KEYNOTEs

Diagnosis of the Posterior Fossa Syndrome and Associated ComorbiditY

Coriene Catsman, MD, PhD, Assistant Professor and Head of the Department of Paediatric Neurology at the Erasmus MC Sophia Children's Hospital in Rotterdam, the Netherlands.

Looking Back: Mutism and Pseudobulbar Palsy in 1984 - Today

Jeffrey Wisoff MD, Professor of Neurosurgery and Director of Division of Pediatric Neurosurgery at the NYU Langone Medical Center in New York NY, USA

The Cerebellar Cognitive Affective Syndrome

Jeremy D. Schmahmann MD, Professor of Neurology and Director of the Ataxia Unit & Laboratory for Neuroanatomy and Cerebellar Neurobiology at MGH and Harvard Medical School in Boston MA, USA

Surgeon's View: Reduction of Risk

Robert F. Keating MD, Professor and Chief of Pediatric Neurosurgery at the Children's National Medical Center and The Center for Neuroscience and Behavioral Medicine in Washington DC, USA

Follow-up of the Posterior Fossa Syndrome

Karin Walsh PsyD. Neuropsychologist at the Children's National Medical Center, Brain Tumor Institute and Neurofibromatosis Institute, Assistant Professor at Georgetown Washington Univeristy Medical Center in Washington DC, USA

Prevention of Posterior Fossa Syndrome in Medulloblastoma with Pre-operative Chemotherapy

Stephanie Puget MD, Professor of Pediatric Neurosurgery at Hôpital Necker-Enfants Malades in Paris, France and Christelle Dufour MD, Department of Pediatric and Adolescent Oncology, Gustave Roussy Institute, Villejuif, France

Linguistics Aspects of the Posterior Fossa Syndrome

Peter Mariën PhD, Professor of Neurolinguistics and Neurocognition at the Department of Neurology & Memory Clinic, ZNA Middelheim Hospital in Antwerp, Belgium

Prediction of Risk of Cerebellar Mutism using Imaging

David Walker MD, Professor of Pediatric Oncology at Queens Medical Centre and Children's Brain Tumour Research Centre, Faculty of Medicine and Health Sciences, University of Nottingham, UK

Abstracts

Nordic study of the cerebellar mutism syndrome (CMS) in children with brain tumours of the posterior fossa

Marianne Juhler, MD, DRMC, Professor of Experimental Neurosurgery at University Hospital Rigshospitalet, Copenhagen, Denmark                                         

Primary author of study protocol: Thora Gudrunardottir

Background: Approximately 25 % of childhood cancers are CNS tumours, and the majority of these are located in the cerebellum. Cerebellar mutism syndrome (CMS) is one of the most serious complications to posterior fossa surgery in children occurring in up to 25% of cases. Although some patients recover, many are left with permanent sequelae. Currently there are three known risk factors for cerebellar mutism (brainstem involvement by the tumor, midline location and tumor type) but the exact aetiology, additional risk factors, clinical course and strategies for prevention are yet to be determined.

Scope and timeframe: This observational prospective multicentre study is planned to include 500 children with posterior fossa CNS tumours. The study opened in October 2014, and by March 2015 24 patients had been included. The study is now consolidated in four Nordic and one Baltic centre, and it is intended to include centres in other European countries and the USA.

Aims of this study are to describe: 1) Which surgical methods are least likely to cause CMS and if there is a difference in risk between primary surgery and re-operation 2) The role of host genome variants on development and clinical course of CMS 3) The effect of glucocorticosteroids on the development and clinical course of the syndrome 4) Differences in incidence and clinical course of CMS according to sex, age, tumour type, comorbidities, handedness, radiological features and speech, language and neuropsychological abilities before and after surgery. Although effects of other therapeutic interventions (e.g. attempted symptomatic medication, chemo- and radiotherapy) are not part of the primary aims, information will be gathered and analysis of secondary parameters will be feasible later. We aim to achieve a better understanding of the risk factors and clinical course of the CMS with the ultimate goal of developing strategies for prevention of this severely disabling condition.

Method: All patients will be treated according to local standards. Clinical data are collected through online registration and imaging and will be reviewed centrally. Samples collected are speech recordings and host DNA for genome-wide association studies.

Authors: Morten Wibroe, Johan Cappelen, Charlotte Castor, Niels Clausen, Pernilla Grillner, Thora Gudrunardottir, Ramneek Gupta, Bengt Gustavsson, Mats Heyman, Stefan Holm, Atte Karppinen, Camilla Klausen, Tuula Lönnquist, René Mathiasen, Pelle Nilsson, Karsten Nysom, Karin Persson, Olof Rask, Kjeld Schmiegelow, Astrid Sehested, Harald Thomassen, Ingrid Tonning-Olsson, Barbara Zetterqvist, Marianne Juhler.

Association of Hypertrophic olivary degeneration with posterior fossa syndrome following tumour resection

Shivaram Avula, MD, Consultant Radiologist at Alder Hey Children's NHS Foundation Trust in Liverpool, UK

Objectives: Hypertrophic olivary degeneration (HOD) is a neural degeneration caused by disruption of the dentato-rubro-olivary pathway. Surgery for posterior fossa tumours is one among its various causes. We aim to evaluate if there is a significant relationship between HOD and PFS in children undergoing surgery for posterior fossa tumours to contribute our understanding of its pathogenesis.

