Role of inflammasome in cluster headache pathophysiology and the evaluation of autonomic findings

Dissertation Information: Şahin E, Role of inflammasome in cluster headache pathophysiology and the evaluation of autonomic findings, Istanbul University Istanbul Faculty of Medicine, Department of Neurology, Neurology Dissertation, Istanbul, 2020. Introduction and Objective: The mechanisms behind cluster headache are not yet fully understood. The clustering of the attacks at the same time interval is a striking time-related characteristic, and this brings to mind the existence of a mechanism externally and periodically activated by viral/allergenic stimuli. The accompanying findings' confirmation of cranial autonomic activation leads to the conclusion that sympathetic and parasympathetic systems have some dysfunction. Our goal is to investigate the relations of this disease with inflammation and autonomic involvement to better understand its pathophysiology and suggest new management options. Method: Patients with cluster headache and healthy control groups were added to our study in accordance with the inclusion criteria. NLRP1, NLRP3, ASC, HMGB1, CASP1, NFΚB, TNF alpha, IL-1 beta, IL4, IL6, IL10, IL18, S100b, NSE, nNOS, eNOS and iNOS levels were examined to investigate the possible role of inflammation in the pathology. The patients underwent 24-hour rhythm holter monitoring and electrophysiological examinations during interictal periods to observe the disease's impact on the autonomic nervous system. Ethics committee approval and signed written consents were obtained from all participants prior to the research. Findings: The mean age of the included 35 patients with cluster headache (27 men) was 37.2613.32 years and the average duration of disease was 7.897.444 years. NLRP1 (p=0.017), HMGB1 (p=0.038), IL18 (p=0.042), S100b (p=0.013), NSE (p=0.021), nNOS (p=0.028) and eNOS (p=0.034) levels were significantly lower in patients with 3 or more autonomic findings. NLRP3 (p=0.014), HMGB1 (p=0.004), IL18 (p=0.033), S100b (p=0.001), NSE (p=0.020), nNOS (p=0.025) and eNOS (p=0.004) levels were significantly lower in smokers compared to non-smokers. IL18 (p=0.021) and eNOS (p=0.035) levels were lower in patients with a history of hyperlipidemia. Blood samples taken from ten patients during both periods with and without attacks did not show any significant difference in cytokine levels. IL18, NLRP1, NLRP3, nNOS and NFΚB cytokine levels were compared to healthy controls by real time polymerase chain reaction in six patients and IL18 levels were found to be 11.56 times higher, strikingly. In analysis of holter data, RMSSD (p=0.001) and pNN50 (p=0.024) values, representing parasympathetic system activity as a short-term heart rate variation parameter, were found to be significantly high among the patient group. Average heart rate (p=0.046) of patients with many autonomic findings was found to be significantly high. R-R intervals variability rate (p=0.007) while at rest was significantly high in patients with a history of hyperlipidemia. Discussion: The lack of significant differences between the inflammation parameters' levels of our patients and control group as well as during attack periods lead us to think that inflammasomes do not play a determining role in cluster headache pathophysiology. The decrease in proinflammatory cytokines such as NLRP3, HMGB1, S100b, NSE, nNOS and eNOS, some of which are markers of cell damage in patients with 3 or more autonomic findings leads us to think that inflammation is repressed, in contrast to our hypothesis. The low levels of IL18 and eNOS in the general group as well as in hyperlipidemic patients during attack periods revealed relations between hyperlipidemia and inflammatory mechanisms besides the pathways triggered during cluster headaches. The repression of NLRP1, NLRP3, S100b, nNOS and eNOS levels in smokers in interictal periods suggested that both smoking and the disease have an impact on inflammatory mechanisms. The fact that the IL-18 levels of our patients were 11.56 times higher than those of the control group suggested that the striking activation of IL-18, which is an important proinflammatory cytokine, may play a role in cluster headache pathophysiology. Another important conclusion of our study was the significant elevation of RMSSD and pNN50, which indicate increase in parasympathetic activity, among our patients compared to controls. We carried out this evaluation during interictal periods, thus our findings indicate that the disease is related to the disregulation of the autonomic nervous system in a way that is independent from the painful periods. Keywords: Holter, inflammation, inflammasome, heart rate variability, cluster headache, pathophysiology, sympathetic skin response, trigeminal autonomic cephalalgia