Intracranial Pressure Directly Predicts Headache Morbidity in Idiopathic Intracranial Hypertension

Mollan, Susan P; Wakerley, Benjamin R; Alimajstorovic, Zerin; Mitchell, James; Ottridge, Ryan; Yiangou, Andreas; Thaller, Mark; Grech, Olivia; Lavery, Gareth; Brock, Kristian; Sinclair, Alexandra J

doi:10.21203/rs.3.rs-479747/v1

Cited by 11 publications

(24 citation statements)

References 18 publications

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“…Consistent with this, cortical tissue from IIH patients demonstrated pathological features such as astrogliosis, BBB leakage and abnormal mitochondrial morphology, which correlate with pathological ICP waveforms [120][121][122]. Furthermore, ICP may alter central sensitivity to pain: it has been demonstrated that ICP correlates with cutaneous allodynia and that reducing ICP causes a reduction in cutaneous allodynia in IIH patients [123,124]. This suggests that raised ICP could lower the threshold for a migraine attack.…”

Section: Intracranial Pressure Obesity and Headachementioning

confidence: 55%

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

et al. 2021

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Background Obesity confers adverse effects to every system in the body including the central nervous system. Obesity is associated with both migraine and idiopathic intracranial hypertension (IIH). The mechanisms underlying the association between obesity and these headache diseases remain unclear. Methods We conducted a narrative review of the evidence in both humans and rodents, for the putative mechanisms underlying the link between obesity, migraine and IIH. Results Truncal adiposity, a key feature of obesity, is associated with increased migraine morbidity and disability through increased headache severity, frequency and more severe cutaneous allodynia. Obesity may also increase intracranial pressure and could contribute to headache morbidity in migraine and be causative in IIH headache. Weight loss can improve both migraine and IIH headache. Preclinical research highlights that obesity increases the sensitivity of the trigeminovascular system to noxious stimuli including inflammatory stimuli, but the underlying molecular mechanisms remain unelucidated. Conclusions This review highlights that at the epidemiological and clinical level, obesity increases morbidity in migraine and IIH headache, where weight loss can improve headache morbidity. However, further research is required to understand the molecular underpinnings of obesity related headache in order to generate novel treatments.

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Section: Intracranial Pressure Obesity and Headachementioning

confidence: 55%

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

et al. 2021

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“…[32-35] This likely reflects the reduction in ICP, as headache in IIH, whist complex, has been noted to correlate with ICP. [21] A trend to reduction in headache analgesic use, amongst those in the exenatide arm, was also recorded. Headache outcomes may show more benefit over a longer trial duration, as during the relatively short time horizon of this trial other factors may also have contributed to headache such as medication overuse and opiate use which occur in approximately one third of IIH patients.…”

Section: Discussionmentioning

confidence: 98%

“…The hallmark of IIH is raised ICP which causes headaches and visual loss (through compression of the optic nerve and papilloedema). [10, 21, 26] Therefore, to evaluate the efficacy of exenatide the primary outcome for this trial was chosen as ICP. [27] A significant reduction in ICP was seen acutely at 2.5 hours of -4.2mmHg (equivalent to -5.7 cmCSF), which corresponds to peak exenatide serum levels.…”

Section: Discussionmentioning

confidence: 99%

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The effect of GLP-1RA exenatide on Idiopathic Intracranial Hypertension: Randomised Clinical Trial

Mitchell

Lyons

Walker

et al. 2022

Preprint

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Therapeutics to reduce intracranial pressure are an unmet need. Pre-clinical data has demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 receptor signaling. Here, we translate these findings into patients by conducting a randomized, placebo controlled, double-blind trial to assess the effect of exenatide, a glucagon-like peptide-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 hours, 24 hours and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28+/-9, body mass index 38.1+/-6.2 kg/m2, intracranial pressure 30.6+/-5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 hours -5.7+/-2.9 cmCSF (p=0.048); 24 hours of -6.4+/-2.9 cmCSF (p=0.030); and 12 weeks -5.6+/-3.0 cmCSF (p=0.058). No serious safety signals were noted. This data provides confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlights the potential to utilise glucagon-like peptide-1 receptor agonist in other conditions characterised by raised intracranial pressure.

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“…The relationship between the IIH specific metabolites and clinical features were then Headache in IIH is initiated by elevated ICP and causes significantly reduced quality of life, yet the underlying mechanism driving pain are not understood. 3,26 We explored the relationship between metabolites and headache morbidity. Obesity is a typical feature of IIH and has been implicated in disease etiology.…”

Section: Associations Between Metabolites and Clinical Measurementsmentioning

confidence: 99%

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache

et al. 2022

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Background and Objective:We evaluated the metabolomic profile in CSF, serum and urine of participants with idiopathic intracranial hypertension (IIH) compared to controls and measured changes in metabolism associated with clinical markers of disease activity and treatment.Methods:A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria), to a sex, age and body mass index matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with re-evaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema and visual measurements. Spectra of CSF, serum and urine metabolites were acquired utilizing proton nuclear magnetic resonance spectroscopy.Results:Urea was lower in IIH (CSF; controls median ±IQR 0.196 ±0.008, IIH 0.058 ±0.059, p<0.001, urine; controls 5971.370 ±3021.831, IIH 4691.363 ±1955.774, p=0.009), correlated with ICP (urine p=0.019) and headache severity (CSF p=0.031) and increased by 12 months (CSF 12 months; 0.175 ±0.043, p=0.004, urine; 5210.874 ±1825.302, p=0.043). The lactate:pyruvate ratio was increased compared to controls (CSF; controls 49.739 ±19.523, IIH 113.114 ±117.298, p=0.023, serum; controls 38.187 ±13.392, IIH 54.547 ±18.471, p=0.004) and decreased at 12 months (CSF; 113.114 ±117.298, p<0.001). Baseline acetate was higher in IIH (CSF; controls 0.128 ±0.041, IIH 0.192 ±0.151, p=0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003) and was reduced at 12 months (0.160 ±0.060, p = 0.007). Ketones 3-hydroxybutyrate and acetoacetate were altered in CSF at baseline in IIH (3-hydroxybutyrate; controls 0.074 ±0.063, IIH 0.049 ±0.055, p = 0.019, acetoacetate; controls 0.013 ±0.007, IIH 0.017 ±0.010, p = 0.013) and normalized at 12 months (0.112 ±0.114, p = 0.019, 0.029 ±0.017, p = 0.015 respectively).Discussion:We observed metabolic disturbances that are evident in CSF, serum and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized following therapeutic weight loss. CSF:serum urea ratio was altered which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrants mechanistic evaluation.

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Intracranial Pressure Directly Predicts Headache Morbidity in Idiopathic Intracranial Hypertension

Cited by 11 publications

References 18 publications

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

The effect of GLP-1RA exenatide on Idiopathic Intracranial Hypertension: Randomised Clinical Trial

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache

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