Diagnostic and Prognostic Biomarkers of Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, primarily affecting overweight females of childbearing age. Typically, patients experience headache and visual symptoms due to increased intracranial pressure (ICP) and papilledema. The diagnosis is difficult, and outcomes vary from no sequelae to blindness or chronic headaches. No clear prognostic indicators exist. Treatment consists of medication, weight loss, and possibly surgical intervention.There is an unmet need of defining biomarkers with prognostic or diagnostic value and defining predictors of a poor outcome.

This project is a prospective, population-based cohort study including clinical data and a biobank (blood samples and cerebrospinal fluid).

The investigator's primary aim is to identify biomarkers of diagnostic or prognostic value and to create a clinical IIH database. The clinical database will answer questions about patient characteristics at baseline and during follow-up, identify predictors of outcome, and help create a standardized programme for follow-up and

Study Overview

• Status: Recruiting
• Conditions: Benign Intracranial Hypertension
• Intervention / Treatment: Other: Standard treatment

Detailed Description

This study is a multicenter, prospective, population-based cohort study with consecutive inclusion of patients in which the diagnosis of IIH is suspected. This study is carried out in collaboration between the Danish Headache Center, Rigshospitalet-Glostrup, and the Neurological Department at Odense University Hospital.

Patients are eligible for inclusion into the study if:

1. IIH is suspected
2. > 18 years old and able to provide written informed consent.

At baseline included patients will have:

A.) Medical history B.) Neurological, ophthalmological and general medical examination C.) Relevant neuro-imaging D.) Blood samples and lumbar puncture F.) Evaluation by other specialist, including neuro-psychologists, if appropriate.

Subsequently patients are divided into three sub-groups according to revised Friedmann criteria:

1. Certain IIH or IIH-WOP
2. Suspected, but unconfirmed, IIH
3. IIH ruled out

Patients are followed at a headache center and by neuro-ophthalmologist according to standard clinical practice.

• Study Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Johanne Severinsen, M.D.; Phone Number: 004538633553; Email: johanne.juhl.severinsen@regionh.dk

Study Locations

• Denmark
  • Glostrup
    • Copenhagen, Glostrup, Denmark, 2600
      • Recruiting
      • The Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup
      • Contact: Johanne Severinsen, M.D.; Email: johanne.juhl.severinsen@regionh.dk
  • Region Syddanmark
    • Odense, Region Syddanmark, Denmark, 5000
      • Recruiting
      • Odense University Hospital, Department of Neurology
      • Contact: Dagmar Beier, M.D., Ph.D.; Email: dagmar.beier@rsyd.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All admitted or out-patient referrals where IIH is suspected. Patients will be identified and included consecutively once there is a clinical suspicion of IIH, if they wish to participate. Most often IIH will be suspected in a typical patient (female, child-bearing age, overweight) with either bilateral papiledema and normal neuro-imaging, high ICP by lumbar puncture or a new headache with associated visual disturbances or pulsatile tinnitus.

All hospitals in the Capital Region of Denmark and the Southern Region of Denmark can participate and refer patients.

Description

Inclusion Criteria:

1. Able to and willing to provide informed consent
2. More than 18 years of age
3. Suspicion of IIH (based on clinical evaluation by neurologist or opthalmologist)

Exclusion Criteria:

