Cerebellar Mutism Syndrome Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT02300766

Recruitment Status : Recruiting

First Posted : November 25, 2014

Last Update Posted : January 18, 2024

See Contacts and Locations

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborators:

Odense University Hospital

Aarhus University Hospital

Aalborg University Hospital

Technical University of Denmark

Karolinska University Hospital

Skane University Hospital

University Hospital, Linkoeping

Uppsala University Hospital

Sahlgrenska University Hospital, Sweden

University Hospital, Umeå

Oslo University Hospital

Trondheim University Hospital

Haukeland University Hospital

University Hospital of North Norway

Helsinki University Central Hospital

Tampere University Hospital

Kuopio University Hospital

Turku University Hospital

Oulu University Hospital

Radboud University Medical Center

Liverpool University Hospitals NHS Foundation Trust

Great Ormond Street Hospital for Children NHS Foundation Trust

Nottingham University Hospitals NHS Trust

University Hospital Birmingham

University Hospitals Bristol and Weston NHS Foundation Trust

Royal Infirmary of Edinburgh

South Glasgow University Hospitals NHS Trust

University Hospital Tuebingen

Medical University of Vienna

Ospedale Pediatrico Bambin Gesù

Motol University Hospital

University of Leipzig Medical Center

Universitaire Ziekenhuizen KU Leuven

Queen Fabiola Children's University Hospital

Cliniques universitaires Saint-Luc

University Hospital, Ghent

Hospital De La Citadelle

CHC MontLégia

University Hospital, Antwerp

Information provided by (Responsible Party):

Aske Foldbjerg Laustsen, Rigshospitalet, Denmark

Study Description

Brief Summary:

The purpose of this study is to determine why up to 25% of the pediatric patients who have surgery for a tumor in the posterior fossa develops the Cerebellar Mutism Syndrome (CMS). Furthermore the purpose is to explore the clinical course and the best treatment of the syndrome.

Condition or disease
Infratentorial Neoplasms Mutism

Show detailed description

Detailed Description:

Background:

Cancer accounts for 22 % of all deaths among children in Europe and is thus the leading non-traumatic pediatric cause of death. Central nervous system (CNS) tumours constitute 25% of all childhood cancers, and the majority of these are located in the posterior fossa. One of the most troublesome late effects after neurosurgery for such a tumour is the cerebellar mutism syndrome which is seen in up to 25% of the patients. It is characterized by mutism, hypotonia, ataxia and irritability. The exact aetiology, risk factors, clinical course and treatment have yet to be identified. The aim of this study is to accomplish that.

Method:

This is an observational prospective multicentre study that will include a minimum of 500 paediatric patients with posterior fossa CNS tumours from the Nordic countries. Additional countries might be added later once the study is running. The study has started in fall 2014 in 20 centres from 5 Nordic countries. Prior to this a pilot study was performed on 43 Danish adult patients to validate and fine-tune registration procedure. All patients will be treated according to local standards, but clinical data will be collected and imaging will be reviewed centrally.

To calculate the participation rate the annual number of included patients from each country will be compared to the number of registered patients in the cancer registers of the respective country and year.

A blood sample for genetic analysis will be collected from all patients. The patients' neurology and speech functions will be examined both pre-operatively and repeatedly post-operatively, including recording of standardised speech samples. All data will be collected trough a, for the purpose developed, online database.

Registration of data

The following data will be registered at the following 5 time points:

