RARE DISEASE
Idiopathic intracranial hypertension
Idiopathic intracranial hypertension
Idiopathic intracranial hypertension
Synonyms: Benign intracranial hypertension, IIH, Pseudotumor cerebri
Synonyms: Benign intracranial hypertension, IIH, Pseudotumor cerebri
Synonyms: Benign intracranial hypertension, IIH, Pseudotumor cerebri
Drug discovery
4
drugs
With orphan designations
Overview
Idiopathic intracranial hypertension (IIH) is a neurological disorder marked by elevated intracranial pressure of unknown etiology, primarily affecting young, obese women. Symptoms include headaches, vision changes (e.g., transient obscurations, papilledema), pulsatile tinnitus, and potential vision loss. Diagnosis requires exclusion of secondary causes via neuroimaging and confirmed by lumbar puncture with elevated opening pressure (>25 cm CSF). Management focuses on weight loss, pharmacotherapy (e.g., acetazolamide), and surgical interventions (e.g., CSF shunting) for refractory cases [1][5][6][16].
Therapies
First-line: Weight loss (≥5–10% body weight) and sodium restriction [3][18].
Medical: Acetazolamide (reduces CSF production), topiramate (adjunct for headache/weight), or furosemide [8][13][16].
Surgical: CSF diversion (shunts), optic nerve sheath fenestration, or venous sinus stenting in refractory cases [3][8][16].
Categories: rare neurological diseases
Research Papers
1,589 drug discovery papers about Idiopathic intracranial hypertension, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,589 drug discovery papers about Idiopathic intracranial hypertension, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-02 | Developmental transition in pathophysiological mechanisms of pediatric idiopathic intracranial hypertension and growth plate disorders: A multi-level structural equational modeling systematic review and meta-analysis.
Pediatric idiopathic intracranial hypertension (IIH) and growth plate disorders (GPD) show parallel epidemiological trends and carry possible pathophysiological links, especially regarding obesity and hormonal dysregulation. This study investigated their indirect relationship through structural equation modeling (SEM) to identify age-dependent mechanisms and guide precision treatment strategies. Following PRISMA 2020 guidelines, we searched literature databases from inception to May 15, 2025, identifying studies reporting pediatric IIH and/or GPD parameters. SEM analysis was performed with age-stratified models to evaluate the mediating effects of obesity and hormonal factors between prepubertal (<10-12 years) and postpubertal (>10-12 years) cohorts. We included 22 eligible studies with total of 2293 individuals. SEM revealed peculiar age-dependent mechanisms. In prepubertal children, venous pressure (β = 0.68, P-value<0.001) and vitamin D/hormonal pathways (β = 0.56, P-value<0.001) dominated, with obesity showing minimal effect (β = 0.28, P-value = 0.001). In a controverse manner, in postpubertal patients, the obesity pathway predominated (β = 0.76, P-value<0.001) with reduced venous (β = 0.29, P-value = 0.003) and hormonal (β = 0.16, P-value = 0.038) contributions. Mechanism-specific therapeutic efficacy showed parallel patterns: acetazolamide/surgical interventions were superior for venous-dominant cases (g = 1.86/1.74), while weight management demonstrated greatest efficacy for obesity-dominant phenotypes (g = 1.75). Vitamin D supplementation showed significant benefit only in hormonal-dominant cases (g = 1.64). Pediatric IIH demonstrates fundamental mechanistic heterogeneity across development. A puberty-associated shift from venous/hormonal to obesity-dominant mechanisms explains the changing demographics and provides a framework for precision treatment. Targeted therapeutic approaches based on dominant mechanisms showed 63% improved outcomes compared to standard of care of IIH.
2026-07-23 | Carbonic anhydrases I and II.
Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO₂/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.
2026-07-06 | Papilledema is not the point: intracranial pressure dysregulation as a common pathway in migraine and idiopathic intracranial hypertension
Abstract Accumulating evidence challenges the traditional distinction between migraine and idiopathic intracranial hypertension (IIH). We tested whether impaired CSF volume/pressure regulation driven by dural venous sinus stenosis represents a shared substrate. Brain MRI and magnetic resonance venography scans from 161 consecutive patients - migraine without aura (MwoA, n=89), migraine with aura (MwA, n=36) and IIH (n=36) - were retrospectively analysed and compared with 37 prospectively recruited healthy controls. An Extended Combined Conduit Score – designed to quantify the degree and extent of venous-sinus narrowing, with higher values indicating greater outflow impairment, and also evaluating the superior sagittal sinus - quantified stenosis. Additional neuroradiological markers of raised intracranial pressure (empty sella, posterior globe flattening, optic nerve sheath diameter) were recorded. A receiver operating characteristic analysis defined the optimal stenosis degree threshold for distinguishing patients from controls, after which prevalence comparisons were performed. Median Extended Combined Conduit Score increased step wise from controls (2, interquartile range 1–3) to MwoA (3, 2–4), MwA (3, 3–4) and IIH (6, 5–6) (p < 0.001). Both migraine groups scored higher than controls (p <0.001) and lower than IIH (p <0.001). The area under the receiver operating characteristic curve was 0.786 (95% confidence interval 0.716–0.856); a cut off ≥ 3 provided 74.5% sensitivity and 73.0% specificity. Using this threshold, venous stenosis was more frequent in MwoA and MwA than in controls (each p <0.001) and highest in IIH (p <0.001 versus all); MwA exceeded MwoA (p =0.007) and was comparable to IIH (p =0.187). Bilateral stenosis occurred in 0% of controls, nearly 25% of patients with migraine (p <0.001 versus controls) and 77.8% of IIH patients (p <0.001). Empty sella was more common in MwoA (p =0.004) and MwA (p =0.025) than in controls, and markedly enriched in IIH (p <0.001 versus all). Other radiological markers were similarly more prevalent in IIH (all p<0.001) showing no additional significant between-group differences. Findings support a pathogenetic continuum linking MwoA, MwA and IIH, challenging the diagnostic primacy of papilledema, the rarity of IIH without it, and the perceived irrelevance of unilateral sinus narrowing. As already observed in IIH, an impaired intracranial volume/pressure regulation appears a necessary though not sufficient condition for migraine development; a “primary” predisposition to migraine, likely multifactorial and widely variable among individuals and in the same individual over time, is required for typical migraine pain to develop, also modulating its frequency. Future studies should assess whether targeting intracranial pressure, thus potentially preventing calcitonin gene-related peptide release, may complement or substitute calcitonin gene-related peptide based therapies in migraine patients.
2026-06-26 | Acetazolamide-induced metabolic acidosis in pediatric idiopathic intracranial hypertension: associations with bone mineral density, growth, and kidney function.
Although acetazolamide is the main medical treatment for idiopathic intracranial hypertension (IIH), data on acetazolamide-induced metabolic acidosis and its long-term outcomes are limited. This study aimed to investigate the severity of acetazolamide-related metabolic acidosis, associated risk factors, and its effects on bone mineral density (BMD), growth, and kidney function. This retrospective cohort study included pediatric patients with IIH treated with acetazolamide between 2018 and 2025. Demographic and clinical characteristics, anthropometric and laboratory findings at diagnosis and during follow-up, BMD measurements, and ultrasonography findings were collected. Metabolic acidosis was categorized by severity. Minimum and mean serum bicarbonate levels during follow-up were recorded. Forty-one patients (65.9% female; mean age 11.2 ± 3.1 years) were included. Metabolic acidosis was observed in all patients (39.0% mild, 53.7% moderate, 7.3% severe). Patients with moderate-to-severe acidosis had significantly lower BMI Z-scores and younger ages at diagnosis compared with those with mild acidosis. In multivariable analysis, cumulative acetazolamide dose remained independently associated with moderate/severe metabolic acidosis (OR 1.30, 95% CI 1.00-1.69; p = 0.049). BMD was assessed in 35 patients after a median acetazolamide exposure of 14 months and mildly reduced/low BMD was detected in 22.9%. Higher cumulative acetazolamide exposure and lower minimum bicarbonate levels were associated with mildly reduced/low BMD in univariable analyses; however, these associations did not remain significant after multivariable adjustment. Although estimated glomerular filtration rate declined modestly from baseline to the last visit, this change was not associated with acidosis severity, treatment duration, or cumulative acetazolamide dose. Metabolic acidosis is highly prevalent among children receiving acetazolamide for IIH, and greater cumulative acetazolamide exposure appears to be associated with more severe acidosis. Lower bicarbonate levels and higher cumulative acetazolamide exposure were associated with mildly reduced/low BMD in univariable analyses; however, these associations did not remain significant after multivariable adjustment. The limited number of patients undergoing BMD assessment, the relatively short exposure duration in some patients, and the absence of baseline BMD measurements limit definitive conclusions regarding the skeletal effects of acetazolamide.