1.) Unable to consent (e.g. language, mental retardation).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Certain IIH or IIH-WOP; According to revised diagnostic criteria, Friedmann, 2013.	Other: Standard treatment; No intervention, some patients have additional neuro-psychological testing.
Suspected IIH; IIH is suspected, does not fulfill diagnostic criteria.	Other: Standard treatment; No intervention, some patients have additional neuro-psychological testing.
IIH ruled out; Patients in whom another diagnosis is made.	Other: Standard treatment; No intervention, some patients have additional neuro-psychological testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of IIH (diagnostic and prognostic)	Analyses of CSF and blood for protein-markers (method: Proteomics)	2 years
Visual status at conclusion of study	Assessment of visual fields	2 years
Visual status at conclusion of study	Assessment of OCT	2 years
Visual status at conclusion of study	Assessment of visual acuity	2 years
Headache status at conclusion of study	Prevalence of chronic headache (>=15 headache days per month)	2 years
Biomarkers of IIH (diagnostic and prognostic)	Analyses of CSF and blood for markers of metabolism (method: Metabolomics)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline characteristics related to poor outcome	Poor outcome is defined as either a.) Persistent visual field defects, decreased visual acuity after 12 months and or b.) Headache >= 15 days per month after 12 months	1 year
Results of neuropsychological evaluations	Standard neuro-psychological tests	1 year
Treatment and follow-up	Length and type of treatment and follow-up	3 years
Baseline characteristics related to IIH diagnosis	Evaluation of disease presentation in the different sub-groups focusing on headache phenotype, visual disturbances and pulsatile tinnitus.	2 years
Weight change in a standard care program	Unit of measurement is BMI	2 years
Diagnostic criteria and their use in the clinical setting	Revised Friedmann criteria of 2013	2 years
Clinical markers related to disease activity	Clinical markers of relevance: Headache phenotype, pulsatile tinnitus, visual disturbances, weight changes.	2 years
Development of IIH or IIHWOP in patients with borderline elevated ICP not fulfilling diagnostic criteria at baseline	ICP is measured by lumbar puncture, borderline elevated ICP is considered >20-30 mmH2O	2 years

Collaborators and Investigators

• Sponsor: Danish Headache Center
• Collaborators: Odense University Hospital
• Investigators: Study Director: Rigmor Jensen, M.D., Dr.Med., The Danish Headache Center, Rigshospitalet-Glostrup; Study Director: Dagmar Beier, M.D., Ph.D., Odense University Hospital

Publications and helpful links

General Publications

• Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658. No abstract available.
• Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana. Arch Neurol. 1988 Aug;45(8):875-7. doi: 10.1001/archneur.1988.00520320065016.
• Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, McDermott MP; NORDIC Idiopathic Intracranial Hypertension Study Group. The idiopathic intracranial hypertension treatment trial: clinical profile at baseline. JAMA Neurol. 2014 Jun;71(6):693-701. doi: 10.1001/jamaneurol.2014.133.
• Yri HM, Jensen RH. Idiopathic intracranial hypertension: Clinical nosography and field-testing of the ICHD diagnostic criteria. A case-control study. Cephalalgia. 2015 Jun;35(7):553-62. doi: 10.1177/0333102414550109. Epub 2014 Sep 16.
• Yri HM, Ronnback C, Wegener M, Hamann S, Jensen RH. The course of headache in idiopathic intracranial hypertension: a 12-month prospective follow-up study. Eur J Neurol. 2014 Dec;21(12):1458-64. doi: 10.1111/ene.12512. Epub 2014 Jul 29.
• Yri HM, Fagerlund B, Forchhammer HB, Jensen RH. Cognitive function in idiopathic intracranial hypertension: a prospective case-control study. BMJ Open. 2014 Apr 8;4(4):e004376. doi: 10.1136/bmjopen-2013-004376.
• Digre KB, Nakamoto BK, Warner JE, Langeberg WJ, Baggaley SK, Katz BJ. A comparison of idiopathic intracranial hypertension with and without papilledema. Headache. 2009 Feb;49(2):185-93. doi: 10.1111/j.1526-4610.2008.01324.x.
• Peng KP, Fuh JL, Wang SJ. High-pressure headaches: idiopathic intracranial hypertension and its mimics. Nat Rev Neurol. 2012 Dec;8(12):700-10. doi: 10.1038/nrneurol.2012.223. Epub 2012 Nov 20.
• Nielsen HH, Beck HC, Kristensen LP, Burton M, Csepany T, Simo M, Dioszeghy P, Sejbaek T, Grebing M, Heegaard NH, Illes Z. The Urine Proteome Profile Is Different in Neuromyelitis Optica Compared to Multiple Sclerosis: A Clinical Proteome Study. PLoS One. 2015 Oct 13;10(10):e0139659. doi: 10.1371/journal.pone.0139659. eCollection 2015.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2018
• Primary Completion (Anticipated): May 31, 2027
• Study Completion (Anticipated): May 31, 2027

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: July 23, 2019
• First Posted (Actual): July 25, 2019

Study Record Updates

• Last Update Posted (Estimate): March 7, 2023
• Last Update Submitted That Met QC Criteria: March 6, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypertension; Intracranial Hypertension; Pseudotumor Cerebri
• Other Study ID Numbers: S-20170058

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No