Preoperatively Hospital and country, and patient related variables (date of birth, handedness, bilingualism, sex and date of diagnosis). Medical history (Previous neurological/neuropsychological/ psychiatric problems, comorbidities, previous operations or other treatment for the tumour, previous regular use of any kind of medication). Preoperative neurological status will be examined and a language and speech test will be performed and recorded. If the patient is younger than 2 years a bedside assessment of the speech will be performed instead of a test. A blood sample for genetic analysis will be drawn together with the standard blood samples. Alternatively this can be done at any time during follow-up.
Postoperatively within 72 hours of surgery Operation related variables (date, duration and course of operation, surgical position, surgical approach, and tumour removal method), complications, technology employed, preoperative hydrocephalus and estimated completeness of tumour resection.
Postoperatively within 1-4 weeks from surgery Approximately 1-2 weeks post-op: Postoperative language and speech status and for those older than 2 years, a recording of a speech sample. Neurological examination. Glucocorticoid administration pre-, intra- or postoperatively plus other medications used to treat the CMS postoperatively and their effects. Kind(s) of imaging performed on the tumour pre- and postoperatively. Approximately 4 weeks post-op: Development and treatment of postoperative intracranial haematoma and hydrocephalus, leakage of cerebrospinal fluid and need for ventilator.
Postoperatively at about 2 months from surgery Postoperative development of CMS, detailed survey of the status of CMS in those affected including recording of speech sample and neurological examination. Medications used to treat the CMS since last registration and their effects.
Postoperatively at about 12 months from surgery Language and neurological status including a speech sample for those older than 2 years. Medications used to treat the CMS since last registration and their effects. Other anti-cancer treatment given (chemotherapy and/or radiotherapy). Results from the pathology department regarding the kind of tumour histology and genetics. Registration of whether neuropsychological assessment(s) have been performed. Kind(s) of imaging performed on the tumour since 1st follow-up. Copies of the MRIs and descriptions performed pre-op, right after the operation and approximately. 12 months post-op are obtained.

All registered data will be examined by a third party who will check for missing data or misentries in order to ensure a high quality of the data. In case of missing data or misentries the third party will contact the person who made the registration.

The database is administered by the children's cancer epidemiology group (CCEG) at Karolinska Hospital in Stockholm, which is also responsible for the Swedish children's brain tumour registry and the leukaemia database for the Nordic Society of Pediatric Hematology and Oncology (NOPHO)

Other courses:

In case of acute surgery, coma etc. information about the study and the offer to participate can be given within 7 days from the operation. In these cases preoperative data about the patient can be obtained from the patient's medical record and/or from the parents, but a preoperative speech sample cannot be performed. These patients will not be included in the analysis of whether and how preoperative speech and language status affects the risk of developing CMS, but will be included in all the other study analyses. Speech samples will be performed postoperatively in exactly the same manner as in patients that were included before operation to able to monitor the patient's speech postoperatively and register signs of the CMS.

Should the patient have posterior fossa tumour surgery performed again during the 12 months follow-up period, the patient will re-start the follow-up programme from that date. A separate pre-op and all the post-op registrations will be performed again, and used in the analysis of risk of first versus second or further surgery. New genetic blood samples will not be necessary in these cases. Should the patient have posterior fossa tumour surgery performed after the last 12 months follow-up, the patient will be offered to participate in the study again and a new consent will have to be obtained. New genetic blood samples will not be necessary in these cases.

If the patient leaves the study for any reason before the follow-up 12 months post-op, a separate form will be filled out explaining why the patient left.

If the patient turns 18 while included in the study, a new consent to participate will have to be given by the patient him- /herself.

Blood samples and analyses:

As soon as a patient has been registered, the study centre will request a 2 ml anticoagulated blood sample for genetic profiling (Single-Nucleotide Polymorphism (SNP) analysis).

The investigators will use a newly developed single nucleotide polymorphism (SNP) sequencing strategy that allows cost-effective mapping of 25-30.000 genetic polymorphisms within biological domains that could potentially be linked to the development of CMS (e.g. inflammation, vascularization, blood-brain-barrier markers, and apolipoprotein E and other lipoprotein pathway genes). The genetic data will be linked to the clinical data to identify genetic variants associated with the risk of CMS or the course of CMS. Specifically the investigators will map all SNPs in all genes that are known or are likely to be linked to these pathways, including mRNA binding sites and first order protein-protein interactions. Rather than expecting large effects of single SNPs, the strategy of this approach is to use front-line bioinformatics and pathway analyses to explore the additive effect of numerous SNPs involved in the same biological pathway. This will identify high-impact pathways, although with individual low-impact SNPs. The results obtained could guide future therapeutic approaches to CMS.

If the custodial parents do not consent to their child contributing a blood sample to the study, the child may still participate in the study, albeit not in the part involving genetic analysis. The samples as well as the rest of the study data will be protected under the Act on Processing of Personal Data and the Act on the Health Act.

All MRIs are analyzed by neuroradiologists with respect to tumour resection and neuroradiographic signs associated with CMS.

All speech recording are analyzed by speech therapists with respect to signs associated with CMS. The results of neuropsychological tests that may have been performed routinely will be separately obtained and analyzed.

