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Emotional lability as a symptom of extra-axial posterior fossa tumours : a case-control review of neuroanatomy… Prakash, Swetha 2020

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 EMOTIONAL LABILITY AS A SYMPTOM OF EXTRA-AXIAL POSTERIOR FOSSA TUMOURS: A CASE-CONTROL REVIEW OF NEUROANATOMY AND PATIENT-REPORTED QUALITY OF LIFE  by  Swetha Prakash  BSc, The University of British Columbia, 2017    A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in  The Faculty of Graduate and Postdoctoral Studies (Experimental Medicine)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  April 2020 © Swetha Prakash, 2020      iiThe following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled:  Emotional lability as a symptom of extra-axial posterior fossa tumours: a case-control review of neuroanatomy and patient-reported quality of life  submitted by Swetha Prakash in partial fulfillment of the requirements for the degree of Master of Science in Experimental Medicine   Examining Committee: Dr. Ryojo Akagami, Clinical Professor, Surgery, UBC Co-supervisor Dr. Alice Mui, Associate Professor, Surgery, UBC Co-supervisor  Dr. Peter Gooderham, Clinical Assistant Professor, Surgery, UBC Supervisory Committee Member Dr. Samuel Yip, Clinical Instructor, Neurology, UBC Additional Examiner              iiiABSTRACT Introduction: Emotional lability (EL), the uncontrollable and unmotivated expression of emotion, is a rare and distressing symptom of brainstem compression from extra-axial posterior fossa tumours. In published case reports, EL is alleviated by surgical resection of the tumour. The primary goal of this study was to radiographically compare the degree of compression from mass lesions onto brainstem structures between EL cases and matched controls. The secondary goal was to compare changes in patient reported quality of life (QOL) pre- and post-operatively. Methods: In a retrospective review of patients treated for posterior fossa tumours with brainstem compression between 2002 and 2018 at Vancouver General Hospital, 11 patients with confirmed EL were identified. Each case was matched to 3 controls.  Pre-operative axial T2-weighted FLAIR MRI scans were reviewed, and a lateral brainstem compression scale was used to characterize the degree of mass effect at the level of the medulla, pons, and midbrain. Compression was compared between EL patients and control patients. Clinical variables were also compared. Patients routinely complete the Short form-36 (SF36v1) general health survey at clinic appointments, these surveys were retrospectively obtained from patient charts. Pre- versus post-operative changes in survey scores were compared between EL patients and controls.        ivResults: EL symptoms ceased post-operatively for all EL patients. EL tumours exert greater compression onto the pons (EL mean compression score=2.91, control mean compression score=1.91, one-tailed p=0.03). EL patients more commonly have cerebellar findings (p=0.003) pre-operatively. Patients with EL-causing tumours experienced greater improvement post-operatively in “Health Change” (two-tailed p=0.05), which was maintained over time. Control patients experienced greater improvement in the “Role Limitations Due to Physical Health” SF36v1 sub-score (two-tailed p=0.03), which was not maintained over time. Conclusion: This is the largest case series to-date investigating adult extra-axial posterior fossa tumours that cause EL. Findings suggest that compression onto the pons inhibits control over involuntary, stereotyped expression of emotion This adds to evidence that EL may be attributed to deafferentation of the cerebellum from cortical and limbic structures through the basis pontis, leading to impaired modulation of emotional response. The QOL results augment benefits of obtaining EL-alleviating surgery.           vLAY SUMMARY   Emotional lability (EL) is uncontrollable laughter or crying that has no appropriate trigger or related mood change. Brain tumours that grow near the base of the skull can cause this rare symptom. This study aims to determine which brainstem region is involved in causing EL. Since EL can be a social and professional burden, this study also investigates how quality of life changes after surgery for these tumours. EL has been known to stop immediately after the tumour is removed. This study found that the pons region of the brainstem is key to the EL pathway. Secondly, perceived health change after surgery is largely improved for patients who had EL compared to those who did not have EL prior to surgery. As the first case series to investigate this adult brain tumour symptom, we gained insight into its mechanism and learned how surgery could improve patient quality of life.                viPREFACE  This work was conducted at Vancouver General Hospital, in Vancouver, BC. The project and outlined methods were approved by the University of British Columbia’s Research Ethics Board [certificate #H19-00338].  Dr. Ryojo Akagami was the supervisory author on this project and was involved in every step of the process, from concept formation to manuscript composition. I assisted with developing the study design. Additionally, I extracted chart data, processed and analyzed the data, and am the primary author of this document. Dr. Alice Mui and Dr. Peter Gooderham assisted with the study design and provided valuable feedback on the interpretation of results and on this written document.   A version of the ‘Imaging Analysis’ section of this project was presented at Skull Base Con 2019 in Coimbatore, India as an abstract presentation.  A version of the ‘Imaging Analysis’ and ‘Quality of Life’ sections of this project were presented at the North American Skull Base Society (NASBS) Conference in San Antonio, Texas as an Oral Presentation. The NASBS accepted abstract has been published as “Prakash S, Akagami R. Emotional Lability as a Symptom of Extra-axial Posterior Fossa Tumors: A Case-Control Review of Neuroanatomy and Patient-Reported Quality of Life. Journal of Neurological Surgery. Part B, Skull Base. 2020. 81(S 01): S1-S272.”  