR21 CR22 CR23\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and corticosteroids [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e–\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] in treating certain migraine patients further supports the role of inflammation in migraine, and suggests SSiii as a useful simple, universally available, and low-cost snapshot of both innate and adaptive immune system activity associated with immune responses at time of hospitalization and then again after pain levels had been reduced. Thus making SSIIi a potentially useful tool in understanding and managing migraine.\u003c/p\u003e\u003cp\u003ePrevious research has shown increased platelet-leukocyte interactions and platelet activation in migraine patients, suggesting a vascular-inflammatory component to migraine pathobiology[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e–\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Indeed a platelet hypothesis of migraine dates back as early as 1978[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], More recent studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] have continued to explore hematological parameters such as neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) as potential markers of inflammation in migraine patients[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e–\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. For instance, a Belgian outpatient study by Saricam involving 250 migraine patients and 215 healthy volunteers found that inflammatory markers such as NLR, LMR, and PLR were significantly higher in migraine patients compared to healthy controls, particularly those with aura[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Our findings of elevated SSIIi in both MA and MO are consistent with this body of work, suggesting a persistent immune-inflammatory response in migraine[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44 CR45 CR46 CR47\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e–\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our study, we observed a significant drop in SSIIi over time, particularly in the MA cohort, which may suggest that the initial immune-inflammatory response is more transient in patients with aura. Furthermore, it must be noted that both groups received treatment with acute analgesic, medication, usually NSAIDs, which could have influenced the observed second time point values in one group.\u003c/p\u003e\u003cp\u003eThis finding supports the notion that persistent, maladaptive immune-inflammatory processes may play a critical role in the pathobiology of migraine, a concept that can be further understood through the lens of psychoneuroimmunology (PNI)[\u003cspan additionalcitationids=\"CR50 CR51 CR52 CR53 CR54 CR55 CR56\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e–\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] that actually explores the interactions between neural, psychological, and immunologic processes and their impact on human health and behavior. Our observation that SSIIi values in MA and MO patients were approximately twice as high as those reported in HCC by Hu et al [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] patients but no different to episodic migraine controls highlights the potential relationship between neurological disorders and the immune system, particularly in the context of stress, inflammation, and mental health[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan additionalcitationids=\"CR55 CR56\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e–\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] .\u003c/p\u003e\u003ch3\u003eLimitations\u003c/h3\u003e\u003cp\u003eOur study has several limitations that must be acknowledged. Foremost among them being its single-center, retrospective design. Although we took considerable precautions to exclude other potential inflammatory biomarkers like ESR and CRP in either the ER admissions or outpatient control groups, the study's design inherently limits its generalizability. Ideally, a healthy, age-matched control group as well as control groups of migraine (Mo \u0026amp;MA) outpatients, measured at similar diurnal times to inpatient measures would have provided a more robust comparison. Despite these limitations, the finding that SSIIi (Systemic Inflammatory Index) remains elevated in both inpatient groups suggests persistent systemic inflammation, which SSIIi appears to capture effectively among these cohorts[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe study underscores the necessity for future research with more rigorous designs, including the incorporation of expanded test subsets, such as lymphocyte subtypes measured at similar times in the diurnal cycle and specific psychoneuroimmunology markers. As well as identification of specific drug treatments to better explore the biological mechanisms driving migraine pathobiology in millions of affected patients. Despite the limitations mentioned, this study suggests that SSIIi holds potential clinical utility as a simple, accessible tool for assessing systemic inflammation in migraine and other neurological patients, while highlighting the promise of SSIIi as a potential pathway for more personalized and timely interventions in migraine management.\u003c/p\u003e\u003cp\u003eFuture studies should include multi- center designs with better-matched control groups and larger sample sizes to confirm these preliminary findings. Additionally, research should focus on establishing standardized guidelines for the clinical application of SSIIi as a biomarker for systemic inflammation in migraine patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study has shown that SSIIi values in patients with both MA and MO were not significantly elevated compared to community migraine controls, despite suggesting a robust systemic inflammatory response during acute migraine attacks as well among the control group. The observed decline in SSIIi over time, particularly in the MA group, indicates that this inflammatory response may be adaptive and potentially protective, a concept that aligns with the principles of stress related psychoneuroimmunological findings\u003csup\u003e45\u003c/sup\u003e. However, it is important to note that both groups received treatment with acute analgesics, including NSAIDs, which could have influenced the observed second time point values.\u003c/p\u003e \u003cp\u003eOverall, our findings support the hypothesis that systemic inflammation plays a significant role in the pathophysiology of migraine, particularly during acute attacks that necessitate hospital emergency department visits. The SSIIi could have therapeutic implications, serving as a simple and universally accessible biomarker for monitoring inflammation in migraine patients. We propose that more comprehensive, controlled, multicentre studies are needed to further evaluate the role of immune-inflammatory factors in the pathobiology of migraine and to confirm the clinical utility of SSIIi in this context.