2026-06-15 | CGRP-provoked headache is associated with a neuroimmune signature in idiopathic intracranial hypertension.
Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure and disabling headaches, yet its underlying mechanisms remain poorly defined. Calcitonin gene-related peptide (CGRP) is a key neuropeptide implicated in migraine and headache attributed to IIH. CGRP-driven neuroinflammation is implicated in migraine generation but whether CGRP-provoked headache in IIH is accompanied by dynamic neuroimmune activation during the ictal phase remains unknown. We aimed to characterise cytokine alterations during experimentally-induced IIH headache attacks provoked by CGRP. In a randomised, double-blind, placebo-controlled, two-way crossover study (IIH Provoke: ISRCTN13251508), 16 women with IIH underwent two inpatient visits receiving intravenous CGRP (1.5 µg/min for 20 min) or placebo (isotonic saline). Blood samples were collected at baseline and either at peak headache or at the end of the visit, if no headache occurred. Plasma cytokines were measured using the Olink® Target 48 Cytokine Panel. CGRP induced a typical IIH headache attack within the sampling period in 7/16 participants. Compared with baseline, eight cytokines were significantly elevated during CGRP-provoked headache attacks: C-C motif chemokine 4 (CCL4), CCL8, interleukin-6 (IL-6), IL-17C, IL-27, oncostatin M (OSM), hepatocyte growth factor (HGF), and transforming growth factor-α (TGF-α) (P < 0.05). These changes were not observed after placebo or in participants who received CGRP without developing headache. CGRP-provoked IIH headache attacks were associated with elevations in pro-nociceptive mediators (IL-6, CCL4, OSM) and immune-related cytokines (IL-17C, IL-27, HGF, TGF-α). These findings suggest that CGRP-provoked headache in IIH is associated with changes in circulating cytokines consistent with a neuroimmune response during the ictal phase. Larger cohorts are required to validate these observations and explore neuroinflammation as a therapeutic target in IIH headache.
cell therapies
2026-08-04 | Cerebrospinal fluid shunting or dural venous sinus stenting to preserve vision in idiopathic intracranial hypertension (IIH Intervention): protocol for an open-label, multicentre, randomised controlled phase IIb trial.
Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and typically affects young women with obesity. Patients are at risk of permanent visual loss due to papilloedema. Some require emergency intervention to rapidly reduce papilloedema and preserve vision. The international standard of care for patients with sight-threatening IIH is cerebrospinal fluid (CSF) shunting. However, dural venous sinus stenting (DVSS) is an emerging procedure that is offered at many neuroscience centres internationally as the primary intervention. Currently, there are no randomised controlled trial data supporting the efficacy of any interventional approach for preserving vision in sight-threatening IIH. IIH Intervention is a UK-based two-arm, open-label, multicentre, randomised controlled phase IIb clinical trial with integrated health economic evaluation to compare CSF shunting with DVSS in patients who have confirmed IIH and are at risk of permanent visual loss due to severe papilloedema. The primary outcome is the global thickness of the peripapillary retinal nerve fibre layer (RNFL), an indicator of papilloedema, measured by optical coherence tomography (OCT) over a 6-month period. Secondary outcomes are global thickness of the RNFL over 12 and 24 months, as well as macular ganglion cell layer volume, perimetric mean deviation, headache outcomes, intervention reporting measures (including complications and revisions) and patient-reported outcomes over 6, 12 and 24 months. The protocol was approved initially on 12 December 2022 by West Midlands-South Birmingham Research Ethics Committee (ref: 22/WM/0230). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. ISRCTN57142415.
2026-07-21 | Venous Sinus Stenting for Pulsatile Tinnitus: A Systematic Review and Meta-Analysis.
Pulsatile tinnitus (PT) is frequently caused by venous sinus stenosis and may be associated with idiopathic intracranial hypertension (IIH). Venous sinus stenting (VSS) directly addresses venous outflow obstruction and has emerged as a therapeutic option; however, outcome data remain heterogeneous. We performed an updated systematic review and meta-analysis to evaluate the efficacy and durability of VSS for PT and to compare outcomes between IIH-associated and isolated PT. MEDLINE, Scopus, and Web of Science were searched from inception through December 2025 following PRISMA guidelines. Clinical studies reporting PT outcomes after VSS were included. Random-effects meta-analyses of proportions were conducted to estimate pooled rates of overall improvement, complete resolution, and recurrence. Prespecified subgroup analyses compared IIH versus isolated PT. Thirty-two studies comprising 850 patients were included (641 with IIH; 209 with isolated PT). Venous sinus stenosis accounted for 90.3% of treated etiologies. The pooled rate of overall PT improvement was 89.8% (95% CI, 85.5-92.9). Complete resolution occurred in 87.1% (95% CI, 82.5-90.6). Recurrence at last follow-up was 10.9% (95% CI, 8.3-14.2). Improvement and complete resolution rates did not differ significantly between IIH and isolated PT. Recurrence was higher in IIH (12.0%) than in isolated PT (5.7%), without reaching statistical significance. VSS is associated with high rates of PT improvement and complete resolution with low recurrence. Recurrence trends appear higher in IIH, suggesting underlying pathophysiology may influence durability.
2026-06-27 | Endovascular treatment of tumor-related dural sinus stenosis, venous outflow obstruction, and secondary intracranial hypertension: a systematic review of the literature.
Tumors involving dural venous sinuses can lead to venous outflow obstruction and secondary intracranial hypertension. While surgical resection can decompress the sinus, such procedures carry significant risks. With the success of endovascular interventions for idiopathic intracranial hypertension (IIH), venous sinus stenting (VSS) and angioplasty have emerged as potential treatments for tumor-related sinus stenosis. However, evidence remains limited and dispersed. This systematic review aimed to synthesize the available literature on the safety and efficacy of endovascular treatment for tumor-related venous sinus obstruction. A systematic search of PubMed, Embase, and Web of Science was conducted from database inception to November 2025. Eligible studies included any report describing endovascular treatment (VSS and/or angioplasty) for tumor-related venous sinus obstruction, whether due to tumor invasion or compression, or even stenosis following surgery or radiotherapy. Data on patient demographics, tumor characteristics, procedural details, and outcomes were extracted and summarized descriptively. Twenty studies comprising 57 patients were included. Most patients were female (65%) with a mean age of 48 years. Meningioma represented the most common underlying tumor (75%). The majority of obstructions resulted from tumor compression or invasion (86%), and most patients underwent VSS alone (74%), while the rest underwent VSS and angioplasty (23%). No periprocedural complications were reported. Mean trans-stenotic pressure gradient decreased by 10 ± 9 mmHg post-treatment and mean lumbar opening pressure decreased by 11 ± 12 cmH2O. Clinical improvement was reported in 63% of patients, including resolution or improvement of papilledema in 94% and vision changes in 94%. Repeat intervention was required in 28% of cases, and only about half of patients achieved further improvement after reintervention. Endovascular therapy for tumor-related venous sinus stenosis appears safe and effective, leading to meaningful pressure reduction and symptomatic improvement in two-thirds of patients. These findings support VSS as a viable adjunct or alternative to surgery in selected patients. Nonetheless, the certainty of evidence remains very low, and current data cannot establish definitive conclusions.