Power calculations:

For the surgical hypothesis, assuming that 35% of patients are operated with an approach that has a lower risk of CMS (assumed to be 10%) and the remaining 65% of patients are operated using other approaches that carries a 20% risk of CMS, the investigators will with 80% power be able to identify a difference at a 5% significance level if the investigators include a total of 450 patients.

For the genetic analysis, several pathways and SNP-profiles will be explored with appropriate adjustments for multiple comparisons. Multiple SNPs will due to randomness be found to be related with the risk of CMS. Their true biological significance will subsequently be validated through internal validation, as the investigators will explore if other SNPs in the same biological pathway, e.g. SNPs in the same genes but not the same haplotype or SNPs that affect coding or regulatory regions in the identified risk-related genes are more significantly associated with risk of CMS than randomly selected SNPs. Furthermore, the genes/SNPs will be explored by bioinformatic predictions of the impact of the SNPs on protein-folding, binding affinity etc. Once such high-risk SNPs/genes/pathways have been identified and published, the investigators will attempt to have them confirmed in independent patient cohorts from Europe or the US. Based on a projected overall risk of CMS of 20%, a frequency of a specific SNP (or SNP-profile) of 30%, and a projected doubled risk of CMS in the group that harbour the SNP (or SNP-profile), the investigators will with 90% power be able to identify such a genetic predisposition at a 5% significance level, if a total of 343 patients are included in the study. Thus, the study has sufficient power.

To analyze the effect of the above mentioned variables (surgical method, administration of corticosteroid, handedness etc.) on the risk of developing CMS the investigators will perform univariate and multivariate regression analyses as well as standard descriptive analyses. These analyses will be performed using R.

Discussion:

The study will be the largest prospective multicenter study on cerebellar mutism syndrome to date, and the first one of its kind to systematically gather detailed information about 1) the surgical approaches least likely to cause the syndrome, 2) how the syndrome is best treated, 3) the role of genetics and 4) differences in incidence and clinical course of the syndrome for different patients.

The ultimate aim of the study is to reduce the incidence and improve the treatment of cerebellar mutism syndrome and lead to harmonization of the treatment of CNS tumour patients across the Nordic countries.

Study Design

Layout table for study information

Study Type :	Observational [Patient Registry]
Estimated Enrollment :	1000 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Target Follow-Up Duration:	1 Year
Official Title:	Nordic Study of the Cerebellar Mutism Syndrome in Children With Brain Tumours of the Posterior Fossa
Study Start Date :	October 2014
Estimated Primary Completion Date :	December 31, 2028
Estimated Study Completion Date :	December 31, 2028

Groups and Cohorts

Group/Cohort
Posterior fossa tumor patients Children (0-18 years) with a tumour in the posterior fossa (cerebellum/4th ventricle/brainstem ) requiring surgery or open biopsy at one of the participating centres.

Outcome Measures

Primary Outcome Measures :

Development and progress of Cerebellar Mutism Syndrome [ Time Frame: 1 year after surgery ]
The development of CMS is determined by a survey developed Robertson et al. The correlation between the risk of developing CMS and different neurosurgical techniques, genomic variants, treatments, tumor types, comorbidities, neuroradiologic findings, handedness and preoperative language status will be explored.

Secondary Outcome Measures :

Development and progress of reduced speech output [ Time Frame: 1 year after surgery ]
Speech production that is severely reduced and limited to single words or short sentences which can only be elicited after vigorous stimulation

Biospecimen Retention: Samples With DNA

A blood sample from each patient will be collected in order to make SNP analyses on the DNA to explore the role of genomic variants on the development, severity and recovery from the CMS.

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information

Ages Eligible for Study:	up to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

All children (0-18 years) with a tumour in the posterior fossa (cerebellum/4th ventricle/brainstem ) requiring surgery or open biopsy at one of the participating centres.

