The Pathogenesis of Terson Syndrome and the Role of CSF Tau / Amyloid-ß 40 and 42 in Patients With Aneurysmatic Subarachnoid Hemorrhage

Prospective clinical study to investigate the pathogenesis of Terson syndrome and the prognostic value of the CSF-biomarkers tau-protein and amyloid-β 40 and 42 in patients with aneurysmatic subarachnoid hemorrhage. Our two hypotheses are as follows:

1. The incidence of Terson syndrome correlates with the initial intracranial opening pressure (measured with extra ventricular drain)
2. The CSF-biomarkers correlate with the outcome assessed at discharge, 3-, 6- and 12-months postictally using Glasgow-Outcome-Scale-Extended (GOSE) and Euro-Qol-5 as well as with complications related to aneurysmatic subarachnoid hemorrhage such as cerebral vasospasm, delayed cerebral ischemia and re-bleed.

Study Overview

• Status: Completed
• Conditions: Subarachnoid Hemorrhage; Terson Syndrome; CSF-proteines

Detailed Description

In this prospective clinical study the pathogenesis of Terson syndrome and the prognostic value of the CSF-biomarkers tau-proteine and amyloid-β 40 and 42 in patients with aneurysmatic subarachnoidal hemorrhage are investigated. Intracranial opening pressure will be measured in patients requiring CSF-diversion for acute hydrocephalus and correlated with the incidence of Terson syndrome tested by an opthalmologic exam (group A: Terson syndrome positive, group B: Terson syndrome negative). CSF samples from external ventricular drainages are obtained at day 0, 2 and 6 and concentration of tau-protein and amyloid-β 40 and 42 are determined and correlated to secondary outcome measures such as delayed cerebral ischemia, clinical vasospasm, re-bleed, necessity for surgical intervention secondary to raised intracranial pressure or CSF-diversion. Outcome in terms of Glasgow-Outcome-Scale-Extended and Euro-Qol-5 will be assessed at 3, 6 and 12 months.

CSF from patients undergoing diagnostic or therapeutic tapping of their internal ventricles for normal pressure hydrocephalus or shunt diagnostics serve as a reference for CSF-biomarkers concentration in healthy individuals.

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

Study Locations

• Switzerland
  • St. Gallen, Switzerland, 9007
    • Cantonal Hospital St. Gallen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with aneurysmatic subarachnoid hemorrhage requiring CSF-diversion and/or intracranial pressure monitoring

Description

Inclusion Criteria:

• older than 18 years
• diagnosis of subarachnoid hemorrhage secondary to an intracranial aneurysm
• aneurysmatic subarachnoid hemorrhage must be the principal diagnosis for hospitalization
• an intracranial aneurysm must be confirmed by imaging (Computed tomography, magnet resonance tomography or angiography)
• Patients requiring diagnostic/therapeutic tapping of their internal ventricles for CSF-diversion (shunt) for normal pressure hydrocephalus or shunt diagnostics serve as a control group
• informed consent

Exclusion Criteria:

• younger than 18 years
• other diagnosis such as traumatic or perimesencephalic subarachnoid hemorrhage without an intracranial aneurysm

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Subarachnoid hemorrhage with and without Terson syndrome; Patients with aneurysmatic subarachnoid hemorrhage with and without Terson syndrome

