Volumetrics and Proteomics in Shunted Normal Pressure Hydrocephalus

NCT04785560 | Active Not Recruiting FDA Device

• 1 other identifier: 2020-00719
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

Idiopathic normal pressure hydrocephalus (=iNPH) is a condition with disturbed circulation of cerebrospinal fluid (=CSF) causing symptoms such as balance and gait disorders, urinary incontinence and cognitive impairment in patients with cerebral ventricular dilation. The exact incidence is unknown but has been estimated at about 8.9% of the population over the age of 80 and the incidence is estimated to increase with an aging population. The symptoms can be temporarily improved by draining cerebrospinal fluid and so-called shunting (surgery with diversion of cerebrospinal fluid from the brain to the abdominal cavity). The symptoms and pathophysiology of iNPH are poorly described as well as the protein distribution in cerebrospinal fluid (proteomics) of the disease. There is also a need for improved diagnostical and prognostical tools that can guide in patient selection for surgery. The radiological tools in evaluating the disease and it´s progression need to be improved. There is a shunt valve (Codman Certas Plus) used since 2015 that is widely used in clinical use and is well studied in research laboratories but little in clinical studies. The project aims to, before and after surgery, on patients with iNPH who will undergo investigation and shunting with Certas Plus at our department and in comparison with healthy controls: 1. Apply and evaluate a novel method to determine the volume of circulating CSF (volumetry). 2. Study the correlation between changes in volumetry and clinical outcome 3. Study NPH patients' distribution of proteins in cerebrospinal fluid and their change over time after shunting. 4. Evaluate the efficacy and functions of the Certas Plus valve. In this way, the investigators hope to find increased knowledge about the NPH disease and its pathophysiology as well as useful instruments that can both predict the probability for a patient to be improved by a shunt operation and determine if a shunt has stopped working and thus be able to avoid unnecessary risky operations.

Conditions

Hydrocephalus, Normal Pressure; Ventriculomegaly, Cerebral; Shunt; Complications; Hydrocephalus Acquired

Keywords

Hydrocephalus, Normal Pressure; Ventriculomegaly, Cerebral; Shunt; Complications; Hydrocephalus Acquired; Volumetry; Proteomics; Cerebrospinal Fluid; Ventriculoperitoneal shunt; Synthetic MRI

Outcome Measures

Primary Outcomes (9)

• Change in Idiopathic normal pressure hydrocephalus scale

  A validated, continuous, calibrated and norm-based scale for the grading of severity and assessment of treatment outcome in idiopathic normal pressure hydrocephalus (iNPH). Designed for the assessment of the four domains, gait, neuropsychology, balance and continence, using ordinal ratings and continuous measures. A value of 100 represents normal function and 0 the most severe level of dysfunction.

  Assessed within 3 months pre-operatively and 3 months post-operatively.

• Change from baseline CSF volume at 2 days postoperatively.

  Volume of the CSF contained 1. in the cerebral ventricular system. 2. Intracranially outside the cerebral ventricular system. Measured by means of Synthetic MRI. Baseline values are collected at the MRI-scan the day before surgery.

  Assessed on MRI scan 36-48 hours post-operatively.

• Change from baseline CSF volume at 3 months post-operatively.

  Volume of the CSF contained 1. in the cerebral ventricular system. 2. Intracranially outside the cerebral ventricular system. Measured by means of Synthetic MRI. Baseline values are collected at the MRI-scan the day before surgery.

  Assessed on MRI scan 3 months post-operatively

• Change from Baseline iNPH Radscale at 2 Days post-operatively.

  A radiological scale to standardize the evaluation of radiological morphological signs in iNPH. Ranging from 0 to 12, a high iNPH Radscale score combined with clinical symptoms should raise suspicion of iNPH. Baseline value is aquired at the MRI-scan the day before surgery.

  Assessed on MRI scan 36-48 hours post-operatively and 3. 3 months post-operatively

• Change from Baseline iNPH Radscale at 3 months post-operatively.

  A radiological scale to standardize the evaluation of radiological morphological signs in iNPH. Ranging from 0 to 12, a high iNPH Radscale score combined with clinical symptoms should raise suspicion of iNPH. Baseline value is aquired at the MRI-scan the day before surgery.