A manuscript based on this work is being prepared for submission for peer review.       viiTABLE OF CONTENTS ABSTRACT .......................................................................................................................................... iii LAY SUMMARY ................................................................................................................................... v PREFACE ............................................................................................................................................. vi TABLE OF CONTENTS ......................................................................................................................... vii LIST OF TABLES ................................................................................................................................... ix LIST OF FIGURES ................................................................................................................................. x LIST OF ABBREVIATIONS ..................................................................................................................... xi ACKNOWLEDGEMENTS ..................................................................................................................... xii 1. BACKGROUND ................................................................................................................................ 1 1.1 Image Analysis Background ............................................................................................. 2 1.2 Quality of Life Background ............................................................................................... 5 1.3 Image Analysis Aim .......................................................................................................... 7 1.4 Quality of Life Aim ............................................................................................................ 7 2. METHODS ....................................................................................................................................... 7 2.1 Clinical Chart Review ........................................................................................................ 9 2.2 Image Analysis Review ................................................................................................... 10 2.3 Quality of Life Review ..................................................................................................... 12 3. RESULTS ........................................................................................................................................ 13 3.1 Clinical Findings .............................................................................................................. 13 3.2 Imaging Analysis Findings .............................................................................................. 14 3.3 Quality of Life Findings ................................................................................................... 16 3.3.1 First Post-Operative QOL Survey ............................................................................ 17     viii3.3.2 One-year Post-Operative QOL Survey .................................................................... 19 3.3.3 Last Available Post-Operative QOL Survey ............................................................. 21 4. DISCUSSION .................................................................................................................................. 23 4.1 Clinical and Image Analysis Findings ............................................................................. 24 4.1.1 Brainstem Compression Finding ............................................................................. 24 4.1.2 Cerebellar Findings ................................................................................................. 26 4.1.3 Brainstem Compression Scale Application ............................................................. 27 4.1.4 Limitations & Future Direction ............................................................................... 27 4.2 Quality of Life Findings ................................................................................................... 27 4.2.1 First Post-Operative QOL Survey ............................................................................ 28 4.2.2 One-year Post-Operative QOL Survey .................................................................... 29 4.2.3 Last Available Post-Operative QOL Survey ............................................................. 31 4.2.4 Limitations & Future Direction ............................................................................... 33 5. CONCLUSION ................................................................................................................................ 34 REFERENCES ..................................................................................................................................... 35 APPENDICES ...................................................................................................................................... 39 Appendix 1: Statistics Code and Output .............................................................................. 39 Appendix 2: SF36v1 Survey .................................................................................................. 44 Appendix 3: SF36v1 Scoring Guide ....................................................................................... 49         ixLIST OF TABLES Table 1. Summary of case reports for emotional lability in adults caused by extra-axial  posterior fossa mass lesions…………………………………………………………………………………………..… 4 Table 2. Clinical characteristics of EL and control patients…………………………………………..…… 14 Table 3. Lateral brainstem compression scale mean scores………………………………………………  15 Table 4. Mean change in quality of life scores for each SF36v1 subsection and health change as a separate metric using the first post-operative survey………………………………….… 18 Table 5. Mean change in quality of life scores for each SF36v1 subsection and health change as a separate metric using the last survey within 1 year after surgery…………………. 