2026-06-24 | Slit ventricles in idiopathic intracranial hypertension appear to expand after venous sinus stenting: a volumetric analysis.
Venous congestion is associated with tissue swelling in multiple organ systems. In idiopathic intracranial hypertension (IIH), its effects on brain parenchyma are less well defined, but may contribute to slit ventricles through increased parenchymal volume. We therefore analyzed ventricular volumes before and after venous sinus stenting (VSS). Semi-automated ventricular segmentation was performed using 3D Slicer (image analysis and scientific visualization software) on pre- and post-VSS volumetric MRI or CT scans from patients with IIH at a single center (2022-2025). The primary objective was to quantify change in total ventricular volume. Secondary objectives were to assess compartmental changes, predictors of ventricular volume change, and associations between volumetric data and clinical outcomes. 25 patients were included. Median time to post-stent imaging was 6.7 months (IQR 4.7-7.0). Median total ventricular volume increased from 10.96 mL (IQR 8.91-19.21) to 12.8 mL (IQR 9.72-20.32) (+16.8%, P=0.024), driven predominantly by increased lateral ventricular volume (+12.3%, P=0.021). Third and fourth ventricular volumes did not change significantly. No predictors of volume change were identified. Lower baseline ventricular volume was associated with higher odds of a favorable clinical outcome following VSS (OR 1.14, 95% CI 1.01 to 1.32, P=0.047). There is a small but consistent increase in ventricular volume following VSS, driven by expansion of the lateral ventricles. Greater benefit from stenting was observed in patients with lower baseline ventricular volumes. These findings suggest cerebral venous congestion may contribute to slit ventricles in IIH, and that improved venous drainage may permit re-expansion of cerebrospinal fluid spaces.
2026-06-02 | Idiopathic intracranial hypertension presenting with obsessive thoughts: a rare neuropsychiatric manifestation "case report".
Idiopathic intracranial hypertension (IIH) classically presents with headache, papilledema, and visual disturbances. Psychiatric manifestations are rare and may obscure a timely diagnosis. A 23-year-old obese female with no prior psychiatric history presented with new-onset intrusive thoughts and compulsive finger-tapping rituals, leading to a diagnosis of obsessive-compulsive disorder (OCD). Despite treatment with high-dose SSRIs, antipsychotic augmentation, and cognitive-behavioural therapy for six months, she showed no improvement. She concurrently reported a refractory bitemporal headache, tinnitus, and transient visual obscurations. Examination revealed bilateral papilledema. MRI/MRV showed features of raised intracranial pressure (ICP) associated with right transverse sinus stenosis. Lumbar puncture (LP) confirmed an elevated opening pressure of 30 cm H₂O. Despite treatment with acetazolamide (2 g/day), she remained symptomatic. Venous sinus stenting was subsequently performed, restoing sinus caliber and reducing the pressure gradient. Within three months, her headache improved markedly, and her papilledema resolved. Remarkably, her obsessive thoughts and compulsive acts completely disappeared without psychiatric medication, with her Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score dropping from 20 to 5. This case illustrates IIH presenting with predominant psychiatric manifestations mimicking primary OCD. The dramatic resolution of compulsive symptoms following intracranial pressure normalization suggests a possible association between IIH and obsessive thoughts. Clinicians should maintain a high index of suspicion for IIH in atypical psychiatric presentations accompanied by headache, tinnitus, or visual symptoms; in such cases, routine fundoscopy is essential.
proteins
2024-09-02 | Nasal turbinate lymphatic obstruction: a proposed new paradigm in the etiology of essential hypertension.
Hypertension affects an estimated 1.3 billion people worldwide and is considered the number one contributor to mortality via stroke, heart failure, renal failure, and dementia. Although the physiologic mechanisms leading to the development of essential hypertension are poorly understood, the regulation of cerebral perfusion has been proposed as a primary cause. This article proposes a novel etiology for essential hypertension. Our hypothesis developed from a review of nuclear medicine scans, where the authors observed a significantly abnormal increase in nasal turbinate vasodilation in hypertensive patients using quantitative region of interest analysis. The authors propose that nasal turbinate vasodilation and resultant blood pooling obstruct the flow of cerebrospinal fluid passing through nasal turbinate lymphatics, thereby increasing intracranial pressure. The authors discuss the glymphatic/lymphatic clearance system which is impaired with age, and at which time hypertension also develops. The increased intracranial pressure leads to compensatory hypertension via Cushing's mechanism, i.e., the selfish brain hypothesis. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs simultaneously along with the well-established increased sympathetic activity of the cardiovascular system. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of processed food. This hypothesis explains the rapid worldwide rise in essential hypertension in the last 50 years and offers a novel mechanism and a new paradigm for the etiology of essential hypertension. This new paradigm offers compelling evidence for the modulation of parasympathetic nervous system activity as a novel treatment strategy, specifically targeting nasal turbinate regulation, to treat diseases such as hypertension, idiopathic intracranial hypertension, and degenerative brain diseases. The proposed mechanism of essential hypertension presented in this paper is a working hypothesis and confirmatory studies will be needed.
2024-08-05 | Idiopathic Intracranial Hypertension as a Differential Diagnosis in Persistent Idiopathic Facial Pain: A Case Report.
Persistent idiopathic facial pain (PIFP), previously known as atypical facial pain (ATFP), is a chronic pain disorder with the characteristic of persistent, undulating pain in the face or the teeth without a known cause or any structural correlation. Women are more commonly affected than men. We report a case of a 38-year-old married female patient with a history of Crohn's disease who presented to the oral and maxillofacial surgery (OMFS) clinic with chronic dull bilateral facial pain and headache mainly affecting the right side of the face and neck without a known cause. She was initially diagnosed with PIFP due to a badly decayed right wisdom tooth. Wisdom teeth were extracted secondary to vague complaints of discomfort due to wisdom teeth; however, no significant improvement was noticed. Further investigations were carried out with new CT scans and magnetic resonance venography (MRV), which revealed evidence of having idiopathic intracranial hypertension (IIH), described as increased intracranial pressure with facial pain, headache, tinnitus, and papilledema. The patient was referred to neurology and received appropriate treatment. She began her treatment with topiramate, then transitioned to acetazolamide, underwent bilateral botulinum toxin (botox) injections into the temporal region, and underwent regular follow-up. The patient was significantly improved. Idiopathic intracranial hypertension must be ruled out in cases of PIFP that do not respond to ordinary treatment measures.
2023-10-10 | Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency.
The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF)-binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe 5-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 μg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). Treatment with rhIGF-1 was started in 10.4-year- (P3) and 14.5-year (P2)-old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; height velocity increased (3.0 cm/year at baseline; 5.0-7.6 cm/year thereafter) as did height SDS (+0.6). P3's pubertal onset was at 12.4 year. BMD height-adjusted Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-h glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-h glucose: 152 mg/dL) developed during puberty. Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPP-A2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.
2019-09-19 | The Role of Onabotulinum Toxin Type A in the Management of Chronic Non-migraine Headaches
Objectives: FDA has approved Onabotulinum toxin type A (BoNTA) for prophylactic treatment of chronic migraines. Recent studies have explored its potential new indications, like treating post-traumatic headaches. Patients and Methods: This is a retrospective chart review of 717 patients, who had failed at least two prophylactic treatments and received BoNTA injections at University of Missouri Hospital from July 2014 to June 2017. Patient demographics, headache type, associated symptoms, prophylaxes tried were reported. Patient's pain severity (numeric pain scale) and frequency (number of headache days/month) pretreatment, at 6 months, and at 12 months were collected. Results: For a single headache type, post-traumatic headaches showed reduction in headache pain severity at 6 months (2.9 ± 0.7) compared to pre-treatment (7 ± 0.7). Headache frequency for post-traumatic headaches was also reduced at 6 months (10.6 ± 2.3) and 12 months (5.1 ± 1.2) compared to pre-treatment (25 ± 1.8). For pseudotumor cerebri headaches, pain severity at pretreatment was 6.4 ± 0.6 compared to 2 ± 0.8 at 6 months, and headache days reduced at 6 months (9.8 ± 2.5) and 12 months (6 ± 4) compared to pretreatment (26 ± 2.9). Opioid use reduced by 67 ± 55.4 at 6 months and 133.3 ± 106.6 at 12 months in morphine equivalent units. Conclusions: Onabotulinum toxin type A is effective in treating multiple types of chronic non-migraine headaches.
