Metabolic Dysfunction in New-Onset Idiopathic Intracranial Hypertension: Identification of Novel Biomarkers.

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.

Neurofilament light chain is elevated in patients with newly diagnosed idiopathic intracranial hypertension: A prospective study.

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 (Aß-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/Aß-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aß-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/Aß-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.

Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established. METHODS: This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA. RESULTS: A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [IQR 30.0-41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F(2,524) = 84.79; p < 0.001) and headache absence (F(2,524) = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987-0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters. CONCLUSIONS: Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH.

Serum glial fibrillary acidic protein (GFAP)-antibody in idiopathic intracranial hypertension.

AIM: Idiopathic intracranial hypertension (IIH), a disease of obscure origin, is characterized by headache and visual disturbances due to increased intracranial pressure. Recent line of evidence has suggested involvement of inflammation in IIH pathogenesis thus bringing forward anti-glial autoimmunity as a potential contributor of IIH. Glial fibrillary acidic protein (GFAP) is a major astrocytic autoantigen associated with a specific form of meningoencephalitis. MATERIALS AND METHODS: In this study, we investigated the presence of GFAP-antibody in 65 sera (49 obtained during active disease and 16 during remission) and in 15 cerebrospinal fluid (CSF) samples of 58 consecutively recruited IIH patients using cell based assay and indirect immunohistochemistry. RESULTS: GFAP-antibody was found in active period sera of 2 IIH patients with classical symptoms and good treatment response. Two remission period sera obtained at different time points from one of these cases showed lower titers of GFAP-antibody positivity. IgG from positive samples yielded an astrocytic immunoreactivity pattern. None of the CSF samples showed GFAP-antibodies. CONCLUSIONS: These results suggest that anti-astrocyte autoimmunity might be present in a fraction of IIH patients. Exact pathogenic significance of this association needs to be further studied.

Evidence for potential involvement of pro-inflammatory adipokines in the pathogenesis of idiopathic intracranial hypertension.

Background Although specific role players are currently unknown, contribution of inflammatory mediators has been suggested in the pathophysiology of idiopathic intracranial hypertension (IIH), which is a disease more prevalent in obese female individuals of childbearing age. We aimed to investigate the levels of adipokines and cytokines to demonstrate possible markers for inflammation that participate in IIH pathophysiology and their association with clinical features of IIH. Methods IIH patients, diagnosed according to the revised criteria, and age-, gender- and body mass index (BMI)-matched healthy controls were enrolled in this study. Serum samples were evaluated for insulin-like growth factor 1, insulin, nesfatin, adiponectin, interleukin (IL)-1ß, IL-6, IL-8, leptin, plasminogen activator inhibitor type-1, resistin, tumour necrosis factor-alpha (TNF-α) and monocyte chemotactic protein 1 via enzyme-linked immunosorbent assay or multiplex immunoassays. Results IL-1ß level was significantly higher ( p = 0.012), and IL-8 and TNF-α levels were significantly lower in the IIH group ( p < 0.001 and p = 0.008, respectively) compared to the control group. There were no correlations between the cytokine/adipokine levels and age, BMI, disease duration, and cerebrospinal fluid oligoclonal bands. There were also no significant differences in cytokine and adipokine levels between IIH patients regarding visual impairment. However, statistically significant differences were found between IIH patients with relapse versus healthy controls regarding IL-1ß ( p = 0.007), IL-8 ( p = 0.001) and TNF-α ( p = 0.017) levels. Other investigated cytokines and adipokines showed no significant alterations in IIH patients investigated in the remission period. Conclusion Altered serum levels of IL-1ß, IL-8 and TNF-α seem to be associated with IIH pathogenesis, and these cytokines may be used as prognostic markers in IIH to predict relapse.

Glial and neuronal antibodies in patients with idiopathic intracranial hypertension.

