Endoscopic Third Ventriculostomy for Adults: A Prognostic Model for Success

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Brief Title

Endoscopic Third Ventriculostomy for Adults: A Prognostic Model for Success

Official Title

Endoscopic Third Ventriculostomy for Adults With Hydrocephalus: Creating a Prognostic Model for Success - A Retrospective Multicenter Study

Brief Summary

      Endoscopic Third Ventriculostomy for Adults with Hydrocephalus: Creating a Prognostic Model
      for Success - A Retrospective Multicenter Study

      Background: Endoscopic third ventriculostomy (ETV) is becoming an increasingly widespread
      treatment for hydrocephalus, but most of the research is based on paediatric populations. The
      ETV Success Score (ETVSS) was developed in 2009 to predict the outcome of ETV in children.
      There is no similar tool for predicting outcome in adults.

      Objective: The purpose of this study is to create a prognostic model to predict the success
      of ETV for adult patients with hydrocephalus

      Methods: The study will adhere to the TRIPOD reporting guidelines and will be conducted as a
      retrospective chart review of all patients ≥18 years old treated with ETV at the
      participating centres between Jan 1st, 2010 and Dec 31st, 2018. Data collection is conducted
      locally in REDCap. Univariate analyses will be used to identify several strong predictors to
      be included in a multivariate logistic regression model. The model will be validated using
      K-fold cross validation. Discrimination will be assesses using AUROC and calibration with
      calibration belt plots.

      Expected outcomes: The ability to predict who will benefit from an ETV will allow better
      primary patient selection both for ETV and shunting. This would reduce additional second
      procedures due to primary treatment failure. A success score specific for adults could also
      be used as a communication tool to provide better information and guidance to patients.
    

Detailed Description

      Endoscopic Third Ventriculostomy for Adults with Hydrocephalus: Creating a Prognostic Model
      for Success - a retrospective multicenter study

      Background:

      The most common treatment for hydrocephalus is a ventriculoperitoneal shunt (VPS), to divert
      excess CSF from the ventricles to be absorbed in the peritoneum. The treatment can be applied
      to different aetiologies of hydrocephalus, but there is a high complication risk both short
      and long term. A retrospective review of 17,035 adult patients who had undergone their first
      VPS surgery for hydrocephalus, report that one third (33.4%) of the patients experienced at
      least one complication, during the follow up (3.9 years), and 22% required revision. 21.4% of
      the complications occurred within the first year. Another revew of 683 adult patients, found
      that 32% experienced shunt failure, with 74% occurring within 6 months.

      Endoscopic third ventriculostomy (ETV) is an alternative treatment option, creating a passage
      between the ventricles and the subarachnoid space, by perforating the floor of the third
      ventricle. It is minimally invasive and leaves no mechanical foreign body behind, thereby
      avoiding many of the implant complications associated with VPS.

      The overwhelming majority of research on endoscopic third ventriculostomy (ETV) is conducted
      in paediatric or mixed paediatric/adult populations. ETV Success Score (ETVSS) was created in
      2009 to predict the outcome of ETV treatment in children. The ETVSS consists of three
      factors: age, aetiology and shunt history. Based on these factors a score from 0-90 is given,
      representing the predicted probability of successful ETV outcome 6 months postoperatively.
      The ETVSS was tested in a mixed population of 168 patients with a mean age of 40 years (range
      3-85 years) and found to have inadequate discrimination with an AUC of 0.61 but good
      calibration.

      The ETVSS is based on paediatric populations, and the age differentiation stops after the
      patient has reached 10 years. 50 out of a possible 90 points are given if the patient is more
      than 10 years old, making this parameter in the ETVSS redundant when used in adults.
      Furthermore, the ETVSS does not include several common aetiologies for adult hydrocephalus
      such as idiopathic normal pressure hydrocephalus (iNPH), subarachnoid haemorrhage (SAH) and
      long-standing overt ventriculomegaly in adults (LOVA). Previous shunt treatment seems to play
      an important role in adults as well. A review of 163 adult patients reported an overall
      success rate of 80%, with patients treated with ETV as the primary treatment faring
      significantly better than those with a previous shunt, at 87% and 65% respectively.