1997-10-23 | Possible regulation of intracranial pressure by human atrial natriuretic peptide in cerebrospinal fluid.
To clarify the function of human atrial natriuretic peptide (hANP) in the cerebrospinal fluid (CSF), we examined hANP levels in the CSF of patients with various neurological diseases. The subjects were 16 controls without neurological disease and 45 patients with neurological disease. The 45 patients with neurological disease were divided into a group of 15 patients with intracranial hypertension (IH) and a group of 30 patients with normal pressure (NP). hANP in both CSF (1-hANP) and serum (s-hANP) was measured by RIA. Patients with IH were followed up. We analyzed correlations between 1-hANP and other parameters of CSF. Increase in concentration of 1-hANP was positively correlated with intracranial pressure (ICP; r = 0.72; p < 0.01), but not with other CSF parameters or with s-hANP. The concentration of 1-hANP appeared to be increased especially over a threshold value of ICP. In a followup study of patients with IH, changes in 1-hANP paralleled changes in ICP in every case (r = 0.79; p < 0.01). Our findings strongly suggest that 1-hANP plays an important role in the regulation of ICP in humans.
antibodies
2025-09-22 | Concurrent Presentation of C3 Glomerulopathy and Benign Intracranial Hypertension in a Young Woman: A Case Report
Background: C3 glomerulopathy (C3G) is a rare complement-mediated glomerular disease characterized by dysregulation of the alternative complement pathway, leading to C3-dominant glomerular deposits and variable renal manifestations. Benign intracranial hypertension (BIH), or idiopathic intracranial hypertension, presents with increased intracranial pressure in the absence of structural lesions. While BIH has been reported in association with immune-complex glomerulonephritis, its co-occurrence with C3G has not been previously described. Case presentation. We report the case of a 25-year-old Asian woman presenting with a two-week history of progressive occipital headache, vomiting, and subsequent diplopia and blurred vision. Examination revealed bilateral papilledema and sixth nerve palsy. MRI findings and elevated lumbar puncture opening pressure (>25 cm H₂O) confirmed BIH, and acetazolamide was initiated with gradual improvement in symptoms. Routine investigations revealed renal dysfunction, non-nephrotic proteinuria, thrombocytopenia, and low C3 with normal C4. Renal biopsy demonstrated crescentic mesangioproliferative glomerulonephritis with C3-dominant deposits on immunofluorescence, confirmed by electron microscopy. Complement analysis showed reduced factor H levels. She was treated with prednisolone, mycophenolate mofetil, and a renin-angiotensin system blocker, with partial improvement in renal and neurological status. Genetic testing revealed a CFH variant of uncertain significance. Given her partial response and evidence of complement dysregulation, eculizumab is planned if no further improvement is observed. Conclusions: This is, to our knowledge, the first reported case of concurrent C3G and BIH. The coexistence of these conditions suggests a potential shared immunopathogenic pathway involving alternative complement pathway dysregulation, with possible effects on both renal and central nervous system vasculature. This case highlights the importance of considering intracranial hypertension in patients with C3G presenting with visual symptoms or headache and supports further research into complement-mediated mechanisms linking renal and neurological disease.
2025-06-03 | Treatment of Persistent Headache After Normalization of CSF Pressure.
Headache is the most common symptom of intracranial hypertension and hypotension and may not remit after normalization of intracranial pressure. This article reviews the clinical presentation, mechanism, differential diagnosis, treatment, prognosis, and monitoring of persistent headache after normalization of intracranial pressure in the setting of idiopathic intracranial hypertension and spontaneous intracranial hypotension. Erenumab, a monoclonal antibody to the calcitonin gene-related peptide receptor, was shown to reduce headache frequency in the first-ever prospective study of headache treatment in patients with idiopathic intracranial hypertension in ocular remission. Similar avenues remain to be explored for spontaneous intracranial hypotension even though it has been shown that some patients continue with headache despite radiographic resolution of CSF leaks. Headache is the most common symptom to herald an intracranial pressure disturbance and may not resolve despite normalization of pressure. Neurologists must be aware that persistent headache does not automatically imply abnormal intracranial pressure in patients with previous disorders of CSF dynamics and informed of the possible alternative headache etiologies in these populations.
2025-04-30 | Calcitonin gene-related peptide in newly diagnosed idiopathic intracranial hypertension: a prospective, cross-sectional, case-control study of cerebrospinal fluid and plasma.
Calcitonin Gene-Related Peptide (CGRP) is involved in migraine pain signaling, and blockage hereof is effective in migraine treatment. Headache in idiopathic intracranial hypertension (IIH) is often migraine-like but the underlying mechanisms are not understood. We report levels of CGRP in plasma and cerebrospinal fluid (CSF) of patients with newly diagnosed IIH to elucidate CGRP involvement in the pathogenesis of headache in IIH. We consecutively enrolled patients suspected of having IIH in a prospective cohort at two Danish tertiary headache centers. Patients are confirmed to have IIH or disproven of it (non-IIH). We included non-IIH with primary headache disorders as headache controls to IIH cases. We also recruited sex-, age- and BMI-matched healthy controls (HC). All participants had CSF and blood drawn and CGRP was analyzed using a validated radioimmunoassay. CSF plasma-ratios were calculated. Between-group levels were compared with ANOVA or Kruskal-Walli's test. In sub-analyses we restricted comparison of HC to non-IIH/IIH with chronic migraine; we also compared IIH with versus without headache. We correlated CGRP to lumbar opening pressure (OP), and BMI, and assessed the correlation between CGRP in plasma and CSF. Generalized or linear regression was applied to adjust for confounding by BMI, age, and active smoking. Comparing 97 patients with IIH, 52 non-IIH, and 37 HC, we found no between-group differences in CGRP levels in plasma (p = 0.78), CSF (p = 0.79), or in CSF:plasma-ratio (p = 0.13). Adjusting for BMI, age, and smoking yielded similar results. CGRP levels were neither associated with having a migraine phenotype or chronic headache, nor with having any headache versus no headache in IIH. CGRP in plasma correlated with CGRP in CSF (p < 0.0001). CGRP did not correlate with OP or BMI. CGRP levels in plasma and CSF and their ratios were comparable in IIH, non-IIH patients with headache, and sex-, age-, and BMI-matched HC. CGRP in plasma correlated with CGRP in CSF. Due to methodology, we probably measured basal resting CGRP. The role of CGRP in IIH-headache needs further clarification. A headache preventive effect in IIH of anti-CGRP targeted therapy remains a relevant unexplored area.
2024-03-01 | Migraine, idiopathic intracranial hypertension, and calcitonin gene‐related peptide antibodies
Plain language summary Idiopathic intracranial hypertension (IIH) is a condition of high pressure in the spinal fluid that is common in young women who are overweight or obese. Headache happens in most individuals with IIH and can continue after the early phase of IIH has resolved. We studied the use of a newer type of medication developed for migraine called calcitonin gene‐related peptide antibodies and we found that these medications can be helpful for patients who have had IIH, although studies with more patients will be helpful.