Headache and visual disturbances are the main presenting symptoms of idiopathic intracranial hypertension (IIH) characterized by increased intracranial pressure (ICP) with an unknown cause. We aimed to investigate the antibodies against optic neuritis-associated glial antigens, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) and uncharacterized neuronal membrane antigens in IIH patients. Consecutive patients diagnosed according to Friedman revised diagnostic criteria and control subjects were included after their consent. All serum samples were analyzed for antibodies against AQP4 and MOG using cell-based immunofluorescent assays and for uncharacterized neuronal membrane antigens by indirect immunocytochemistry utilizing live neurons. Sera of 34 patients with IIH and 40 control subjects were investigated but none of the patients showed AQP4 and MOG antibodies. However, serum IgG of five IIH patients showed reactivity against membrane antigens of rat hippocampal and cortical neurons. Interestingly, three out of these five patients had nonspecific white matter lesions on MRI, whereas only four of all other patients had these lesions (p = 0.048). AQP4 and MOG antibodies do not seem to have a role in the pathophysiology of IIH. However, association of immunocytochemistry findings with the presence of white matter lesions may suggest that immunological factors contribute to the pathogenesis of IIH in at least some of the patients.

Can elevated IGF-1 levels among patients with Ehlers-Danlos syndrome cause idiopathic intracranial hypertension?

We offer for consideration a possible association between hypermobility syndrome seen in Ehlers-Danlos syndrome and risk of potential development of idiopathic intracranial hypertension - mediated primarily through the effects of insulin-like growth factor-1.

Elevated neurofilament light chain CSF/serum ratio indicates impaired CSF outflow in idiopathic intracranial hypertension.

BACKGROUND: Impaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients. METHODS: NfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry. RESULTS: CSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = - 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort. CONCLUSIONS: The observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis.

Aquaporin-4 antibodies are not present in patients with idiopathic intracranial hypertension.

OBJECTIVES: We aimed to investigate anti-aquaporin-4 (AQP-4) water channel antibodies, affecting cerebrospinal fluid (CSF) secretion and absorption, in idiopathic intracranial hypertension (IIH) patients. METHODS: Patients fulfilling the modified Dandy's diagnostic criteria for IIH were included and their clinical features and CSF findings were reviewed. Their serum samples and control groups were investigated by immunofluorescence and a cell-based assay for anti-AQP-4 antibodies and by immunohistochemistry for IgG binding patterns. RESULTS: Twenty-nine patients diagnosed with IIH were investigated. We could not detect any anti-AQP-4 antibodies in our series. However, we identified different serum IgG binding patterns in 11 IIH patients. CONCLUSION: There is only one report investigating the anti-AQP4 antibodies in IIH. Our study with a larger sample confirmed the results of this report and indicated that AQP4 antibodies did not have a primary role in IIH pathogenesis, but provided some support for the contribution of inflammatory mechanisms in IIH.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

OBJECTIVE: The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well-recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH. DESIGN: Paired serum and cerebrospinal fluid (CSF) specimens were collected from 26 patients with IIH and compared to 62 control subjects. Samples were analysed for leptin, resistin, adiponectin, insulin, IL-1beta, IL-6, IL-8 (CXCL8), TNFalpha, MCP-1 (CCL2), hepatocyte growth factor, nerve growth factor and PAI-1 using multiplex bead immunoassays. RESULTS: CSF leptin was significantly higher in patients with IIH (P = 0.001) compared to controls after correction for age, gender and body mass index (BMI). In the control population, BMI correlated with serum leptin (r = 0.34; P = 0.007) and CSF leptin (r = 0.51; P < 0.0001), but this was not the case for the IIH population. Profiles of other inflammatory cytokines and adipokines did not differ between IIH patients and controls once anthropometric factors had been accounted for. CONCLUSIONS: IIH was characterized by significantly elevated CSF leptin levels which did not correlate with BMI. We suggest that CSF leptin may be important in the pathophysiology of IIH and that obesity in IIH may occur as a result of hypothalamic leptin resistance.

Cytokines and chemokines in idiopathic intracranial hypertension.

BACKGROUND: The pathogenesis of idiopathic intracranial hypertension (IIH) remains unclear and as such it remains a diagnosis of exclusion. OBJECTIVES: To identify cerebrospinal fluid (CSF) and serum cytokine and chemokine profiles associated with IIH. METHOD: Semiquantitative assessment with cytokine antibody arrays was used to detect the relative expression of 42 different cytokines and chemokines in the CSF and serum of 8 IIH patients and 8 controls. Subsequently, quantitative assay with enzyme linked immunosorbent assay was performed for chemokine CCL2, interleukin-1 alpha (IL-1alpha), and leptin. RESULTS: Cytokine antibody array showed elevated levels of CCL2 in the CSF and CCL7, CCL8, IL-1alpha, and leptin levels in serum in IIH patients compared with controls. Subsequent quantitative assessment with enzyme linked immunosorbent assay showed significantly elevated CSF CCL2 in IIH patients compared with controls (P < .01) but there was no significant difference in leptin and IL-1alpha levels between the groups. CONCLUSION: This is the first report demonstrating differences in cytokine expression in the serum and CSF in IIH patients compared with controls. Since the pathogenesis of IIH is unclear, the heterogeneity of the cytokine expression reported here may help understand the pathogenesis of this condition.