  Assessed on MRI scan 3 months post-operatively.

• Number of participants with shunt complications

  Complications are defined as adverse effects of shunt surgery such as misplacement, dislocation, obstruction, malfunction, post-operative bleeding (subdural hematoma) and shunt infection.

  From the day of surgery until 3 months post-operatively.

• Proteomic pattern of alpha-1B-glycoprotein in lumbar, ventricular CSF and blood plasma.

  The proteome is the entire set of proteins that is produced or modified by an organism or organ system. Proteomics generally refers to the large-scale experimental analysis of proteins and proteomes, in this case the iNPH disease specific pattern of proteins present in the above mentioned body fluids where the concentration of multiple proteins can be elevated or lowered compared with healthy subjects. More specifically we will study the concentration of alpha-1B-glycoprotein compared with healthy subjects, change of concentration compared to baseline at 3-, 12- and 36-months post-operatively.

  Assessed from intra-operative samples the day of surgery, 3-, 12- and 36-months post-operatively.

• Proteomic pattern of apolipoproteins A-1 & A-IV in lumbar, ventricular CSF and blood plasma.

  The proteome is the entire set of proteins that is produced or modified by an organism or organ system. Proteomics generally refers to the large-scale experimental analysis of proteins and proteomes, in this case the iNPH disease specific pattern of proteins present in the above mentioned body fluids where the concentration of multiple proteins can be elevated or lowered compared with healthy subjects. More specifically we will study the concentration of apolipoproteins A-1 \& A-IV compared with healthy subjects, change of concentration compared to baseline at 3-, 12- and 36-months post-operatively.

  Assessed from intra-operative samples the day of surgery, 3-, 12- and 36-months post-operatively.

• Proteomic pattern of alpha-1-antitrypsin in lumbar, ventricular CSF and blood plasma.

  The proteome is the entire set of proteins that is produced or modified by an organism or organ system. Proteomics generally refers to the large-scale experimental analysis of proteins and proteomes, in this case the iNPH disease specific pattern of proteins present in the above mentioned body fluids where the concentration of multiple proteins can be elevated or lowered compared with healthy subjects. More specifically we will study the concentration of alpha-1-antitrypsin compared with healthy subjects, change of concentration compared to baseline at 3-, 12- and 36-months post-operatively.

  Assessed from intra-operative samples the day of surgery, 3-, 12- and 36-months post-operatively.

Study Arms (2)

Shunt setting 4 (=110 mm H20)

ACTIVE COMPARATOR

Patients randomised to have the Certas Plus valve initial shunt setting post-operatively set to 4 (110 mm H20), our standard setting.

Device: Initial shunt setting post-operatively of the Certas Plus shunt valve.

Shunt setting 8 (=400 mm H20)

ACTIVE COMPARATOR

Patients randomised to have the Certas Plus valve initial shunt setting post-operatively set to 8 (400 mm H20 a k a virtual off), in practice a closed non-functional shunt.

Device: Initial shunt setting post-operatively of the Certas Plus shunt valve.

Interventions

Initial shunt setting post-operatively of the Certas Plus shunt valve. DEVICE

The setting/resistance of the Certas Plus Shunt valve implanted is set according to randomisation and is not changed until the first post-operative MRI is performed 36-48 hours after surgery.

Also known as: CODMAN CERTAS PLUS

Shunt setting 4 (=110 mm H20); Shunt setting 8 (=400 mm H20)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Must meet the clinical criteria for iNPH according to the International Guide lines of 2005
• Must undergo shunt implantation at the Dpt of Neurosurgery Linköping University Hospital.

You may not qualify if:

• Individuals not able to participate/cooperate in study tasks with regard to cognitive symptoms
• Individuals with claustrophobia that makes awake MRI examination impossible.
• Individuals with implants that make MRI examination impossible (for instance pacemaker, refers only to the MRI examinations included in the study).
• Patients with severe co-existing chronical neurological diseases (refers only to the proteomic examinations included in the study).
• FOR CONTROL GROUP VOLUNTEERS:
• Must undergo surgery under spinal anesthesia at the Dpt of Orthopaedics, Urology or Gynaecology at the University Hospital Linkoping.
• Must consider themselves neurologically healthy and have not undergone neurological disease.
• Individuals with claustrophobia that makes awake MRI examination impossible.
• Individuals with implants that make MRI examination impossible
• Individuals with malignant disease or oncological treatment for such disease.
• Individuals with neurological disorders detected after study MRI.