20 Table 6. Mean change in quality of life score for each SF36v1 subsection and health  change as a separate metric using the last available post-op survey………………………………… 22 Table 7. Deviance residuals of the binomial logistic regression model of clinical characteristics. ………………………………………………………………………………………………………………… 39 Table 8. Coefficients of the binomial logistic regression model of clinical characteristics…. 39 Table 9. Deviance residuals of the binomial logistic regression model of lateral brainstem compression score.…………………………………………………………………………………………………..………. 40 Table 10. Coefficients of the binomial logistic regression model of lateral brainstem compression..………………………………………………………………………………………………………………..….. 40 Table 11. First Post-Operative QOL Survey: coefficients for the linear mixed-effects model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric…………………………………………………………………………………………………………………………….…. 42 Table 12. One-year Post-Operative QOL Survey: coefficients for the linear mixed-effects  model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric………………………………………………………………………………………………………………….……………. 42 Table 13. Last Available Post-Operative QOL Survey: coefficients for the linear mixed-effects model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric……………………………………………………………………………………………………………..……. 43       xLIST OF FIGURES  Figure 1. Example of measuring and calculating brainstem compression at the level of the (A) medulla, (B) pons, and (C) midbrain….………………………………………………………………..… 11 Figure 2. Lateral brainstem compression scale…………………………………………………………………. 11 Figure 3. Lateral brainstem compression mean scores for the EL group compared to the control group at the medulla, pons, and midbrain……………………………………………………………. 15 Figure 4. Patient inclusion flowchart for the QOL analyses……………….……………………………….. 16 Figure 5. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the first post-operative survey………………………………………………………………………………………………………………………………. 18 Figure 6. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the last survey within 1 year after surgery………………….…………………………………………………………………………………………………. 20 Figure 7. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the last available post-op survey………………………………………………………………………………………………………………………………. 22                xiLIST OF ABBREVIATIONS  BP Bodily Pain (SF36v1 sub score) EF Energy/fatigue (SF36v1 sub score) EL Emotional lability EW Emotional well-being (SF36v1 sub score) GH General health (SF36v1 sub score) HC Health Change (SF36v1 metric) PF Physical functioning (SF36v1 sub score)  QOL Quality of life  RE Role limitations due to emotional problems (SF36v1 sub score) RP Role limitations due to physical health (SF36v1 sub score) SF Social functioning (SF36v1 sub score) SF36v1 Short form-36 version 1 general health survey   VGH Vancouver General Hospital         xiiACKNOWLEDGEMENTS  I would like to sincerely thank my co-supervisor Dr. Ryojo Akagami for his ongoing support and guidance during every step of this process. I am very grateful for his time and expertise, without which I would not have been able to complete this project. I would additionally like to acknowledge and thank Dr. Gooderham and Dr. Mui for their time, feedback, and guidance on this project. They were extremely generous and supportive during the course of my degree.      1 1. BACKGROUND Extra-axial brain tumours include a wide range of pathologies originating from the meninges, cranial nerves, or other surrounding structures of the brain. Extra-axial tumours in the posterior fossa of the cranial cavity may cause brainstem compression depending on its size and proximity to brainstem structures. The brainstem regulates information flow between the cerebrum, the cerebellum, and the rest of the body2. Compression of the brainstem can lead to a variety of nefarious symptoms that can affect breathing, heart rate regulation, and wakefulness3. Emotional lability, the dysregulation of emotional expression, as a symptom of brainstem compression is rare. There have been fewer than 20 reports of extra-axial tumours causing emotional lability due to compression of the brainstem.  Emotional lability (EL) is uncontrollable and unmotivated expression of emotion, often presenting as laughter or crying4. There is no perceived mood change associated with these episodes, and it is distinct from mood disorders where dysregulation occurs at the level of primary emotion formation4. Primary emotion formation occurs in the prefrontal cortex and in the limbic system5. EL is also distinct from gelastic seizures, which are paired with abrupt sympathetic system activation6. EL is not an issue of generating the motor function since the motor behavior of laughter and crying episodes mimic the authentic expression 4. EL is common among patients with amyotrophic lateral sclerosis7, multiple sclerosis8, severe traumatic brain injury9, and stroke10. The nosology regarding EL is imprecise so the following terms, phrases, and concepts will be included under the umbrella term ‘emotional lability’ for this research      2 project: ‘emotionalism’, ‘pseudobulbar affect’, ‘labile affect’, ‘emotional incontinence’, ‘pathological laughter’, ‘pathological crying’, and ‘pathological laughter and crying’.  1.1 Image Analysis Background  The pathophysiological mechanism of EL caused by mass lesions has not yet been determined. In reviewing and synthesizing proposed mechanisms from case reports, overlapping theories were found. While authors cited different structures of the affected brain for causing EL, the general regions remained consistent over reports. To substantiate a stronger foundation for this study, we also extrapolated findings from EL-causing intra-axial tumours and strokes within the brainstem.  