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthical approval\u003c/h2\u003e \u003cp\u003e Ethical approval was received from Western Health IRB, Australia with approval number QA2014/24.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.W and C.W wrote the main mansucript. M.M and L.K performed the statiscal analysis. All authors reviewed and edited the manuscript. All authors approved the final submission\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors would like to thank the Health Information Unit, Western Health Australia for providing access to electronic data for the retrospective analysis and all the patients.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files. Additional data can be provided as needed with a reasonable request through the corresponding author\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWijeratne T, Grisold W, Dodick D, Carroll W, World Brain (2019) Day 2019: migraine, the painful truth. 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Front Immunol 10:2699. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2019.02699\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2019.02699\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Migraine, inflammation, Serial Systemic Immune-Inflammatory Indices (SSIIi), cortical spreading depression, aura","lastPublishedDoi":"10.21203/rs.3.rs-5209065/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5209065/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMigraine is the most common complex neurological disorder, affecting over a billion people worldwide. Neurogenic inflammation has long been recognized as a key factor in the pathophysiology of migraine though little research has been directed to investigating whether inflammation is greatest in migraine with aura or without, and whether inflammation is a permanent state in migraine or whether is an event related transitory state. Thus, the primary aim of this single-centre, retrospective study was to explore the potential clinical utility of the systemic immune-inflammatory indices as a measure of duration and severity of inflammation derived from relative blood cell counts in migraine patients within an acute inpatient setting. Specifically, we assessed the role of serial white blood cell counts to calculate Serial Systemic Immune-Inflammatory Indices (SSIIi) (calculated using the formula: neutrophil count x platelet count/lymphocyte count) between aura (N\u0026thinsp;=\u0026thinsp;67) and no-aura (N\u0026thinsp;=\u0026thinsp;119) migraine patients at time of admission to a tertiary care centre in Melbourne, Australia, and at 24 hours post admission versus stable in-community migraineur controls (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\u003ch2\u003eMain Body:\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of medical records from patients presenting with migraine at Western Health over an 18-month period. Patients were categorized as having migraine with aura (MA) or without aura (MO) according to ICHD-3 criteria. Baseline demographics and brain imaging findings were evaluated for each group. Patients who had at least two sets of white blood cell counts drawn within 24 hours during their admission were included in the study. A mixed-design ANOVA showed a significant main effect of SSIIi between patients with migraine with aura (MA) and migraine without aura (MO) during acute inpatient presentation, in comparison to a convenience sample of outpatients with migraine (MA and MO) with similar blood measures.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSSIIi levels were significantly lower in patients with migraine with aura (MA), who also showed a greater, though non-significant, decrease between the two measurements compared to those with migraine without aura (MO) and controls, whose SSIIi levels remained consistently higher. The control group displayed similar findings to MO inpatients, suggesting persistent systemic inflammation in a subset of migraine patients regardless of the acuity of presentation. Further studies are needed to evaluate the role of systemic inflammation in migraine pathophysiology, chronicity, and progression.\u003c/p\u003e","manuscriptTitle":"Serial Systemic Immune Inflammation Indices: Markers of Acute Migraine Events or Indicators of Persistent Inflammatory Status?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-01 16:51:41","doi":"10.21203/rs.3.rs-5209065/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-22T14:30:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-22T14:25:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237462344130670757213120616134077601515","date":"2024-11-22T09:26:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-21T20:34:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79692354449670172562343517989994328973","date":"2024-10-20T17:49:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"114728062677821069947847432480662273555","date":"2024-10-09T11:44:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-09T08:39:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-07T10:28:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-07T10:25:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Journal of Headache and Pain","date":"2024-10-05T13:04:04+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-journal-of-headache-and-pain","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tjhp","sideBox":"Learn more about [The Journal of Headache and Pain](https://thejournalofheadacheandpain.biomedcentral.com/)","snPcode":"10194","submissionUrl":"https://submission.nature.com/new-submission/10194/3","title":"The Journal of Headache and Pain","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f035c961-c35a-4624-b951-25bdcbfa814a","owner":[],"postedDate":"December 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-13T16:05:01+00:00","versionOfRecord":{"articleIdentity":"rs-5209065","link":"https://doi.org/10.1186/s10194-024-01929-6","journal":{"identity":"the-journal-of-headache-and-pain","isVorOnly":false,"title":"The Journal of Headache and Pain"},"publishedOn":"2025-01-10 15:58:02","publishedOnDateReadable":"January 10th, 2025"},"versionCreatedAt":"2024-12-01 16:51:41","video":"","vorDoi":"10.1186/s10194-024-01929-6","vorDoiUrl":"https://doi.org/10.1186/s10194-024-01929-6","workflowStages":[]},"version":"v1","identity":"rs-5209065","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5209065","identity":"rs-5209065","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}