Method: All children who had posterior fossa surgery between July 2007 and December 2012 were included. The immediate postoperative scan and scans in the following 12 months were anonymised and evaluated by two paediatric neuroradiologists for HOD. The Inferior olivary nucleus (ION) was also independently evaluated using a semi-automated region-growing technique. Feature selection techniques were used to identify the most relevant features amongst the MRI data, demographics and clinical data. A support vector machine (SVM) was used to analyse the discriminative ability of selected features. The clinical data of these patients were independently evaluated by the paediatric neurologist for the diagnosis of PFS.

Results: 48 children were included in the study. HOD was identified in 15 children with bilateral involvement in 9 children. PFS was identified in 15 children. Radiological evaluation revealed significant association between PFS and presence of HOD (p=0.001). PFS was significantly associated with bilateral HOD (p=0.002) and not unilateral HOD (p=0.08). Computational evaluation, carried out on 28 children, revealed an overall higher change in contrast and volume in the left ION in children with PFS. The diagnosis of HOD (by radiological assessment) as a predictor of PFS was approximately half as predictive as automated assessment of hyperintensity in the left ION.

Conclusion: The significant association between HOD and PFS suggests the involvement of dentato-rubro-olivary pathway in the development of PFS. Significant change involving the left ION in PFS implies damage to the right cerebellar efferent pathway as an important etiological factor.

Authors: S Avula, M Spiteri, C Ong, S Harave, E Lewis, D Windridge, B Pizer, C Mallucci, R Kumar

Postoperative Posterior Fossa Syndrome: The Contribution of MRI to Unravel Etiology and Underlying Pathophysiology

Zoltan Patay, MD, PhD, Chied of Department of Radiological Sciences, St. Jude Children’s Research Hospital in Memphis, TN, USA

Purpose: Posterior fossa syndrome (PFS) is a severe, early postoperative complication occurring in 25+% of patients undergoing posterior fossa (PF) surgery. In recent years MRI-based new data significantly contributed to improvements of our understanding of the etiology and pathophysiology of PFS. This review highlights major findings arising from several research projects conducted in a single institution.

Materials and Methods: We used anatomical and dynamic susceptibility-weighted contrast-enhanced perfusion MRI data acquired in pediatric patients with PFS and age/gender matched controls without PFS enrolled in different clinical trials developed for the treatment of medulloblastoma in our institution. We evaluated: (1) The post-surgical structural damage patterns of the proximal efferent cerebellar pathways pECPs and their relationship with the development of PFS, (2) Remote effects of surgical pECP disruption on cerebral cortex and inferior olivary nuclei (ION).

Results: Positive correlation between bilateral pECP damage and the development of PFS. All patients with bilateral ION degeneration had PFS clinically. In patients with PFS cerebral perfusion data showed reduced cerebral blood volume and flow within frontal lobes and a trend toward global cortical hypoperfusion.
Conclusion: Anatomical and physiological MRI techniques are uniquely well positioned to elucidate key structural changes and pathophysiological processes involved in the development of PFS. Imaging research confirmed that PFS follows bilateral surgical damage to pECPs and suggested that resultant depression of cerebral cortical perfusion may represent cerebello-cerebral diaschisis. Since hypoperfusion is most prominent in frontal regions, cerebellar mutism may correspond to speech apraxia. Bilateral ION degeneration may be a sensitive and in appropriate clinical settings a fairly reliable “a posteriori” surrogate imaging indicator of PFS opening new opportunities to develop better clinical definitions for various phenotypes of PFS.

poster

Development of a potential pre-operative risk stratification tool for cerebellar mutism syndrome in children with posterior fossa tumor

David Walker, MD, Consultant and Professor of Pediatric Oncology at the Queens Medical Centre and the Children's Brain Tumour Research Centre, Faculty of Medicine and Health Sciences, University of Nottingham, UK.

Introduction: Previous studies have identified potential clinical and radiological predictors of post-operative cerebellar mutism syndrome (CMS); however, a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The project aimed to develop a risk stratification tool via: (1) a retrospective analysis of clinical and radiological data at an institution to develop a preliminary model; then (2) validate and modify the model further in a larger cohort. 

Method: Post-operative CMS status was ascertained from clinical notes. Pre-operative MRI scans underwent structured evaluation for a 21 tightly-defined candidate imaging risk markers based on prior literature. The strongest predictors identified from logistic regression were used to test their ability to stratify patient risk.

Results: The first cohort consists of 51 patients (age: 2-23yrs, gender 14M 37F, 24 medulloblastoma, 23 pilocytic astrocytoma, 4 ependymoma, 13 developed CMS). A risk model combining IV ventricular location and brainstem invasion allowed separation of the cohort into low (5%), intermediate (25.5%) and high-risk (71.5%). This model will be further validated by the inclusion of a cohort of 38 patients recruited with similar methodology (age: 2-18yrs, gender: 14M, 24F, 15 developed CMS) in March 2015.  

Conclusion: A risk stratification model for post-operative CMS was developed, which would indicate increased risk pre-operatively and allow reconsideration of primary intervention. This would limit risk of surgical damage, in particular, where the areas of post operative damage seem to affect the inferior olivary nucleus and associated brainstem tracts.

Authors: RA Dineen(1), S Avula(2), T Chambers(3), M Dutta(3), D Macarthur(1), S Howarth(1), C Ong(2), C Mallucci(2),  R Kumar(2), B Pizer(2), D Walker(3)
(1) Nottingham University NHS Trust, Nottingham, UK; (2) Alder Hey Children's NHS Foundation Trust, Liverpool, UK; (3) University of Nottingham, Nottingham, UK