Of the published case reports for emotional lability in adult patients with extra-axial tumours (Table 1), meningiomas were found in the following regions: in the petroclival region11, 12, 13, 14, ventral to the pons15, in the tentorium16, and in the petrous apex region17. Patients with schwannomas6, neuromas18, 19, and chordomas20, 21 have also presented with EL. Similarly, EL has been noted in a subsect of patients with intra-axial tumours, specifically brainstem gliomas22, 23, ependymomas24, and cysts 4, 20. In all reports, EL was immediately and entirely alleviated with surgical resection of the tumour. In the paediatric population, Hargrave et al. reported a cohort of 17 intra-axial pontine glioma patients with pathological laughter that improved or resolved with tumour resection25. Of note, EL symptoms resumed at recurrence of the tumour in several patients25 and emotional lability symptoms often presented earlier than other neurological deficits13.      3 Many of the reviewed case reports proposed a mechanism for why patients experienced this symptomatology, these stipulations have been highlighted here. Muzumdar et al. suspected that compression onto the brainstem and medial temporal brain structures causes pathological laughter13 and Bhatjiwale et al. hypothesized that significant distortion causing “crescentic pons” are a radiological sign associated with pathological laughter18. Another proposed mechanism stipulated that key regulatory nuclei in the pons and medulla may be distorted by compression from a mass lesion11. Ascending serotonergic transmission from the raphe nuclei have been associated with pathological crying specifically6. Kim et al. postulated that disruption at any point in the cortico-ponto-cerebellar circuit can cause emotional lability28. Numerous studies have further associated disruption of the basis pontis with EL 4, 29, 30.   Parvizi et al. suggests that the basis pontis is the only region where a discrete lesion can cause emotional lability27. The findings from Dr. Parvizi’s seminal papers4, 27, 30 outline the basis of our hypothesis that increased compression from mass lesions onto the basis pontis structures causes emotional lability symptoms. It is theorized that deafferentation of the cerebellum leads to dysregulation of emotional expression. Projections from cortical and limbic regions of the brain communicate through the pons to the cerebellum. Tumours can cause displacement of brainstem structures from their neutral anatomical position, causing stretching and dislocation of the tracts that communicate through nearby structures. This investigation aims to address a gap in neurophysiology as there is no current case series to outline the link between emotional lability and brainstem compression from posterior fossa tumours in adults. Studying this disorder furthers our understanding about how the brain, specifically the cerebellum, regulates      4 emotion. There are pertinent clinical applications for this study since EL often presents earlier than other neurological symptoms: an established pathophysiological mechanism for emotional lability could support its inclusion as a useful clinical symptom, for which patients can be screened.  Table 1. Summary of case reports for emotional lability in adults caused by extra-axial posterior fossa mass lesions. Author Year Title Country Num of Patients Diagnosis Publication Details Cantu et al. 1966 Pathological Laughing and Crying Associated with a Tumor Ventral to the Pons USA 1 Meningioma Ventral to the Pons Volume 24: Issue 6 (Jun 1966) in Journal of Neurosurgery Stevenson et al.  1966 A Transcervical Transclival Approach to the Ventral Surface of the Brain Stem for Removal of a Clivus Chordoma USA 1 Clivus Chordoma Volume 24: Issue 2 (Feb 1966) in Neurosurgery  Matsuoka et al. 1993 Clival Chordoma associated with pathological laughter - Case report Japan 1 Clival Chordoma Volume 79: Issue 3, pp 428-433 (Sep 1993) in Journal of Neurosurgery Shafqat et al. 1998 Petroclival meningioma presenting with pathological laughter USA 1 Petroclival Meningioma Volume 50: Issue 6, pp 1918-1919 (Jun 1998) in Neurology Tsutsumi et al 2000 Tentorial Meningioma Associated with Pathological Laughter-Case Report Japan 1 Tentorial Meningioma Volume 40, pp 272-274 (2000) in Neurologia Medico-Chirurgica Bhatjiwale et al. 2000 Pathological Laughter as a Presenting Symptom of Massive Trigeminal Neuromas: Report of Four Cases India 4 Trigeminal Neuromas Volume 47: Issue 2, pp 469-472 (Aug 2000) in Journal of Neurosurgery Muzumdar et al.  2001 Pathological Laughter as a Presenting Symptom of Petroclival Meningioma India 1 Petroclival Meningioma Volume 41: Issue 10, pp 505-507 (2001) in Neurologia Medico-Chirurgica      5 Virani et al. 2001 Trigeminal Schwannoma associated with pathological laughter and crying India 1 Cerebellopontine Angle Trigeminal Schwannoma Volume 49: Issue 2, pp 162-165 (Jun 2001) in Neurology India McCormick et al. 2002 Pseudobulbar Palsy Caused by a Large Petroclival Meningioma Report of Two Cases USA 2 Petroclival Meningiomas Volume 12: Issue, pp 61-71 (May 2002) in Skull Base Cheng et al. 2003 Petroclival Meningioma Presenting with Pathological Laughter: Report of a Case and Review of the Literature Taiwan 1 Petroclival Meningioma Volume 12: Issue 4, pp 187-190 (Nov 2003) in Acta Neurol Taiwan Nadkarni et al.  2009 Trochlear nerve neurinoma presenting as pathological laughter India 1 Trochlear Nerve Neurinoma Volume 13: Issue 3, pp 212-213 (Jul 2009) in British Journal of Neurosurgery Hassan et al.  2018 Pseudobulbar Affect Due to Skull Base Meningioma Resolving After Temporal Lobectomy for Epilepsy Canada 1 Petrous Apex Meningioma  Volume 45: Issue 4, pp. 485-486 (Jul 2018) in Can J Neurol Sci.  Total 16   1.2 Quality of Life Background  The increased psychiatric and psychological encumbrance caused by EL renders the symptom a worthwhile phenomenon to better understand. Stroke patients with EL experience higher rates of depression31. When controlled for elevated depression rates, these patients also experience greater reported irritability and delusions of reference compared to the general population31. There is a clear social and professional burden associated with this condition as patients are unable to control their outbreaks, leading to socially awkward or inappropriate situations. This can have a detrimental effect of a patient’s quality of life (QOL). Patients who suffer from EL after stroke, due to demyelinating disease, or other irreversible conditions can be treated with      6 antidepressants and dopaminergic agents, which mitigate the symptom at optimal dosing32. For patients with EL-causing mass lesions, the symptom can be cured immediately and entirely after the tumour is removed. This provides unique insight into how EL independently affects patient reported QOL.  