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Objective: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity., Methods: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry., Results: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH., Interpretation: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aβ-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension., Methods: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure., Results: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aβ-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aβ-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001)., Conclusions: cNfL, pNfL and total-tau/Aβ-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KS: No conflicts of interest. JJK: Received funding from the Lundbeck Foundation, Rigshospitalet-Glostrup and Odense University Hospital. RHJ: Paid lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck; Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Recived research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. TP: No conflicts of interest. CSK: No conflicts of interest. SGH: No conflicts of interest. SMH: No conflicts of interest. EAW: Medical Advisory Board for StatuManu ICP ApS. Received research funding from Øjenforeningen (Fight for Sight, Denmark) and the Synoptik Foundation. LDM: No conflicts of interest. DB: Presentations (TEVA, Novartis, Pfizer), Travel Support (Allergan, TEVA, Pfizer, Abbvie), Advisory Boards (Novartis, Lilly, Teva, Lundbeck, Pfizer, Abbvie) and Participations in clinical trials (TEVA, Lundbeck, Novartis, Lilly, Novo Nordic Foundation) outside the submitted work (other headache disorders), receiving grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduction of the work.

Introduction: Retinal vessel dynamics analysis has proven to be a viable, non-invasive surrogate marker for increased intracranial pressure. We aimed to test this method in patients with suspected idiopathic intracranial hypertension., Methods: Patients with suspected idiopathic intracranial hypertension were prospectively enrolled for hand-held fundus-videography during diagnostic lumbar puncture. After extracting optic disc images, peripapillary arteriole-to-venule-ratios were measured using machine-learning algorithms with manual identification control. A general linear model was applied to arteriole-to-venule-ratios and corresponding lumbar opening pressures to estimate cerebrospinal fluid pressure., Results: Twenty-five patients were included with a significant difference in arteriole-to-venule-ratio between patients with ( n  = 17) and without ( n  = 8) idiopathic intracranial hypertension (0.78 ± 0.10 vs 0.90 ± 0.08, p  = 0.006). Arteriole-to-venule-ratio correlated inversely with lumbar opening pressure (slope regression estimate -0.0043 (95% CI -0.0073 to -0.0023), p  = 0.002) and the association was stronger when lumbar opening pressure exceeded 15 mm Hg (20 cm H 2 O) (slope regression estimate -0.0080 (95% CI -0.0123 to -0.0039), p  < 0.001). Estimated cerebrospinal fluid pressure predicted increased lumbar opening pressure >20 mm Hg (27 cm H 2 O) with 78% sensitivity and 92% specificity (AUC 0.81, p  = 0.02). A stand-alone arteriole-to-venule-ratio measurement predicting lumbar opening pressure >20 mm Hg (27 cm H 2 O) was inferior with a 48% sensitivity and 92% specificity (AUC 0.73, p =  0.002)., Conclusion: Retinal vessel dynamics analysis with the described model for estimating cerebrospinal fluid pressure is a promising non-invasive method with a high sensitivity and specificity for detecting elevated intracranial pressure at follow-up assessments of patients with confirmed idiopathic intracranial hypertension if initial lumbar opening pressure and arteriole-to-venule-ratio data are available.

Background: Our objective was to assess optic nerve sheath diameter (a marker of elevated intracranial pressure) and optic disc elevation (a marker of papilledema) in pseudotumor cerebri syndrome using transorbital sonography., Methods: The study was a prospective case-control study. We included patients with new-onset pseudotumor cerebri syndrome and matched healthy controls. All had fundoscopy, lumbar puncture with opening pressure and transorbital sonography. Sonography was assessed by a blinded observer., Results: We evaluated 45 patients and included 23 cases. We recruited 35 controls. Optic nerve sheath diameter was larger in pseudotumor cerebri syndrome compared to controls (6.3 ± 0.9 mm versus 5.0 ± 0.5 mm, p < 0.001) and so was optic disc elevation (0.9 ± 0.4 mm versus 0.4 ± 0.1 mm, p < 0.001). The optimal cut-off point for optic nerve sheath diameter was 6 mm with a sensitivity of 74% for prediction of pseudotumor cerebri syndrome and 68% for prediction of elevated opening pressure. Specificity was 94%. The optimal cut-off point for optic disc elevation was 0.6 mm. Sensitivity was 100% and specificity 83% for prediction of pseudotumor cerebri syndrome., Conclusion: Optic disc elevation and optic nerve sheath diameter are increased in new-onset pseudotumor cerebri syndrome. Optic disc elevation achieved high specificity and excellent sensitivity for diagnosis of pseudotumor cerebri syndrome. Transorbital sonography (TOS) is a potential, non-invasive screening tool for pseudotumor cerebri syndrome in headache clinics.