European Study on Prediction of Outcome in Patients With Idiopathic Normal Pressure Hydrocephalus
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Diagnostic
|Official Title:||European Multicenter Study on the Prediction of Outcome in Patients With Idiopathic Normal Pressure Hydrocephalus|
- Modified Rankin Scale [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- Neuropsychological measures (Stroop test, REy-auditory verbal learing test, PEG-BOARD TEST), Balance -score, Incontinence-score, Gait-score, Walking-score [ Time Frame: three and 12 months ] [ Designated as safety issue: No ]
- Balance -score [ Time Frame: three and 12 months ] [ Designated as safety issue: No ]
- Incontinence-score [ Time Frame: three and 12 months ] [ Designated as safety issue: No ]
- Gait-score [ Time Frame: three and 12 months ] [ Designated as safety issue: No ]
- Walking-score [ Time Frame: three and 12 months ] [ Designated as safety issue: No ]
|Study Start Date:||October 2004|
|Estimated Study Completion Date:||June 2009|
|Primary Completion Date:||March 2008 (Final data collection date for primary outcome measure)|
Procedure: Ventriculo-peritoneal Shunt
The selection of patients with idiopathic normal pressure hydrocephalus (INPH) for shunting remains difficult. The upcoming guidelines for the diagnosis and management of INPH state that there is no accepted standard for the clinical presentation, the results of imaging and the various tests that provide information on CSF dynamics 1. Hebb and Cusiamo could not find a single test that reliably predicts outcome after shunting in their systematic review of INPH 2. To properly evaluate the predictive value of diagnostic tests for the outcome of shunting all patients should receive a shunt irrespective of the test results. Only a few studies set up to examine the diagnostic reliability of tests of CSF dynamics fulfilled this condition. The common finding of these studies was that the predictive value of a positive test was high but the negative predictive values were disappointingly low.
In the Dutch Normal Pressure Hydrocephalus Study, containing 101 patients, the positive and negative predictive values of lumbar constant flow infusion were 92% and 34% for an Rout of 18 mmHg/ml/min and 100% and 27% for an Rout of 24 3. External lumbar CSF drainage for 4 days resulted in positive and negative predictive values of 87% and 36% 4. The predictive value of the cerebrospinal fluid tap test reported by Wikkelso et al in 1986 was 100% for a positive and 45% for a negative test 5 Another parameter of CSF dynamics is elastance that can be expressed by the pressure volume-index (PVI). In a group of 30 patients with NPH high elastance, i.e low PVI was the best predictor of a marked and rapid reduction of ventricular size after shunting 6.
One of the major issues is whether the false negative tests mostly occur in the same population. In these patients the INPH might be caused not so much by a CSF circulation disorder but by parenchymal disease. From our clinical experience we think that different patients have false negative tests, we frequently encounter cases with a positive tap test and a negative infusion test or the reverse. This is also shown in a study by Kahlon et al. who performed an infusion test and a tap test in 68 patients suspected of NPH. Both tests agreed in only 45% and they were both negative in 31% of patients 7.
An important drawback of all INPH studies so far is the rather limited number of patients and, the "mixing" of idiopathic NPH patients (primary NPH) with those of known cause (secondary NPH) such as trauma, subarachnoid hemorrhage and stroke.INPH is considered a multfactorial condition with a disturbance of CSF circulation as well as parenchymal abnormalities in a vulnerable population with much comorbidity. Because of the many outcome variables a study on the prediction of outcome needs large numbers of INPH patients. With a few exceptions, previous studies on CSF dynamics in INPH were conducted in single high quality institutions. We also have to demonstrate that the same or even better results can be obtained with international cooperation providing higher patients numbers. Therefore we intend to conduct a large European multicentre study on INPH including at least 200 patients. All these patients will receive the same shunt system and will be followed-up by a standardized protocol using primary and secondary NPH outcome measures. Because of the continuing controversy with respect to the appropriate shunt opening pressure and the many problems of over- and underdrainage after insertion of the shunt, we chose the Codman Hakim programmable valve 8.
To determine primarily the sensitivity, specificity, positive- and negative predictive value of resistance to outflow of CSF (Rout) and the CSF-Tap-Test for prediction of the effect of shunt surgery in patients with idiopathic NPH (INPH) by a prospective "blinded" confirmative study.
Secondarily the predictive value of elastance and CSF biochemical markers will be evaluated in the same population.
Further, the predictive value of other tests as rCBF and vascular reserve capacity (PET or SPECT), MR investigations (i.e. fMRI, MRS and/or diffusion tensor imaging etc.), continuous CSF drainage, B-wave analyses and other investigations can be evaluated by cooperation between individual centres.
General study design:
A prospective "blinded" confirmative study of at least 200 consecutively included patients with INPH fulfilling the clinical and radiological inclusion and exclusion criteria. Patients will be included during a period of 2 years by 20 or more centres that will enrol at least 5 patients per year each. All patients in the study will receive a ventriculo-peritoneal shunt, using the Codman Programmable valve.
After inclusion but prior to surgery 4 obligatory tests will be performed. We will measure the resistance to outflow of CSF (Rout) and the intracranial elastance, a CSF-Tap-Test will be carried out and CSF biochemical markers are determined. The caretakers are blinded for these results. Rout and the results of the tap test are the primary investigations.
Optional tests as rCBF and vascular reserve capacity (PET or SPECT), MR investigations (i.e. fMRI, MRS and/or diffusion tensor imaging ), continuous CSF drainage and B-wave analyses will also be performed prior to surgery. The number of patients included in a study of an optional test should be at least 30 in order to qualify for recording of the data in the database.
The patients are evaluated by a battery consisting of a handicap scale (modified Rankin scale) and 7 tests that measure gait, cognition and bladder function, before and 3 and 12 months after surgery or establishment of a working shunt. The patients are also checked one month after surgery to secure shunt efficacy.
The changes in clinical signs and disability after surgery are correlated to the results of the obligatory and optional tests. The primary outcome measures are the differences between the pre-operative and 12 months scores in the Rankin Scale and the composite NPH scale. These will be correlated with the results of the two primary investigations, resistance to CSF outflow (mmHg/ml/min) and CSF Tap Test (% change).
Patients data will be stored electronically in a web-based central data base using a special data security system for data transfer. Access to the database will be provided through an official homepage protected by a certified username/password based authenticity mechanism.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00874198
|International Neuroscience Institute Hannover|
|Hannover, Lower Saxony, Germany, 30625|
|Principal Investigator:||Petra M Klinge, MD||International Neuroscience Institute Hannover|
|Principal Investigator:||Carsten I Wikkelsoe, MD||Sahlgrenska University, Gothenburg, Sweden|
|Principal Investigator:||Jos TH Tans, MD||Westeinde Hospital, Den Haag, Netherlands|