2023-06-28 | High CCL2 Levels Detected in CSF of Patients with Pediatric Pseudotumor Cerebri Syndrome
Pseudotumor cerebri (PTC) is a disorder characterized by increased intracranial pressure in the absence of a structural lesion or other identifiable cause. Cytokines, which are involved in the regulation of immune responses and inflammation, have been implicated in the pathogenesis of PTC. In a prospective, cross-sectional study at three centers in Israel, we analyzed cerebrospinal fluid (CSF) samples from 60 children aged 0.5-18 years, including 43 children with a definitive diagnosis of PTC and a control group of 17 children. Levels of IL-4, IL-10, IL-17, CCL2, CCL7, CCL8, CCL13, BDNF, and IFN-γ were measured using ELISA kits. Levels of CCL2 were significantly higher in the PTC group compared to the control group (p < 0.05), with no other significant differences in the measured cytokines between the two groups. The groups did not differ significantly in clinical presentation, imaging, treatment, or ophthalmic findings. Our findings provide preliminary evidence that CCL2 may be involved in the pathogenesis of PTC and may serve a potential target for therapy in PTC.
small molecules
2026-08-02 | Developmental transition in pathophysiological mechanisms of pediatric idiopathic intracranial hypertension and growth plate disorders: A multi-level structural equational modeling systematic review and meta-analysis.
Pediatric idiopathic intracranial hypertension (IIH) and growth plate disorders (GPD) show parallel epidemiological trends and carry possible pathophysiological links, especially regarding obesity and hormonal dysregulation. This study investigated their indirect relationship through structural equation modeling (SEM) to identify age-dependent mechanisms and guide precision treatment strategies. Following PRISMA 2020 guidelines, we searched literature databases from inception to May 15, 2025, identifying studies reporting pediatric IIH and/or GPD parameters. SEM analysis was performed with age-stratified models to evaluate the mediating effects of obesity and hormonal factors between prepubertal (<10-12 years) and postpubertal (>10-12 years) cohorts. We included 22 eligible studies with total of 2293 individuals. SEM revealed peculiar age-dependent mechanisms. In prepubertal children, venous pressure (β = 0.68, P-value<0.001) and vitamin D/hormonal pathways (β = 0.56, P-value<0.001) dominated, with obesity showing minimal effect (β = 0.28, P-value = 0.001). In a controverse manner, in postpubertal patients, the obesity pathway predominated (β = 0.76, P-value<0.001) with reduced venous (β = 0.29, P-value = 0.003) and hormonal (β = 0.16, P-value = 0.038) contributions. Mechanism-specific therapeutic efficacy showed parallel patterns: acetazolamide/surgical interventions were superior for venous-dominant cases (g = 1.86/1.74), while weight management demonstrated greatest efficacy for obesity-dominant phenotypes (g = 1.75). Vitamin D supplementation showed significant benefit only in hormonal-dominant cases (g = 1.64). Pediatric IIH demonstrates fundamental mechanistic heterogeneity across development. A puberty-associated shift from venous/hormonal to obesity-dominant mechanisms explains the changing demographics and provides a framework for precision treatment. Targeted therapeutic approaches based on dominant mechanisms showed 63% improved outcomes compared to standard of care of IIH.
2026-07-23 | Carbonic anhydrases I and II.
Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO₂/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.
2026-07-06 | Papilledema is not the point: intracranial pressure dysregulation as a common pathway in migraine and idiopathic intracranial hypertension
Abstract Accumulating evidence challenges the traditional distinction between migraine and idiopathic intracranial hypertension (IIH). We tested whether impaired CSF volume/pressure regulation driven by dural venous sinus stenosis represents a shared substrate. Brain MRI and magnetic resonance venography scans from 161 consecutive patients - migraine without aura (MwoA, n=89), migraine with aura (MwA, n=36) and IIH (n=36) - were retrospectively analysed and compared with 37 prospectively recruited healthy controls. An Extended Combined Conduit Score – designed to quantify the degree and extent of venous-sinus narrowing, with higher values indicating greater outflow impairment, and also evaluating the superior sagittal sinus - quantified stenosis. Additional neuroradiological markers of raised intracranial pressure (empty sella, posterior globe flattening, optic nerve sheath diameter) were recorded. A receiver operating characteristic analysis defined the optimal stenosis degree threshold for distinguishing patients from controls, after which prevalence comparisons were performed. Median Extended Combined Conduit Score increased step wise from controls (2, interquartile range 1–3) to MwoA (3, 2–4), MwA (3, 3–4) and IIH (6, 5–6) (p < 0.001). Both migraine groups scored higher than controls (p <0.001) and lower than IIH (p <0.001). The area under the receiver operating characteristic curve was 0.786 (95% confidence interval 0.716–0.856); a cut off ≥ 3 provided 74.5% sensitivity and 73.0% specificity. Using this threshold, venous stenosis was more frequent in MwoA and MwA than in controls (each p <0.001) and highest in IIH (p <0.001 versus all); MwA exceeded MwoA (p =0.007) and was comparable to IIH (p =0.187). Bilateral stenosis occurred in 0% of controls, nearly 25% of patients with migraine (p <0.001 versus controls) and 77.8% of IIH patients (p <0.001). Empty sella was more common in MwoA (p =0.004) and MwA (p =0.025) than in controls, and markedly enriched in IIH (p <0.001 versus all). Other radiological markers were similarly more prevalent in IIH (all p<0.001) showing no additional significant between-group differences. Findings support a pathogenetic continuum linking MwoA, MwA and IIH, challenging the diagnostic primacy of papilledema, the rarity of IIH without it, and the perceived irrelevance of unilateral sinus narrowing. As already observed in IIH, an impaired intracranial volume/pressure regulation appears a necessary though not sufficient condition for migraine development; a “primary” predisposition to migraine, likely multifactorial and widely variable among individuals and in the same individual over time, is required for typical migraine pain to develop, also modulating its frequency. Future studies should assess whether targeting intracranial pressure, thus potentially preventing calcitonin gene-related peptide release, may complement or substitute calcitonin gene-related peptide based therapies in migraine patients.
2026-06-26 | Acetazolamide-induced metabolic acidosis in pediatric idiopathic intracranial hypertension: associations with bone mineral density, growth, and kidney function.
Although acetazolamide is the main medical treatment for idiopathic intracranial hypertension (IIH), data on acetazolamide-induced metabolic acidosis and its long-term outcomes are limited. This study aimed to investigate the severity of acetazolamide-related metabolic acidosis, associated risk factors, and its effects on bone mineral density (BMD), growth, and kidney function. This retrospective cohort study included pediatric patients with IIH treated with acetazolamide between 2018 and 2025. Demographic and clinical characteristics, anthropometric and laboratory findings at diagnosis and during follow-up, BMD measurements, and ultrasonography findings were collected. Metabolic acidosis was categorized by severity. Minimum and mean serum bicarbonate levels during follow-up were recorded. Forty-one patients (65.9% female; mean age 11.2 ± 3.1 years) were included. Metabolic acidosis was observed in all patients (39.0% mild, 53.7% moderate, 7.3% severe). Patients with moderate-to-severe acidosis had significantly lower BMI Z-scores and younger ages at diagnosis compared with those with mild acidosis. In multivariable analysis, cumulative acetazolamide dose remained independently associated with moderate/severe metabolic acidosis (OR 1.30, 95% CI 1.00-1.69; p = 0.049). BMD was assessed in 35 patients after a median acetazolamide exposure of 14 months and mildly reduced/low BMD was detected in 22.9%. Higher cumulative acetazolamide exposure and lower minimum bicarbonate levels were associated with mildly reduced/low BMD in univariable analyses; however, these associations did not remain significant after multivariable adjustment. Although estimated glomerular filtration rate declined modestly from baseline to the last visit, this change was not associated with acidosis severity, treatment duration, or cumulative acetazolamide dose. Metabolic acidosis is highly prevalent among children receiving acetazolamide for IIH, and greater cumulative acetazolamide exposure appears to be associated with more severe acidosis. Lower bicarbonate levels and higher cumulative acetazolamide exposure were associated with mildly reduced/low BMD in univariable analyses; however, these associations did not remain significant after multivariable adjustment. The limited number of patients undergoing BMD assessment, the relatively short exposure duration in some patients, and the absence of baseline BMD measurements limit definitive conclusions regarding the skeletal effects of acetazolamide.
2026-06-15 | CGRP-provoked headache is associated with a neuroimmune signature in idiopathic intracranial hypertension.
Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure and disabling headaches, yet its underlying mechanisms remain poorly defined. Calcitonin gene-related peptide (CGRP) is a key neuropeptide implicated in migraine and headache attributed to IIH. CGRP-driven neuroinflammation is implicated in migraine generation but whether CGRP-provoked headache in IIH is accompanied by dynamic neuroimmune activation during the ictal phase remains unknown. We aimed to characterise cytokine alterations during experimentally-induced IIH headache attacks provoked by CGRP. In a randomised, double-blind, placebo-controlled, two-way crossover study (IIH Provoke: ISRCTN13251508), 16 women with IIH underwent two inpatient visits receiving intravenous CGRP (1.5 µg/min for 20 min) or placebo (isotonic saline). Blood samples were collected at baseline and either at peak headache or at the end of the visit, if no headache occurred. Plasma cytokines were measured using the Olink® Target 48 Cytokine Panel. CGRP induced a typical IIH headache attack within the sampling period in 7/16 participants. Compared with baseline, eight cytokines were significantly elevated during CGRP-provoked headache attacks: C-C motif chemokine 4 (CCL4), CCL8, interleukin-6 (IL-6), IL-17C, IL-27, oncostatin M (OSM), hepatocyte growth factor (HGF), and transforming growth factor-α (TGF-α) (P < 0.05). These changes were not observed after placebo or in participants who received CGRP without developing headache. CGRP-provoked IIH headache attacks were associated with elevations in pro-nociceptive mediators (IL-6, CCL4, OSM) and immune-related cytokines (IL-17C, IL-27, HGF, TGF-α). These findings suggest that CGRP-provoked headache in IIH is associated with changes in circulating cytokines consistent with a neuroimmune response during the ictal phase. Larger cohorts are required to validate these observations and explore neuroinflammation as a therapeutic target in IIH headache.
cell therapies
2026-08-04 | Cerebrospinal fluid shunting or dural venous sinus stenting to preserve vision in idiopathic intracranial hypertension (IIH Intervention): protocol for an open-label, multicentre, randomised controlled phase IIb trial.
Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and typically affects young women with obesity. Patients are at risk of permanent visual loss due to papilloedema. Some require emergency intervention to rapidly reduce papilloedema and preserve vision. The international standard of care for patients with sight-threatening IIH is cerebrospinal fluid (CSF) shunting. However, dural venous sinus stenting (DVSS) is an emerging procedure that is offered at many neuroscience centres internationally as the primary intervention. Currently, there are no randomised controlled trial data supporting the efficacy of any interventional approach for preserving vision in sight-threatening IIH. IIH Intervention is a UK-based two-arm, open-label, multicentre, randomised controlled phase IIb clinical trial with integrated health economic evaluation to compare CSF shunting with DVSS in patients who have confirmed IIH and are at risk of permanent visual loss due to severe papilloedema. The primary outcome is the global thickness of the peripapillary retinal nerve fibre layer (RNFL), an indicator of papilloedema, measured by optical coherence tomography (OCT) over a 6-month period. Secondary outcomes are global thickness of the RNFL over 12 and 24 months, as well as macular ganglion cell layer volume, perimetric mean deviation, headache outcomes, intervention reporting measures (including complications and revisions) and patient-reported outcomes over 6, 12 and 24 months. The protocol was approved initially on 12 December 2022 by West Midlands-South Birmingham Research Ethics Committee (ref: 22/WM/0230). Participants will be required to provide written informed consent. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. ISRCTN57142415.
2026-07-21 | Venous Sinus Stenting for Pulsatile Tinnitus: A Systematic Review and Meta-Analysis.
Pulsatile tinnitus (PT) is frequently caused by venous sinus stenosis and may be associated with idiopathic intracranial hypertension (IIH). Venous sinus stenting (VSS) directly addresses venous outflow obstruction and has emerged as a therapeutic option; however, outcome data remain heterogeneous. We performed an updated systematic review and meta-analysis to evaluate the efficacy and durability of VSS for PT and to compare outcomes between IIH-associated and isolated PT. MEDLINE, Scopus, and Web of Science were searched from inception through December 2025 following PRISMA guidelines. Clinical studies reporting PT outcomes after VSS were included. Random-effects meta-analyses of proportions were conducted to estimate pooled rates of overall improvement, complete resolution, and recurrence. Prespecified subgroup analyses compared IIH versus isolated PT. Thirty-two studies comprising 850 patients were included (641 with IIH; 209 with isolated PT). Venous sinus stenosis accounted for 90.3% of treated etiologies. The pooled rate of overall PT improvement was 89.8% (95% CI, 85.5-92.9). Complete resolution occurred in 87.1% (95% CI, 82.5-90.6). Recurrence at last follow-up was 10.9% (95% CI, 8.3-14.2). Improvement and complete resolution rates did not differ significantly between IIH and isolated PT. Recurrence was higher in IIH (12.0%) than in isolated PT (5.7%), without reaching statistical significance. VSS is associated with high rates of PT improvement and complete resolution with low recurrence. Recurrence trends appear higher in IIH, suggesting underlying pathophysiology may influence durability.
2026-06-27 | Endovascular treatment of tumor-related dural sinus stenosis, venous outflow obstruction, and secondary intracranial hypertension: a systematic review of the literature.
Tumors involving dural venous sinuses can lead to venous outflow obstruction and secondary intracranial hypertension. While surgical resection can decompress the sinus, such procedures carry significant risks. With the success of endovascular interventions for idiopathic intracranial hypertension (IIH), venous sinus stenting (VSS) and angioplasty have emerged as potential treatments for tumor-related sinus stenosis. However, evidence remains limited and dispersed. This systematic review aimed to synthesize the available literature on the safety and efficacy of endovascular treatment for tumor-related venous sinus obstruction. A systematic search of PubMed, Embase, and Web of Science was conducted from database inception to November 2025. Eligible studies included any report describing endovascular treatment (VSS and/or angioplasty) for tumor-related venous sinus obstruction, whether due to tumor invasion or compression, or even stenosis following surgery or radiotherapy. Data on patient demographics, tumor characteristics, procedural details, and outcomes were extracted and summarized descriptively. Twenty studies comprising 57 patients were included. Most patients were female (65%) with a mean age of 48 years. Meningioma represented the most common underlying tumor (75%). The majority of obstructions resulted from tumor compression or invasion (86%), and most patients underwent VSS alone (74%), while the rest underwent VSS and angioplasty (23%). No periprocedural complications were reported. Mean trans-stenotic pressure gradient decreased by 10 ± 9 mmHg post-treatment and mean lumbar opening pressure decreased by 11 ± 12 cmH2O. Clinical improvement was reported in 63% of patients, including resolution or improvement of papilledema in 94% and vision changes in 94%. Repeat intervention was required in 28% of cases, and only about half of patients achieved further improvement after reintervention. Endovascular therapy for tumor-related venous sinus stenosis appears safe and effective, leading to meaningful pressure reduction and symptomatic improvement in two-thirds of patients. These findings support VSS as a viable adjunct or alternative to surgery in selected patients. Nonetheless, the certainty of evidence remains very low, and current data cannot establish definitive conclusions.
2026-06-24 | Slit ventricles in idiopathic intracranial hypertension appear to expand after venous sinus stenting: a volumetric analysis.
Venous congestion is associated with tissue swelling in multiple organ systems. In idiopathic intracranial hypertension (IIH), its effects on brain parenchyma are less well defined, but may contribute to slit ventricles through increased parenchymal volume. We therefore analyzed ventricular volumes before and after venous sinus stenting (VSS). Semi-automated ventricular segmentation was performed using 3D Slicer (image analysis and scientific visualization software) on pre- and post-VSS volumetric MRI or CT scans from patients with IIH at a single center (2022-2025). The primary objective was to quantify change in total ventricular volume. Secondary objectives were to assess compartmental changes, predictors of ventricular volume change, and associations between volumetric data and clinical outcomes. 25 patients were included. Median time to post-stent imaging was 6.7 months (IQR 4.7-7.0). Median total ventricular volume increased from 10.96 mL (IQR 8.91-19.21) to 12.8 mL (IQR 9.72-20.32) (+16.8%, P=0.024), driven predominantly by increased lateral ventricular volume (+12.3%, P=0.021). Third and fourth ventricular volumes did not change significantly. No predictors of volume change were identified. Lower baseline ventricular volume was associated with higher odds of a favorable clinical outcome following VSS (OR 1.14, 95% CI 1.01 to 1.32, P=0.047). There is a small but consistent increase in ventricular volume following VSS, driven by expansion of the lateral ventricles. Greater benefit from stenting was observed in patients with lower baseline ventricular volumes. These findings suggest cerebral venous congestion may contribute to slit ventricles in IIH, and that improved venous drainage may permit re-expansion of cerebrospinal fluid spaces.