Improving patient-reported quality of life is an important goal of medical and surgical treatment. Skull base tumour patients are treated to mitigate future deterioration and, when possible, to improve current deficits caused by the lesion. Barring intra-operative and post-operative complications, skull base tumour resection surgery typically improves patient reported quality of life33. For patients with EL-causing tumours, the list of symptoms improved by surgery would additionally include cessation of EL symptoms. In order to assess whether surgically curing EL symptoms leads to a greater improvement in QOL, we compared survey scores between EL patients and control patients. Quantifying patient reported QOL health scores adds an additional goal of surgery for EL patients: to improve QOL by relieving EL symptoms.  We hypothesized that patient-reported quality of life will improve post-operatively for patients with EL. This is in keeping with the expected QOL improvement after skull base tumour resection, barring complications. We also postulated that immediate post- versus pre-operative QOL improvements for patients with EL would be greater than those of matched control patients due to post-operative cessation of EL and associated social burdens of the symptom.       7 1.3 Image Analysis Aim The primary purpose of this project was to compare pre-operative brain imaging between EL and non-EL patients to determine which, and to what extent, brainstem structures were compressed by EL-causing mass lesions.   1.4 Quality of Life Aim The secondary outcome of this project was to compare, between EL and control patients, the changes in quality of life scores pre- versus post-operatively.   2. METHODS The Vancouver General Hospital (VGH) neurosurgical/neurophysiology database was retrospectively reviewed. This database contains records for all resections of posterior fossa tumours with brainstem compression since neuro-monitoring is essential for cases where tumours are in close proximity to brainstem structures and cranial nerves. The date range for this study was 01 January 2002 to 31 December 2018. This date range was selected because it matches the tenure of the skull base neurosurgeon at VGH. During this time, intraoperative monitoring of cranial nerves became commonplace for complex cases, included those reviewed in this study.        8 Neurosurgical pre-operative clinic notes were reviewed. EL symptoms, when present, were noted in the ‘Physical Examination’ or the ‘History’ section. Patients with explicit mention of having EL symptoms in their consultation report were further screened for exclusionary factors. All eligible patients were included in this investigation.  Control patients were matched to EL cases in a 1:3 ratio (cases: controls). To mitigate confounding factors, controls were assigned in the following manner:   a) For each EL patient, a list of possible controls was created. Controls were matched for: • the treating neurosurgeon • time of surgical treatment (+ 2 years) • tumour pathology • general tumour location b) From the list, 3 patients were randomly selected using a random number generator c) Scans of the selected controls were reviewed to ensure that the tumour type and general location were consistent with pre-selection categorization. Any discrepancies in tumours pathology and/or general location were corrected by repeating steps b and c to select another control d) If the selected patient met the exclusion criteria, steps b and c were repeated to select another control         9 Exclusion Criteria (for EL and Control Patients) • Patients under 18 years of age • Patients who have more than one mass lesion visible on their pre-operative MRI scan • Patients who have had a brain tumour at any other point during their life • Patients who are diagnosed with Neurofibromatosis type 2 • Patients who have had any previous psychiatric diagnosis • Patients who have had any neurodegenerative or demyelinating disease diagnosis • Patients who have had moderate to severe brain injury • Patients who have had any previous strokes or has evidence of previous infarcts on their pre-operative MRI scan  2.1 Clinical Chart Review A clinical chart review was completed. Patient demographics, clinical presentation, radiological characteristics, surgical features, mortality, clinical outcomes, and radiological outcomes were collected for the cases and matched controls. Clinical variables were compared between EL patients and control patients.  Descriptive statistics are outlined, and clinical characteristics are tabulated and presented in tables. Binomial logistic regression was used to compare clinical characteristics between EL patients and matched controls. For all analysis, the cut-off significance value was set a priori to 0.05.       10 2.2 Image Analysis Review Pre-operative axial T2-weighted FLAIR MRI scans were reviewed for each case and control patient. If several pre-operative scans were available, the one closest in date to the surgery was reviewed. To standardize the process, the following procedure was completed for each scan (Figure 1). At the level of the medulla, a horizontal line was drawn between the jugular foramina. At the level of the pons, a horizontal line was drawn between the internal acoustic canals. At the level of the midbrain, a horizontal line was drawn between the inferior horns of the lateral ventricle. A vertical line was then drawn at each level from the nasal septum, through the measured center-point of the respective aforementioned horizontal line, to the occipital bone. Within the superior-inferior anatomical boundaries of each brainstem structure, the widest point of the tumour was used for the measurement of brainstem compression.   