Neuron-specific enolase levels as a marker for possible neuronal damage in idiopathic intracranial hypertension.

Although formerly considered as a "benign" disease, the presence of some important problems such as vision loss, resistance to appropriate medical treatment and relapses suggests that neuronal damage might play a role in the pathophysiology of IIH. In order to demonstrate possible neuronal damage/dysfunction participating in IIH pathophysiology, we aimed to investigate the relationship between serum neuron-specific enolase (NSE) levels and clinical features in patients with idiopathic intracranial hypertension (IIH). Thirty-six patients with IIH, diagnosed according to the revised criteria, and 40 age, gender and body mass index-matched healthy controls were enrolled in this study after their consent. Serum samples were evaluated for NSE via enzyme-linked immunosorbent assay method. NSE levels were higher in the IIH group (23.7 ± 14.53 ng/ml) compared to the control group (22.7 ± 13.11 ng/ml), but the difference was not statistically significant (p = 0.824). There were also no statistically significant differences in NSE levels in IIH patients regarding the presence of visual loss, relapse, oligoclonal bands and papilledema. We could not demonstrate any correlations between NSE levels and age, body mass index, cerebrospinal fluid opening pressure and disease duration. The present study is the first to analyze NSE levels in IIH patients and showed no significant difference between patients and controls, and also between different clinical subgroups of IIH patients.

Role of vitamin A metabolism in IIH: Results from the idiopathic intracranial hypertension treatment trial.

INTRODUCTION: Vitamin A and its metabolites (called retinoids) have been thought to play a role in the development of idiopathic intracranial hypertension (IIH). The IIH Treatment Trial (IIHTT) showed the efficacy of acetazolamide (ACZ) in improving visual field function, papilledema grade, quality of life and cerebrospinal fluid (CSF) pressure. We postulated that IIH patients would demonstrate elevated measures of vitamin A metabolites in the serum and CSF. METHODS: Comprehensive measures of serum vitamin A and its metabolites were obtained from 96 IIHTT subjects, randomly assigned to treatment with ACZ or placebo, and 25 controls with similar gender, age and body mass index (BMI). These included retinol, retinol binding protein, all-trans retinoic acid (ATRA), alpha- and beta-carotenes, and beta-cryptoxanthin. The IIHTT subjects also had CSF and serum vitamin A and metabolite measurements obtained at study entry and at six months. RESULTS: At study entry, of the vitamin A metabolites only serum ATRA was significantly different in IIHTT subjects (median 4.33nM) and controls (median 5.04nM, p=0.02). The BMI of IIHTT subjects showed mild significant negative correlations with serum ATRA, alpha- and beta-carotene, and beta-cryptoxanthin. In contrast, the control subject BMI correlated only with serum ATRA. At six months, the serum retinol, alpha-carotene, beta-carotene, and CSF retinol were increased from baseline in the ACZ treated group, but only increases in alpha-carotene (p=0.02) and CSF ATRA (p=0.04) were significantly greater in the ACZ group compared with the placebo group. No other vitamin A measures were significantly altered over the six months in either treatment group. Weight loss correlated with only with the change in serum beta-carotene (r=-0.44, p=0.006) and the change in CSF retinol (r=-0.61, p=0.02). CONCLUSION: Vitamin A toxicity is unlikely a contributory factor in the causation of IIH. Our findings differ from those of prior reports in part because of our use of more accurate quantitative methods and measuring vitamin A metabolites in both serum and CSF. ACZ may alter retinoid metabolism in IIH patients.

Increased red blood cell aggregation in patients with idiopathic intracranial hypertension. A hitherto unexplored pathophysiological pathway.