2026-06-02 | Idiopathic intracranial hypertension presenting with obsessive thoughts: a rare neuropsychiatric manifestation "case report".
Idiopathic intracranial hypertension (IIH) classically presents with headache, papilledema, and visual disturbances. Psychiatric manifestations are rare and may obscure a timely diagnosis. A 23-year-old obese female with no prior psychiatric history presented with new-onset intrusive thoughts and compulsive finger-tapping rituals, leading to a diagnosis of obsessive-compulsive disorder (OCD). Despite treatment with high-dose SSRIs, antipsychotic augmentation, and cognitive-behavioural therapy for six months, she showed no improvement. She concurrently reported a refractory bitemporal headache, tinnitus, and transient visual obscurations. Examination revealed bilateral papilledema. MRI/MRV showed features of raised intracranial pressure (ICP) associated with right transverse sinus stenosis. Lumbar puncture (LP) confirmed an elevated opening pressure of 30 cm H₂O. Despite treatment with acetazolamide (2 g/day), she remained symptomatic. Venous sinus stenting was subsequently performed, restoing sinus caliber and reducing the pressure gradient. Within three months, her headache improved markedly, and her papilledema resolved. Remarkably, her obsessive thoughts and compulsive acts completely disappeared without psychiatric medication, with her Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score dropping from 20 to 5. This case illustrates IIH presenting with predominant psychiatric manifestations mimicking primary OCD. The dramatic resolution of compulsive symptoms following intracranial pressure normalization suggests a possible association between IIH and obsessive thoughts. Clinicians should maintain a high index of suspicion for IIH in atypical psychiatric presentations accompanied by headache, tinnitus, or visual symptoms; in such cases, routine fundoscopy is essential.
proteins
2024-09-02 | Nasal turbinate lymphatic obstruction: a proposed new paradigm in the etiology of essential hypertension.
Hypertension affects an estimated 1.3 billion people worldwide and is considered the number one contributor to mortality via stroke, heart failure, renal failure, and dementia. Although the physiologic mechanisms leading to the development of essential hypertension are poorly understood, the regulation of cerebral perfusion has been proposed as a primary cause. This article proposes a novel etiology for essential hypertension. Our hypothesis developed from a review of nuclear medicine scans, where the authors observed a significantly abnormal increase in nasal turbinate vasodilation in hypertensive patients using quantitative region of interest analysis. The authors propose that nasal turbinate vasodilation and resultant blood pooling obstruct the flow of cerebrospinal fluid passing through nasal turbinate lymphatics, thereby increasing intracranial pressure. The authors discuss the glymphatic/lymphatic clearance system which is impaired with age, and at which time hypertension also develops. The increased intracranial pressure leads to compensatory hypertension via Cushing's mechanism, i.e., the selfish brain hypothesis. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs simultaneously along with the well-established increased sympathetic activity of the cardiovascular system. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of processed food. This hypothesis explains the rapid worldwide rise in essential hypertension in the last 50 years and offers a novel mechanism and a new paradigm for the etiology of essential hypertension. This new paradigm offers compelling evidence for the modulation of parasympathetic nervous system activity as a novel treatment strategy, specifically targeting nasal turbinate regulation, to treat diseases such as hypertension, idiopathic intracranial hypertension, and degenerative brain diseases. The proposed mechanism of essential hypertension presented in this paper is a working hypothesis and confirmatory studies will be needed.
2024-08-05 | Idiopathic Intracranial Hypertension as a Differential Diagnosis in Persistent Idiopathic Facial Pain: A Case Report.
Persistent idiopathic facial pain (PIFP), previously known as atypical facial pain (ATFP), is a chronic pain disorder with the characteristic of persistent, undulating pain in the face or the teeth without a known cause or any structural correlation. Women are more commonly affected than men. We report a case of a 38-year-old married female patient with a history of Crohn's disease who presented to the oral and maxillofacial surgery (OMFS) clinic with chronic dull bilateral facial pain and headache mainly affecting the right side of the face and neck without a known cause. She was initially diagnosed with PIFP due to a badly decayed right wisdom tooth. Wisdom teeth were extracted secondary to vague complaints of discomfort due to wisdom teeth; however, no significant improvement was noticed. Further investigations were carried out with new CT scans and magnetic resonance venography (MRV), which revealed evidence of having idiopathic intracranial hypertension (IIH), described as increased intracranial pressure with facial pain, headache, tinnitus, and papilledema. The patient was referred to neurology and received appropriate treatment. She began her treatment with topiramate, then transitioned to acetazolamide, underwent bilateral botulinum toxin (botox) injections into the temporal region, and underwent regular follow-up. The patient was significantly improved. Idiopathic intracranial hypertension must be ruled out in cases of PIFP that do not respond to ordinary treatment measures.
2023-10-10 | Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency.
The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF)-binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe 5-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 μg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). Treatment with rhIGF-1 was started in 10.4-year- (P3) and 14.5-year (P2)-old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; height velocity increased (3.0 cm/year at baseline; 5.0-7.6 cm/year thereafter) as did height SDS (+0.6). P3's pubertal onset was at 12.4 year. BMD height-adjusted Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-h glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-h glucose: 152 mg/dL) developed during puberty. Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPP-A2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.
2019-09-19 | The Role of Onabotulinum Toxin Type A in the Management of Chronic Non-migraine Headaches
Objectives: FDA has approved Onabotulinum toxin type A (BoNTA) for prophylactic treatment of chronic migraines. Recent studies have explored its potential new indications, like treating post-traumatic headaches. Patients and Methods: This is a retrospective chart review of 717 patients, who had failed at least two prophylactic treatments and received BoNTA injections at University of Missouri Hospital from July 2014 to June 2017. Patient demographics, headache type, associated symptoms, prophylaxes tried were reported. Patient's pain severity (numeric pain scale) and frequency (number of headache days/month) pretreatment, at 6 months, and at 12 months were collected. Results: For a single headache type, post-traumatic headaches showed reduction in headache pain severity at 6 months (2.9 ± 0.7) compared to pre-treatment (7 ± 0.7). Headache frequency for post-traumatic headaches was also reduced at 6 months (10.6 ± 2.3) and 12 months (5.1 ± 1.2) compared to pre-treatment (25 ± 1.8). For pseudotumor cerebri headaches, pain severity at pretreatment was 6.4 ± 0.6 compared to 2 ± 0.8 at 6 months, and headache days reduced at 6 months (9.8 ± 2.5) and 12 months (6 ± 4) compared to pretreatment (26 ± 2.9). Opioid use reduced by 67 ± 55.4 at 6 months and 133.3 ± 106.6 at 12 months in morphine equivalent units. Conclusions: Onabotulinum toxin type A is effective in treating multiple types of chronic non-migraine headaches.
1997-10-23 | Possible regulation of intracranial pressure by human atrial natriuretic peptide in cerebrospinal fluid.