Sponsors & Collaborators

• University Hospital, Linkoeping: lead

Study Sites (1)

Neurosurgical department University Hospital Linköping

Linköping, 58185, Sweden

Location

Related Publications (23)

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• Marmarou A, Bergsneider M, Relkin N, Klinge P, Black PM. Development of guidelines for idiopathic normal-pressure hydrocephalus: introduction. Neurosurgery. 2005 Sep;57(3 Suppl):S1-3; discussion ii-v. doi: 10.1227/01.neu.0000168188.25559.0e.

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• Toma AK, Papadopoulos MC, Stapleton S, Kitchen ND, Watkins LD. Systematic review of the outcome of shunt surgery in idiopathic normal-pressure hydrocephalus. Acta Neurochir (Wien). 2013 Oct;155(10):1977-80. doi: 10.1007/s00701-013-1835-5. Epub 2013 Aug 23.

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• Shellock FG, Bedwinek A, Oliver-Allen M, Wilson SF. Assessment of MRI issues for a 3-T "immune" programmable CSF shunt valve. AJR Am J Roentgenol. 2011 Jul;197(1):202-7. doi: 10.2214/AJR.10.5915.

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• McConnell KA, Zou KH, Chabrerie AV, Bailey NO, Black PM. Decreases in ventricular volume correlate with decreases in ventricular pressure in idiopathic normal pressure hydrocephalus patients who experienced clinical improvement after implantation with adjustable valve shunts. Neurosurgery. 2004 Sep;55(3):582-92; discussion 592-3. doi: 10.1227/01.neu.0000134385.23401.01.

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• Virhammar J, Laurell K, Cesarini KG, Larsson EM. Increase in callosal angle and decrease in ventricular volume after shunt surgery in patients with idiopathic normal pressure hydrocephalus. J Neurosurg. 2019 Jan 1;130(1):130-135. doi: 10.3171/2017.8.JNS17547. Epub 2018 Feb 2.

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• Virhammar J, Warntjes M, Laurell K, Larsson EM. Quantitative MRI for Rapid and User-Independent Monitoring of Intracranial CSF Volume in Hydrocephalus. AJNR Am J Neuroradiol. 2016 May;37(5):797-801. doi: 10.3174/ajnr.A4627. Epub 2015 Dec 24.

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• Chen CPC, Huang YC, Chang CN, Chen JL, Hsu CC, Lin WY. Changes of cerebrospinal fluid protein concentrations and gait patterns in geriatric normal pressure hydrocephalus patients after ventriculoperitoneal shunting surgery. Exp Gerontol. 2018 Jun;106:109-115. doi: 10.1016/j.exger.2018.01.027. Epub 2018 Feb 2.

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• Hellstrom P, Klinge P, Tans J, Wikkelso C. A new scale for assessment of severity and outcome in iNPH. Acta Neurol Scand. 2012 Oct;126(4):229-37. doi: 10.1111/j.1600-0404.2012.01677.x. Epub 2012 May 16.

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• Scollato A, Terreni A, Caldini A, Salvadori B, Gallina P, Francese S, Mastrobuoni G, Pieraccini G, Moneti G, Bini L, Messeri G, Di Lorenzo N. CSF proteomic analysis in patients with normal pressure hydrocephalus selected for the shunt: CSF biomarkers of response to surgical treatment. Neurol Sci. 2010 Jun;31(3):283-91. doi: 10.1007/s10072-009-0181-0. Epub 2009 Nov 21.

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  PMID: 31141553 RESULT

MeSH Terms

Conditions

Hydrocephalus, Normal Pressure; Hydrocephalus

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Peter Zsigmond, MD, ass prof

  Assistant professor

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: January 18, 2021
• First Posted: March 8, 2021
• Study Start: March 8, 2021
• Primary Completion: July 1, 2025
• Study Completion: July 1, 2025
• Last Updated: April 3, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)