We created a novel lateral brainstem compression scale (Figure 2) to characterize the degree of mass effect at the level of the medulla, pons, and midbrain. The degree of compression from the mass lesion onto the respective brainstem structure was measured using the demarked lines and categorized according to the lateral brainstem compression scale. Three compression scores, at the medulla, pons, and midbrain, were collected for each patient. Scores at each level were subsequently compared between EL patients and control patients.   Binomial logistic regression was used to determine whether a statistically significant difference exists for lateral brainstem compression scale scores between EL participants and matched controls. For all analysis, the cut-off significance value was set a priori to 0.05.      11  Figure 1. Example of measuring and calculating brainstem compression at the level of the (A) medulla, (B) pons, and (C) midbrain.   Figure 2. Lateral brainstem compression scale A B C      12 2.3 Quality of Life Review As standard of care, patients who have a skull base neurosurgery clinic appointment at VGH complete a Short form-36 version 1 (SF36v1) survey prior to seeing the surgeon. The SF36v1 is a general health survey. The prospectively collected scores were retrospectively obtained from patient charts. Pre-operative and post-operative SF36v1 survey scores were retrieved for each EL case and control patient.   Only patients with a complete set of at least one pre- and post-op survey were included.  Several patients had more than one pre- or post-operative survey. The pre-operative survey with the date closest to the surgery date was used for all patients in all analyses. Three analyses were completed: 1. First Post-Operative QOL Survey: the first post-operative survey was used for comparison. Per standard of care, the first post-operative follow-up appointment is scheduled for approximately 6-8 weeks after surgery.  2. One-year Post-Operative QOL Survey: the last survey within a 1-year post-operative period was used for comparison. Patients are typically scheduled for a 6-month follow-up appointment per standard of care. If a patient has no post-op survey in the 1 year after surgery, they will be excluded from this analysis. 3. Last Available Post-Operative QOL Survey: the last available survey was used for comparison. Long-term follow-up varies greatly based on the patient’s ongoing symptoms.      13 SF36v1 scores were tabulated using the standard scoring protocol for this health survey34.  Subsection scores and “Health Change” as a separate metric were calculated. In all analyses, each patient served as their own control: the pre-operative score was subtracted from the post-operative score to calculate change in QOL score. The change in scores were compared between EL and control patients for each analysis. A linear mixed-effects model was used to compare the change in SF36v1 sub-scores and in the health change metric between EL cases and matched controls. For all analysis, the cut-off significance value was set a priori to 0.05.   3. RESULTS 3.1 Clinical Findings Of the 673 posterior fossa tumour patients treated for brainstem-compressing extra-axial tumours between 01 January 2002 and 31 December 2018, 11 (2%) patients were found to have EL symptoms pre-operatively. Of these 11 cases, 7 (64%) were female and the mean age was 50.0 years (range 32-65) at the time of presentation (Table 2). The mean tumour size was 38.1 mm (range 15-56 mm). Of the 11 EL patients, 7 (64%) had meningiomas while 4 (36%) had acoustic neuromas. Of the meningiomas, 5 were petroclival meningiomas while 2 were cerebellopontine angle meningiomas. EL ceased for all 11 patients post-operatively. The majority of patients in both groups underwent a gross-total or a near-total resection of their tumour.  A binomial logistic regression was done to assess differences between the EL and control groups. The proportion of EL patients with cerebellar findings, including dysmetria, clumsiness,      14 and slowness, was significantly greater than the proportion in the control population (p=0.003). Cerebellar findings pre-operatively were the sole clinical characteristic that demonstrated a statistically significant difference between the two groups.   Table 2. Clinical characteristics of EL and control patients (* denotes a statistically significant difference) Variable  EL (n=11) Control (n=33) p value Sex            Male 4 (36%) 16 (48%) 0.711         Female 7 (64%) 17 (52%) Age             Mean (years) 50.0 51.3 0.704 Handedness            Right 9 (82%) 32 (97%) 0.918         Left 2 (18%) 1 (3%) Tumour Laterality            Right 6 (55%) 20 (61%) 0.438         Left 5 (45%) 13 (39%) Tumour Size            Mean (mm) 38.1 37.2 0.695 Cerebellar Findings            Present 7 (64%) 1 (3%) 0.003*   3.2 Imaging Analysis Findings All 11 EL patients and 33 matched controls were included in the lateral brainstem compression analysis. The mean compression scores for the two groups at each of the 3 brainstem levels are outlined in Table 3. A binomial logistic regression found that compared to the control group, EL-causing tumours exert greater compression onto the pons (mean EL compression score=2.9, mean control compression score=1.9, two-tailed p=0.02). EL tumours compress the pons on      15 average in the 50-74% range while the non-EL tumours compress in the 25-49% range.  There was no difference in lateral compression found at the level of the midbrain or the medulla (Figure 3).   Table 3. Lateral brainstem compression scale mean scores (* denotes a statistically significant difference). Brainstem Structure EL (n=11) Control (n=33) p value         Medulla 1.1 0.9 0.84         Pons 2.9 1.9 0.02*         Midbrain 1.5 1.0 0.31  Figure 3. Lateral brainstem compression mean scores for the EL group compared to the control group at the medulla, pons, and midbrain (* denotes a statistically significant difference)     1.12.91.50.91.9100.511.522.533.54Medulla Pons MidbrainCompression Scale ScoreRegionBRAINSTEM COMPRESSION SCORES EL Control*     16 3.3 Quality of Life Findings Figure 4 outlines which patients were included in each of the 3 QOL analyses. In order to effectively detect quality of life change, only those with a complete set of pre- and post-operative SF36v1 health surveys were compared to their matched controls. Similarly, only controls with a complete set of SF36v1 health surveys were included. 