Criteria

Inclusion Criteria:

Age < 18 years at the date of first imaging showing this tumour
Tumour in the cerebellum/4th ventricle/brainstem with intention to treat with surgical resection or open biopsy. Second and further surgeries are also included.
Informed consent from custodial parent(s)

Exclusion Criteria:

None

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02300766

Contacts

Layout table for location contacts

Contact: Aske F Laustsen, MD, PhD stud	+45 40218998	aske.foldbjerg.laustsen@regionh.dk
Contact: Astrid M Sehested, MD	+45 35451367	astrid.marie.sehested@regionh.dk

Locations

Show 30 study locations

Layout table for location information

Austria
Medical University of Vienna	Recruiting
Vienna, Austria
Contact: Andreas Peyrl +43 1 40400 32320 andreas.peyrl@meduniwien.ac.at
Belgium
University Hospital Leuven	Recruiting
Leuven, Belgium
Contact: Jurgen Lemiere
Czechia
Motol University Hospital	Recruiting
Praha, Czechia
Contact: Vladimir Benes
Denmark
Aalborg University Hospital	Recruiting
Aalborg, Denmark, 9100
Contact: Steen Rosthøj, MD steen.rosthoej@rn.dk
Aarhus University Hospital	Recruiting
Aarhus, Denmark, 8000
Contact: Niels Clausen, MD +45 78451700 nc@dadlnet.dk
Contact: Karen O Møller, Nurse +45 78451719 karemoel@rm.dk
Rigshospitalet	Recruiting
Copenhagen, Denmark, 2100
Contact: Aske F Laustsen, MD, PhD stud +45 40218998 aske.foldbjerg.laustsen@regionh.dk
Contact: Marianne Juhler, MD, Dr. med +45 35452088 marianne.juhler@gmail.com
Sub-Investigator: Astrid Sehested, MD
Sub-Investigator: Jonathan K Groenbaek, MD, PhD
Odense University Hospital	Recruiting
Odense, Denmark, 5000
Contact: Peder S Wehner, MD +45 6541 2086 peder.skov.wehner@ouh.regionsyddanmark.dk
Finland
Helsinki University Central Hospital	Recruiting
Helsinki, Finland
Contact: Tuula Lönnqvist tuula.lonnqvist@hus.fi
Contact: Atte Karppinen Atte.Karppinen@hus.fi
Kuopio University Hospital	Not yet recruiting
Kuopio, Finland
Contact: Jouni Pesola jouni.pesola@kuh.fi
Oulu University Hospital	Not yet recruiting
Oulu, Finland
Contact: Satu Lehtinen satu.lehtinen@ppshp.fi
Tampere University Hospital	Not yet recruiting
Tampere, Finland
Contact: Kristiina Nordfors kristiina.nordfors@gmail.com
Turku University Hospital	Not yet recruiting
Turku, Finland
Contact: Päivi Lähteenmäki paivi.maria.lahteenmaki@tyks.fi
Contact: Marika Gronroos marika.gronroos@tyks.fi
Germany
University of Leipzig Medical Center	Recruiting
Leipzig, Germany
Contact: Ulf Nestler
Hungary
Semmelweis University, 2nd Dept of Pediatrics	Recruiting
Budapest, Hungary
Contact: Péter Hauser, MD, PhD hauserpeti@yahoo.com
Italy
Ospedale Pediatrico Bambino Gesù	Recruiting
Rome, Italy, 00165
Contact: Andrea Carai, MD
Lithuania
Hospital of Lithuanian University of Health Sciences Kauno klinikos	Recruiting
Kaunas, Lithuania
Contact: Rosita Kiudeline rosikiud@gmail.com
Contact: Giedre Rutkauskiene giedre.rutkauskiene@gmail.com
Netherlands
Radboud University Nijmegen Medical Centre	Recruiting
Nijmegen, Gelderland, Netherlands, 6525
Contact: Leonie v d Abbeele Leonie.vandenAbbeele@radboudumc.nl
UMC Groningen	Active, not recruiting
Groningen, Netherlands
UMC Utrecht	Recruiting
Utrecht, Netherlands
Contact: Kirsten van Barsen K.M.vanBaarsen-2@umcutrecht.nl
Norway
Haukeland University Hospital	Recruiting
Bergen, Norway
Contact: Ingrid K Torsvik ingrid.kristin.torsvik@helse-bergen.no
Oslo University Hospital	Not yet recruiting
Oslo, Norway
Contact: Einar Stensvold
University Hospital of North Norway	Not yet recruiting
Tromsø, Norway
Contact: Tore Stokland tore.stokland@unn.no
St. Olav's Hospital	Recruiting
Trondheim, Norway
Contact: Harald Thomassen harald.thomassen@stolav.no
Contact: Johan Cappelen johan.cappelen@stolav.no
Sweden
Sahlgrenska University Hospital	Recruiting
Gothenburg, Sweden
Contact: Magnus Sabel magnus.sabel@vgregion.se
Linköping University Hospital	Recruiting
Linköping, Sweden
Contact: Irene Devenney Irene.Devenney@lio.se
Skåne University Hospital	Recruiting
Skåne, Sweden
Contact: Charlotte Castor charlotte.castor@med.lu.se
Karolinska University Hospital	Recruiting
Stockholm, Sweden
Contact: Pernilla Grillner +46 08-524 879 55 Pernilla.Grillner@ki.se
University Hospital of Umeå	Recruiting
Umeå, Sweden
Contact: Mattias Mattsson mattias.mattsson@vll.se
Uppsala University Hospital	Recruiting
Uppsala, Sweden
Contact: Christoffer Ehrstedt christoffer.ehrstedt@akademiska.se
Contact: Pelle Nilsson pelle.nilsson@akademiska.se
United Kingdom
Alder Hey Childrens NHS Foundation Trust	Recruiting
Liverpool, United Kingdom
Contact: Conor Mallucci conor.mallucci@alderhey.nhs.uk