      Radiological findings are not included in the ETVSS, and although most radiological signs of
      obstruction are subjective evaluations based on the observer's experience, some quantifiable
      signs have been identified. Downward bowing of the third ventricular floor has been
      identified as a strong predictor of ETV success. The bowing was measured by placing a line
      through the chiasma to the top of the mesencephalon or the mamillary bodies. Downward bowing
      was defined as inferior displacement of the third ventricle floor below this line.

      Although there are a few studies analysing long-term ETV survival in adults, most are in
      paediatric or mixed populations. The existing long-term series on adult patients show most
      failures occurring shortly after the procedure although late failures are reported. Kaplan
      Meier curves for ETV survival have an initial steep decline, followed by a gradual fall-off
      before it seems to stabilise with few failures after a certain point. By determining the
      composition of patient characteristics these three different parts of the curve. The initial
      fall off is hypothesised to represent patients without benefit of the procedure and
      significant symptoms requiring early re-operation. The second group are also ineffective from
      the beginning, but present with more chronic symptomatology giving more time to evaluate the
      effect before re-operation. The failures occurring in the stable part of the curve represents
      initial success with a late closure of the stoma.

      With ETV becoming an increasingly widespread treatment for adult hydrocephalus there is a
      need for a new prognostic model specific for this patient population. The ability to predict
      who will benefit from an ETV will allow better primary patient selection both for ETV and
      shunting, reduce additional second procedures because of primary treatment failure, and
      possibly prevent further unnecessary procedures.

      Objective

      The purpose of this study is to create a prognostic model to predict the short-term success
      of ETV for adult patients with hydrocephalus.

      Specific aims for this research project is to:

        1. Identify factors associated with both success and failure of ETV in adults, to establish
           a prognostic model.

        2. Report on ETV success rates, complications and survival in adult patients at the
           partici-pating centres.

      A success score specific for adults will improve patient selection and can also be used as a
      communication tool to provide better information and guidance to patients. The prognostic
      model will be tested in a future prospective study conducted at the participating centres. As
      well as follow up on the study population in the future to report long-term outcomes.

      Hypotheses

      Main hypothesis:

      An adult ETVSS can be created based on patient demographics, symptomatology, aetiology, shunt
      history and radiologic findings.

      Secondary hypotheses:

        -  Age is still a relevant factor but has the inverse effect in adults with less successful
           out-comes with older age.

        -  Aetiology and shunt history have prognostic value but must be recalibrated to reflect the
           spectrum of hydrocephalus conditions in adults.

        -  It is possible to develop a radiological hydrocephalus classification and scoring system
           providing additional prognostic value.

        -  There are different characteristics in the failures occurring during the different
           phases seen on the Kaplan Meier survival curve.

      Methodology

      Study design:

      The study will be conducted as a retrospective review of electronic patient charts and will
      adhere to the TRIPOD guidelines in the development of the prediction model. A multivariate
      logistic regression model will be used to identify prognostic factors for success of ETV
      treatment. This model is expected to be simplified to include only 3 to 4 strong predictors
      to make it useful in daily clinical practice.

      Data collection and monitoring:

      Each of the participating centres will be responsible for the data collection in a
      standardised database, that will include demographic information (date of birth, sex) and
      details on aetiology (haemorrhage, infection, tumour or cyst, trauma, congenital or
      idiopathic), symptomatology (acute and chronic symptoms), previous shunt treatment (number
      revisions, cause of malfunction, duration of shunt treatment), radiological investigations
      (visible obstruc-tion or radiological signs of obstruction), surgical details (date,
      equipment, technique, concur-rent procedures, following procedures) complications (intra- and
      postoperative, length of stay) and follow-up (at 3-12 months and most recent) All ETVs
      performed at the participating centres will be entered in the database and then includ-ed or
      excluded based on the below delineated criteria. Reason for exclusion will be registered, and
      the in-built tools in REDCap used to uncover missing data.