8 EL patients and 20 control patients fit this requirement. For the “One-year Post-Operative QOL Survey” analysis, patients without a post-operative survey in the 1 year after surgery were additionally excluded.    Figure 4. Patient inclusion flowchart for the QOL analyses.   Assessed for eligibility (EL n=11, Controls n=33) Excluded (EL n=3, Controls n= 13)  • Did not have at least 1 pre-op and 1 post-op survey  First Post-Operative QOL Survey (EL n=8, Controls n=20) • Included in analysis One-year Post-Operative QOL Survey (EL n=6, Controls n=14) • Included in analysis  Last Available Post-Operative QOL Survey (EL n=8, Controls n=20) • Included in analysis  Excluded (EL n=2, Controls n= 6)  • 2 EL patients did not have a post-op survey within 1 year of surgery   • Matched controls for these 2 EL patients were removed from analysis       17 3.3.1 First Post-Operative QOL Survey (EL n=8, controls n=20) This analysis compared patients’ pre-op survey to their first post-op survey. The median time between the pre-operative survey and surgery was 5.6 weeks (range 0.9 – 37.1 weeks) for EL patients and 9.9 weeks (range 2.0 – 68.6 weeks) for control patients. The median time between the surgery and the first post-operative survey was 9.8 weeks (range 5.9 – 72.9 weeks) for EL patients and 8.6 weeks (range 5.9 – 35.6 weeks) for control patients.  The change in QOL scores are outlined in Table 4.  The mean total SF36v1 improvement experienced by EL patients (167-point improvement) was greater than that experienced by control patients (143-point improvement). “Health Change” is not included in the sum of SF36v1 sub-scores. A linear mixed-effects model found that patients with EL-causing tumours experience greater improvement post-operatively in the “Health Change” category (two-tailed p=0.05). “Health Change” demonstrates patient perception of health and function. Of note, control patients were found to experience greater improvement than EL patients post-operatively in the “Role Limitations Due to Physical Health” (two-tailed p=0.03). Changes in the remaining SF36v1 subcategories did not demonstrate a statistically significant difference (Figure 5).           18 Table 4. Mean change in quality of life scores for each SF36v1 subsection and health change as a separate metric using the first post-operative survey (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change) Patient Group SF36v1 Subsection  ∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ HC EL -2.0 -3.1 29.3 35.6 38.5 29.9 17.8 20.6 53.1 Control 8.3 32.5 31.8 16.9 13.2 14.4 14.2 12.3 8.8 p value 0.166 0.023* 0.359 0.462 0.573 0.559 0.663 0.719 0.047*   Figure 5. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the first post-operative survey (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change, * denotes a statistically significant difference).   -20020406080100120140160180∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ Sum ∆ HCChange in ScoreSF36v1 Sub-categoryCHANGE IN SF36V1 SUB-CATEGORY SCORES (F IRST  POST-OP SURVEY)EL Control* *      19 3.3.2 One-year Post-Operative QOL Survey (EL n=6, controls n=14) This analysis compared patients’ pre-op survey to their last survey within a 1-year post-op period. There were 2 EL patients removed from this analysis because their post-operative survey(s) did not fall within the 1-year window after surgery. Matched controls for these 2 EL patients were also removed from this analysis. Ultimately, 6 EL patients and 14 controls were included in this analysis. For patients who had only one post-operative survey that happened to be completed within the first year after surgery, the QOL score change for this analysis would be congruent with those stated in the “First Post-Operative QOL Survey” section.  The median time between the pre-operative survey and surgery was 6.7 weeks (range 2.1 – 37.1 weeks) for EL patients and 10.6 weeks (range 2.6 – 45.1 weeks) for control patients. The median time between the surgery and the post-operative survey was 23.8 weeks (range 10.3 – 43.9 weeks) for EL patients and 24.5 weeks (range 7.3 – 43.9 weeks) for control patients.  Change in QOL scores are outlined in Table 5. The mean total SF36v1 improvement experienced at this timepoint by control patients (156-point improvement) was greater than that experienced by EL patients (126-point improvement) as demonstrated in Figure 6. “Health Change” is not included in the sum of SF36v1 sub-scores. A linear mixed-effects model found that patients with EL-causing tumours experience greater improvement at this post-operative timepoint in the “Health Change” category (two-tailed p=0.03). Changes in the remaining SF36v1 subcategories did not demonstrate a statistically significant difference.       20 Table 5. Mean change in quality of life scores for each SF36v1 subsection and health change as a separate metric using the last survey within 1 year after surgery (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change) Patient Group SF36v1 Subsection  ∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ HC EL 10.7 12.5 16.7 32.5 20.7 29.2 -5.7 9.2 62.5 Control 8.9 50.0 26.1 14.6 20.3 21.4 8.4 6.4 12.5 p value 0.692 0.193 0.639 0.246 0.590 0.280 0.076 0.510 0.026*   Figure 6. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the last survey within 1 year after surgery (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change, * denotes a statistically significant difference).     -20020406080100120140160180∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ Sum ∆ HCChange in ScoreSF36v1 Sub-categoryCHANGE IN SF36V1 SUB-CATEGORY SCORES (ONE-YEAR POST-OP SURVEY)EL Control*      21 3.3.3 Last Available Post-Operative QOL Survey (EL n=8, controls n=20) This analysis compared patients’ pre-op survey to their last available post-op survey. If patients had only one post-operative survey, the QOL score change for this analysis would be congruent with those stated in the “First Post-Operative QOL Survey” section. If the last available survey was within the 1-year post-operative window, the QOL score change for this analysis would be congruent with those stated in the “One-year Post-Operative QOL Survey” section. For patients with several post-operative surveys, the relative long-term change in QOL can be noted in this analysis.  