Sponsors and Collaborators

Rigshospitalet, Denmark

Odense University Hospital

Aarhus University Hospital

Aalborg University Hospital

Technical University of Denmark

Karolinska University Hospital

Skane University Hospital

University Hospital, Linkoeping

Uppsala University Hospital

Sahlgrenska University Hospital, Sweden

University Hospital, Umeå

Oslo University Hospital

Trondheim University Hospital

Haukeland University Hospital

University Hospital of North Norway

Helsinki University Central Hospital

Tampere University Hospital

Kuopio University Hospital

Turku University Hospital

Oulu University Hospital

Radboud University Medical Center

Liverpool University Hospitals NHS Foundation Trust

Great Ormond Street Hospital for Children NHS Foundation Trust

Nottingham University Hospitals NHS Trust

University Hospital Birmingham

University Hospitals Bristol and Weston NHS Foundation Trust

Royal Infirmary of Edinburgh

South Glasgow University Hospitals NHS Trust

University Hospital Tuebingen

Medical University of Vienna

Ospedale Pediatrico Bambin Gesù

Motol University Hospital

University of Leipzig Medical Center

Universitaire Ziekenhuizen KU Leuven

Queen Fabiola Children's University Hospital

Cliniques universitaires Saint-Luc

University Hospital, Ghent

Hospital De La Citadelle

CHC MontLégia

University Hospital, Antwerp

Investigators

Layout table for investigator information

Study Chair:	Kjeld Schmiegelow, MD, Dr. med	Rigshospitalet, Denmark
Principal Investigator:	Marianne Juhler, MD, Dr. med	Rigshospitalet, Denmark
Study Chair:	Karsten Nysom, MD	Rigshospitalet, Denmark

More Information

Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wibroe M, Cappelen J, Castor C, Clausen N, Grillner P, Gudrunardottir T, Gupta R, Gustavsson B, Heyman M, Holm S, Karppinen A, Klausen C, Lonnqvist T, Mathiasen R, Nilsson P, Nysom K, Persson K, Rask O, Schmiegelow K, Sehested A, Thomassen H, Tonning-Olsson I, Zetterqvist B, Juhler M. Cerebellar mutism syndrome in children with brain tumours of the posterior fossa. BMC Cancer. 2017 Jun 21;17(1):439. doi: 10.1186/s12885-017-3416-0.

Layout table for additonal information

Responsible Party:	Aske Foldbjerg Laustsen, MD, PhD student, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:	NCT02300766
Other Study ID Numbers:	H-6-2014-002
First Posted:	November 25, 2014 Key Record Dates
Last Update Posted:	January 18, 2024
Last Verified:	January 2024

Keywords provided by Aske Foldbjerg Laustsen, Rigshospitalet, Denmark:


Cerebellar Mutism Syndrome Posterior Fossa Tumor Pediatric cancer Neurosurgical techniques

Additional relevant MeSH terms:

Layout table for MeSH terms

Infratentorial Neoplasms Mutism Speech Disorders Language Disorders Communication Disorders Neurobehavioral Manifestations Neurologic Manifestations Nervous System Diseases Neurodevelopmental Disorders	Mental Disorders Brain Neoplasms Central Nervous System Neoplasms Nervous System Neoplasms Neoplasms by Site Neoplasms Brain Diseases Central Nervous System Diseases

To Top