It was the objective of this study to explore the possibility that the aggregation of red blood cells is enhanced in individuals with increased intracranial hypertension (IIH). This is a prospective cross sectional examination in a cohort of patients with IIH and matched controls. The aggregation of red blood cells in the peripheral venous blood was determined by using a slide test and image analysis. We have presently included a group of 33 women with IIH and the same number of women matched for age, body mass index, vascular risk factors and medications. A significant (p = 0.038) increment in fibrinogen concentrations was noted in the patients (341 +/- 60.8 mg/dl) as opposed to the controls 307.9 +/- 64.8). The same stands for the aggregation of red blood cells (aggregation parameter of 8.7 +/- 4.9 in patients vs.5.9 +/- 3.2 in the controls, p = 0.001). We noted an increment in the aggregation of red blood cells in the peripheral blood of 33 women with IIH as opposed to matched controls. Being associated with capillary slow flow, these findings might be relevant to the ethiopathogenesis of this disease.

Endocrine studies in patients with pseudotumor cerebri. Estrogen levels in blood and cerebrospinal fluid.

In 15 patients fulfilling conventional diagnostic criteria for pseudotumor cerebri, anterior and posterior pituitary functions were examined. Eight of 12 female patients with pseudotumor were grossly overweight. Except for a subnormal response of growth hormone level to insulin-induced hypoglycemia in four patients, no major disturbances were found in pituitary, gonadal, thyroid, or adrenal functions. Vasopressin concentration in the cerebrospinal fluid was increased in patients with pseudotumor, whereas cerebrospinal fluid concentration of estrogens was below detection limit.

An acquired abnormal fibrinogen associated with thromboembolic disease and pseudotumor cerebri.

An abnormal fibrinogen was found in a patient associated with disabling recurrent phlebitis and pulmonary emboli, pseudotumor cerebri, gout and endometriosis. The fibrinogen is characterized by (1) abnormal side-to-side and end-to-end polymerization, (2) abnormal fibrinopeptide release, (3) a delayed gamma-gamma dimerization of the non cross-linked fibrin, (4) a pH optimum of 7--7.8, and (5) a deviation from normal amino acid composition with regard to lysine, aspartic acid, glutamic acid and serine. Since no defect has been found in any of her three children, and since the prothromin and partial thromboplastin times vary from time to time, it is assumed that the defect is acquired. Liver disease, usually associated with acquired abnormal fibrinogen, has been excluded as an etiological cause since liver function tests and biopsy are completely normal.

Recurrence of idiopathic intracranial hypertension after weight loss: the carrot craver.

PURPOSE: To describe a patient with stable idiopathic intracranial hypertension whose papilledema worsened. METHOD: Case report. RESULTS: A patient with documented idiopathic intracranial hypertension had resolution of disc edema with weight loss. Recurrence of papilledema led to the discovery that she consumed large quantities of raw carrots to help maintain her weight. Her increased vitamin A levels normalized, and the disc edema resolved when she stopped eating carrots. CONCLUSION: Patients with idiopathic intracranial hypertension should be counseled regarding carrot intake.

Plasma ghrelin levels are normal in obese patients with idiopathic intracranial hypertension (pseudotumor cerebri).

PURPOSE: Idiopathic intracranial hypertension (IIH) occurs predominantly in young, obese women. Weight loss may alleviate symptoms of IIH yet may be difficult to achieve. Ghrelin, a gastric hormone, is involved in normal body weight and appetite regulation. Its levels are elevated in syndromes of overeating and decline in simple obesity. We postulated that fasting plasma ghrelin levels are elevated in IIH patients and that the typical postprandial decline in plasma ghrelin may not occur. DESIGN: Prospective, observational case-control study. METHODS: Prospective study. SETTING: University hospital and clinic. STUDY POPULATION: Sixty-five patients with a diagnosis of IIH and 25 obese control patients (screened for IIH symptoms). Patients with intracranial abnormalities or a history of gastric surgery were excluded. OBSERVATION PROCEDURE: Fasting plasma ghrelin, leptin, and insulin levels were assessed between 8 am and 10 am. Subjects were fed a standard breakfast, and postprandial ghrelin levels were measured 30 minutes later. RESULTS: Fasting plasma ghrelin levels negatively correlated with body mass index in both IIH subjects (r = -.48) and controls; leptin showed a positive correlation with body mass index in both IIH (r =.59) and controls. Levels were not significantly different between the groups. Postprandial ghrelin declined by 71 +/- 31 (95% CI) pg/ml in the IIH group and 71 +/- 35 (95% CI) pg/ml in the control group. CONCLUSION: Plasma ghrelin levels, both fasting and postprandial, do not differ between IIH patients and obese controls. Obese IIH patients should be encouraged to lose weight and referred for medical weight loss management to maximize their chances of alleviating their symptoms.