      Oversight:

      Approval from the Danish Patient Safety Authority (Styrelsen for Patientsikkerhed) and The
      Danish Data Protection Agency (Datatilsynet) has been granted.

      Definition of ETV-success Success is defined as clinical improvement at first follow up, with
      no further CSF-diversion procedures within the first year of follow up. Clinical improvement
      will be registered based on the records from the first available follow up, but also include
      patients where the ETV was deemed ineffective before the patient was discharged or where a
      second procedure was per-formed during the same admission. If the patient's chart leaves any
      doubt when registering if the patient's symptoms improved postoperatively, it should be
      registered as "not improved". If the patient receives further CSF-diversion procedures during
      the first year, the ETV is considered a failure. Implantation of ICP-monitoring equipment
      does not render the ETV unsuccessful, un-less it is followed by CSF-diversion. Patients
      undergoing repeat ETV are counted as failures when calculating the success rate, but results
      are registered in order to determine the efficacy of re-ETVs. Additional CSF-diversion
      procedures will be registered for the entire observation pe-riod (beyond the first year) to
      determine long-term ETV-survival.

      Sample size:

      There is no clear consensus on the required sample size for prognostic models based on
      retrospective data. However, the paediatric ETVSS was based on 618 paediatric patients, using
      70% (455) of the population for the creation of the model and the remaining 30% (163) for
      validation. Based on this the minimum number of patients required, is approximately 500.
      There is no upper limit, as more patients would give a better foundation for the prediction
      model, especially in the rarer patient categories such as iNPH or hydrocephalus caused by
      infection or SAH. approximately 220 adult ETV patients have been identified in Copenhagen
      2010-2018. With cooperation between several centres the sample should easily meet the minimum
      required sample size and provide the necessary power to create a robust prognostic model.
      Approximately 250 ETVs are expected from each of the participating countries, resulting in
      1000 patients. The model will be tested in a separate prospective study.

      Statistical Analysis:

      Patient demographics, aetiology and shunt history, as well as complications, will be
      summarised using descriptive statistics. The patient's symptoms are categorised as 'improved'
      or 'not improved' following treatment. If the patient requires subsequent CSF diversion
      procedures or fails to show clinical improvement, the ETV is considered a failure. Each of
      the proposed predictors are analysed in a univariate statistical analysis and are
      subsequently included in a multivariate logistic regression model to construct a unified
      prediction model. Statistical significance is defined at p<0.05. The model will be validated
      using K-fold cross validation. Discriminative ability will be assessed using AUROC and
      calibration using calibration belt plots. Significant missing data will be handled using
      multiple imputation. Time to ETV failure will be analysed using Kaplan-Meier curves.

      Financial plan:

      As this is a retrospective chart review, limited funds are required. ST has been partially
      funded by the Lundbeck Foundation and the Hjerne- og Nervekirurgisk Forskningspulje,
      Rigshospitalet. No other specific funding has been received for this study.
    


Study Type

Observational


Primary Outcome

ETV success

Secondary Outcome

 ETV survival

Condition

Hydrocephalus



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

1000

Start Date

May 27, 2020

Completion Date

August 2022

Primary Completion Date

June 2022

Eligibility Criteria

        Inclusion Criteria:

          -  ETV procedure performed

          -  ≥18 years old at time of first ETV

        Exclusion Criteria:

          -  <18 years old at time of first ETV

          -  Permanent intraventricular foreign bodies left behind after the ETV. eg. Shunt or
             stents. Temporary external ventricular drains, ICP-monitoring probes or ligated shunts
             where the ventricular drain is removed, are not excluded.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Sondre Tefre, 81755740, [email protected]

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT04773938

Organization ID

NordicETV


Responsible Party

Principal Investigator

Study Sponsor

Rigshospitalet, Denmark


Study Sponsor

Sondre Tefre, Principal Investigator, Department of Neurosurgery, Copenhagen University Hospital Rigshospitalet


Verification Date

May 2022