To clarify the function of human atrial natriuretic peptide (hANP) in the cerebrospinal fluid (CSF), we examined hANP levels in the CSF of patients with various neurological diseases. The subjects were 16 controls without neurological disease and 45 patients with neurological disease. The 45 patients with neurological disease were divided into a group of 15 patients with intracranial hypertension (IH) and a group of 30 patients with normal pressure (NP). hANP in both CSF (1-hANP) and serum (s-hANP) was measured by RIA. Patients with IH were followed up. We analyzed correlations between 1-hANP and other parameters of CSF. Increase in concentration of 1-hANP was positively correlated with intracranial pressure (ICP; r = 0.72; p < 0.01), but not with other CSF parameters or with s-hANP. The concentration of 1-hANP appeared to be increased especially over a threshold value of ICP. In a followup study of patients with IH, changes in 1-hANP paralleled changes in ICP in every case (r = 0.79; p < 0.01). Our findings strongly suggest that 1-hANP plays an important role in the regulation of ICP in humans.
antibodies
2025-09-22 | Concurrent Presentation of C3 Glomerulopathy and Benign Intracranial Hypertension in a Young Woman: A Case Report
Background: C3 glomerulopathy (C3G) is a rare complement-mediated glomerular disease characterized by dysregulation of the alternative complement pathway, leading to C3-dominant glomerular deposits and variable renal manifestations. Benign intracranial hypertension (BIH), or idiopathic intracranial hypertension, presents with increased intracranial pressure in the absence of structural lesions. While BIH has been reported in association with immune-complex glomerulonephritis, its co-occurrence with C3G has not been previously described. Case presentation. We report the case of a 25-year-old Asian woman presenting with a two-week history of progressive occipital headache, vomiting, and subsequent diplopia and blurred vision. Examination revealed bilateral papilledema and sixth nerve palsy. MRI findings and elevated lumbar puncture opening pressure (>25 cm H₂O) confirmed BIH, and acetazolamide was initiated with gradual improvement in symptoms. Routine investigations revealed renal dysfunction, non-nephrotic proteinuria, thrombocytopenia, and low C3 with normal C4. Renal biopsy demonstrated crescentic mesangioproliferative glomerulonephritis with C3-dominant deposits on immunofluorescence, confirmed by electron microscopy. Complement analysis showed reduced factor H levels. She was treated with prednisolone, mycophenolate mofetil, and a renin-angiotensin system blocker, with partial improvement in renal and neurological status. Genetic testing revealed a CFH variant of uncertain significance. Given her partial response and evidence of complement dysregulation, eculizumab is planned if no further improvement is observed. Conclusions: This is, to our knowledge, the first reported case of concurrent C3G and BIH. The coexistence of these conditions suggests a potential shared immunopathogenic pathway involving alternative complement pathway dysregulation, with possible effects on both renal and central nervous system vasculature. This case highlights the importance of considering intracranial hypertension in patients with C3G presenting with visual symptoms or headache and supports further research into complement-mediated mechanisms linking renal and neurological disease.
2025-06-03 | Treatment of Persistent Headache After Normalization of CSF Pressure.
Headache is the most common symptom of intracranial hypertension and hypotension and may not remit after normalization of intracranial pressure. This article reviews the clinical presentation, mechanism, differential diagnosis, treatment, prognosis, and monitoring of persistent headache after normalization of intracranial pressure in the setting of idiopathic intracranial hypertension and spontaneous intracranial hypotension. Erenumab, a monoclonal antibody to the calcitonin gene-related peptide receptor, was shown to reduce headache frequency in the first-ever prospective study of headache treatment in patients with idiopathic intracranial hypertension in ocular remission. Similar avenues remain to be explored for spontaneous intracranial hypotension even though it has been shown that some patients continue with headache despite radiographic resolution of CSF leaks. Headache is the most common symptom to herald an intracranial pressure disturbance and may not resolve despite normalization of pressure. Neurologists must be aware that persistent headache does not automatically imply abnormal intracranial pressure in patients with previous disorders of CSF dynamics and informed of the possible alternative headache etiologies in these populations.
2025-04-30 | Calcitonin gene-related peptide in newly diagnosed idiopathic intracranial hypertension: a prospective, cross-sectional, case-control study of cerebrospinal fluid and plasma.
Calcitonin Gene-Related Peptide (CGRP) is involved in migraine pain signaling, and blockage hereof is effective in migraine treatment. Headache in idiopathic intracranial hypertension (IIH) is often migraine-like but the underlying mechanisms are not understood. We report levels of CGRP in plasma and cerebrospinal fluid (CSF) of patients with newly diagnosed IIH to elucidate CGRP involvement in the pathogenesis of headache in IIH. We consecutively enrolled patients suspected of having IIH in a prospective cohort at two Danish tertiary headache centers. Patients are confirmed to have IIH or disproven of it (non-IIH). We included non-IIH with primary headache disorders as headache controls to IIH cases. We also recruited sex-, age- and BMI-matched healthy controls (HC). All participants had CSF and blood drawn and CGRP was analyzed using a validated radioimmunoassay. CSF plasma-ratios were calculated. Between-group levels were compared with ANOVA or Kruskal-Walli's test. In sub-analyses we restricted comparison of HC to non-IIH/IIH with chronic migraine; we also compared IIH with versus without headache. We correlated CGRP to lumbar opening pressure (OP), and BMI, and assessed the correlation between CGRP in plasma and CSF. Generalized or linear regression was applied to adjust for confounding by BMI, age, and active smoking. Comparing 97 patients with IIH, 52 non-IIH, and 37 HC, we found no between-group differences in CGRP levels in plasma (p = 0.78), CSF (p = 0.79), or in CSF:plasma-ratio (p = 0.13). Adjusting for BMI, age, and smoking yielded similar results. CGRP levels were neither associated with having a migraine phenotype or chronic headache, nor with having any headache versus no headache in IIH. CGRP in plasma correlated with CGRP in CSF (p < 0.0001). CGRP did not correlate with OP or BMI. CGRP levels in plasma and CSF and their ratios were comparable in IIH, non-IIH patients with headache, and sex-, age-, and BMI-matched HC. CGRP in plasma correlated with CGRP in CSF. Due to methodology, we probably measured basal resting CGRP. The role of CGRP in IIH-headache needs further clarification. A headache preventive effect in IIH of anti-CGRP targeted therapy remains a relevant unexplored area.
2024-03-01 | Migraine, idiopathic intracranial hypertension, and calcitonin gene‐related peptide antibodies
Plain language summary Idiopathic intracranial hypertension (IIH) is a condition of high pressure in the spinal fluid that is common in young women who are overweight or obese. Headache happens in most individuals with IIH and can continue after the early phase of IIH has resolved. We studied the use of a newer type of medication developed for migraine called calcitonin gene‐related peptide antibodies and we found that these medications can be helpful for patients who have had IIH, although studies with more patients will be helpful.
2023-06-28 | High CCL2 Levels Detected in CSF of Patients with Pediatric Pseudotumor Cerebri Syndrome
Pseudotumor cerebri (PTC) is a disorder characterized by increased intracranial pressure in the absence of a structural lesion or other identifiable cause. Cytokines, which are involved in the regulation of immune responses and inflammation, have been implicated in the pathogenesis of PTC. In a prospective, cross-sectional study at three centers in Israel, we analyzed cerebrospinal fluid (CSF) samples from 60 children aged 0.5-18 years, including 43 children with a definitive diagnosis of PTC and a control group of 17 children. Levels of IL-4, IL-10, IL-17, CCL2, CCL7, CCL8, CCL13, BDNF, and IFN-γ were measured using ELISA kits. Levels of CCL2 were significantly higher in the PTC group compared to the control group (p < 0.05), with no other significant differences in the measured cytokines between the two groups. The groups did not differ significantly in clinical presentation, imaging, treatment, or ophthalmic findings. Our findings provide preliminary evidence that CCL2 may be involved in the pathogenesis of PTC and may serve a potential target for therapy in PTC.
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Drug Discovery Landscape
4 orphan drug designations for Idiopathic intracranial hypertension.
4 orphan drug designations for Idiopathic intracranial hypertension.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Octreotide acetate | small molecules | EMA | 2021-12-10 | — | Granzer Regulatory Consulting & Services GmbH |
Octreotide Acetate | peptides | FDA | 2021-07-19 | — | NBO Pharma LLC |
exenatide | peptides | FDA | 2017-05-16 | — | Boyd Consultants Ltd |
Exenatide | peptides | EMA | 2016-03-21 | — | Boyd Consultants Limited |
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