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracranial pressure (ICP) in mmH20	Initial ICP is measured in mmH20 after insertion of EVD with a riser tube or after insertion of an ICP-probe.	after insertion of EVD or ICP-probe (between day 0 and 3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of CSF-protein phospho-tau	Concentration of CSF-protein phospho-tau taken from EVD-CSF	Day 0, 2, 6
Concentration of CSF-protein amyloid-ß 40/42	Concentration of CSF-protein phospho-tau taken from EVD-CSF	Day 0, 2, 6
Delayed cerebral ischemia	For the duration of their hospital stay (which can be expected to be an average of 3 to 5 weeks for SAH patients), occurrence of delayed cerebral schema, diagnosed by CT or MRI, is noted (number of patients of cohort).	Daily for the duration of hospital stay, an expected average of 3 to 5 weeks
Clinically manifest vasospasm	For the duration of their hospital stay (which can be expected to be an average of 3 to 5 weeks for SAH patients), occurrence of clinically manifest vasospasm is noted (number of patients of cohort). Screening will be performed daily by transcranial doppler and confirmation of diagnosis done by CTA or angiography.	Daily for the duration of hospital stay, an expected average of 3 to 5 weeks
Re-bleed	For the duration of their hospital stay (which can be expected to be an average of 3 to 5 weeks for SAH patients), occurrence of an intracranial re-bleed, diagnosed by CT or MRI, is noted (number of patients of cohort).	Daily for the duration of hospital stay, an expected average of 3 to 5 weeks
Surgery for refractory ICP (decompressive hemicraniectomy)	For the duration of their hospital stay (which can be expected to be an average of 3 to 5 weeks for SAH patients), the need for surgery for refractory ICP (decompressive hemicraniectomy) is noted (number of patients of cohort). Indication for surgery is made by the treating staff consultant based on ICP, CPP and clinical status.	Daily for the duration of hospital stay, an expected average of 3 to 5 weeks
Necessity of CSF-shunt	For the duration of their hospital stay (which can be expected to be an average of 3 to 5 weeks for SAH patients), the need for permanent CSF-diversion is noted (number of patients of cohort). Indication for permanent CSF-diversion (usually a ventriculoperitoneal shunt) is made by the treating staff consultant based on radiographic and clinical signs of hydrocephalus secondary to SAH.	Daily for the duration of hospital stay, an expected average of 3 to 5 weeks
Opthalmologic exam	Occurrence of Terson syndrome is assessed by fundoscopy with chemically dilated pupils (number of patients of cohort). Intraocular pressure (mmHg) is measured.	Day 0 to 3; before discharge if initial exam negative

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glasgow-Outcome-Scale-Extended (GOSE)	Health outcome is assessed by the study physicians or a study nurse using the Glasgow-Outcome-Scale-Extended (GOSE) with the help of family members if necessary.	initial, 3, 6, 12 months after SAH
Life quality (Euro-Qol-5)	Life quality is assessed by the study physicians or a study nurse using the Euro-Qol-5 questionnaire with the help of family members if necessary.	initial, 3, 6, 12 months after SAH
Neuropsychological deficits	The Montreal Cognitive Assessment (MoCA) is performed at day 14 days. A neuropsychological assessment by a neuropsychologist will then be performed at 3 and 12 months after SAH and includes a combination of the following tests: Alertness (Testbatterie zur Aufmerksamkeitsprüfung, TAP 2.2), Go/Nogo (TAP 2.2), Geteilte Aufmerksamkeit (TAP 2.2), Deux Barrage (2002), Farbe-Wort-Interferenztest (FWIT, after J.R. Stroop, 1985), Regensburger Wortflüssigkeitstest (RWT (2000)), 5-Punkte-Test (HAMASCH, H5PT-R), Frontal Assessment Battery Bedside (FAB), Verbaler Lern- und Merkfähigkeitstest (VLMT), Rey Complex Figure Test (RCFT (1995)), Tiere-Wörter-Test of the test battery Consortium to Establish A Registry for Alzheimer (CERAD), Boston Naming Test (CERAD), Mini-Mental-Status-Examination (CERAD), Trail-Making-Test A (CERAD) and B (CERAD), S-Wörter-Test (CERAD), Apraxie-Prüfung (Goldenberg). Patients' cognitive status is graded as no (regular), or as minimal, moderate or severely disabled.	On day 14 and at 3 and 12 months

Collaborators and Investigators

• Sponsor: Holger Joswig
• Collaborators: Innogenetics N.V., Belgium

Publications and helpful links

General Publications

• Joswig H, Fournier JY, Hildebrandt G, Stienen MN. Sentinel Headache: A Warning Sign Preceding Every Fourth Aneurysmal Subarachnoid Hemorrhage. AJNR Am J Neuroradiol. 2015 Sep;36(9):E62-3. doi: 10.3174/ajnr.A4467. Epub 2015 Jul 16. No abstract available.

Helpful Links

• Study synopsis

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: April 27, 2014
• First Submitted That Met QC Criteria: April 29, 2014
• First Posted (Estimate): May 1, 2014

Study Record Updates

• Last Update Posted (Estimate): March 8, 2016
• Last Update Submitted That Met QC Criteria: March 7, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: subarachnoid hemorrhage; beta-amyloid; terson syndrome; CSF-proteines; phospho-tau
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Intracranial Hemorrhages; Syndrome; Hemorrhage; Subarachnoid Hemorrhage
• Other Study ID Numbers: ICPTS-Sma-2012