The median time between the pre-operative survey and surgery was 5.6 weeks (range 0.9 – 37.1 weeks) for EL patients and 9.9 weeks (range 2.0 – 68.6 weeks) for control patients. The median time between surgery and the last available post-operative survey was 71.9 weeks (range 27.9 – 426.9 weeks) for EL patients and 35.6 weeks (range 7.4 – 262.1 weeks) for control patients.   The change in QOL scores are outlined in Table 6. The mean total SF36v1 improvement experienced by EL patients (141-point improvement) was greater than that experienced by control patients (132-point improvement) as demonstrated in Figure 7. “Health Change” is not included in the sum of SF36v1 sub-scores. A linear mixed-effects model found that there was no statistically significant difference between EL patients and controls patients in any SF36v1 sub-score or in the “Health Change” metric in this analysis.        22 Table 6. Mean change in quality of life score for each SF36v1 subsection and health change as a separate metric using the last available post-op survey (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change)   Figure 7. Change in quality of life score for each SF36v1 subsection, the sum of subsections, and health change as a separate metric using the last available post-op survey (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change).   0.0050.00100.00150.00200.00∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ Sum ∆ HCChange in ScoreSF36v1 Sub-categoryC H A N G E  I N  S F 3 6 V 1  S U B - C AT EG O RY  S CO R ES( L A ST  AVA I L A B L E  P O ST- O P  S U RV E Y )EL ControlPatient Group SF36v1 Subsection  ∆ PF ∆ RP ∆ RE ∆ EF ∆ EW ∆ SF ∆ BP ∆ GH ∆ HC EL 13.6 9.4 20.9 35.6 28.5 20.4 5.5 7.5 43.8 Control 8.5 36.3 28.3 12.4 17.4 18.1 3.1 7.5 18.8 p value 0.855 0.190 0.530 0.212 0.753 0.847 0.849 0.381 0.498      23 4. DISCUSSION The main findings of this project were that a) patients with EL pre-operatively have greater brainstem compression at the level of the pons, b) patients with EL pre-operatively more often have cerebellar findings on neurological exam, and c) patient perception of health improves in the period immediately after surgery and continues for at least 1 year when resection cures EL symptoms. There is a dearth of clinical literature regarding mass lesions and emotional lability. This is the largest case series to date on adult extra-axial posterior fossa tumours that cause emotional lability.   The homogeneity in surgical treatment paradigm and post-operative care received by patients strengthens our foundational understanding of this rare clinical phenomenon. All the data was collected from a single institution and all patients were treated by the same fellowship-trained skull base neurosurgeon, meaning that all patients were treated according to a uniform surgical treatment paradigm. This homogeneity limits discrepancies that may arise when comparing surgeons who subscribe to a “wait and watch” approach versus those who prefer aggressive resection. The uniformity of post-operative care and rehabilitation resources available to patients at Vancouver General Hospital strengthens the quality of life findings herein. Cases were matched to controls that had a similar timeframe for surgery (+ 2 years) to ensure that these consistencies were maintained. For an initial study, the narrow scope of these conditions was a strength. To improve generalizability, future studies ought to examine whether these findings, especially the quality of life findings, are consistent at other institutions.      24 Since the link between EL and brainstem-compressing posterior fossa tumours is not widely known, there may be underreporting of the symptom. Since there is no expected frequency for EL symptoms, it is possible that the outbreaks go unnoticed during a standard 1-hour neurosurgery consultation. Patients and their family members may not associate the inappropriate outbreaks to a brain tumour, thus failing to report EL when prompted for the patient’s history and symptoms. With greater understanding of how mass lesions can cause EL, general practitioners and neurosurgeons can specifically ask patients with brainstem-compressing tumours whether they have experienced this symptom. More accurate screening and reporting of EL symptoms would be helpful for both clinical purposes and future research aims.   4.1 Clinical and Image Analysis Findings 4.1.1 Brainstem Compression Finding Our results demonstrate that EL tumours compress the pons laterally to a greater degree than non-EL tumours. Specifically, EL tumours were found to compress the pons on average in the 50-74% range while the non-EL tumours compress in the 25-49% range. Compression scores at the level of the medulla and midbrain did not demonstrate a statistically significance difference between groups. Additionally, there was no discrepancy in mean tumour size between groups. These findings support our hypothesis that the basis pontis may be implicated in the EL pathway.       25 The cerebellum is essential for movement co-ordination. The current body of evidence in the literature suggests that the cerebellum also modulates stereotyped expressions of emotion according to specific contextual information4. Depending on social context, expressions of laughter and crying to the same stimulus can be scaled up, suppressed marginally, or inhibited completely by input from the cerebellum. This theory was introduced by Parvizi and colleagues in 2001 as an alternative theory to the “disinhibition model”, which was proposed by Wilson in 192435. Parvizi’s model emphasizes the cerebellum as a center for coordination of pre-programmed stereotyped expressions of emotion through the cortico-ponto-cerebellar pathway. Through this pathway, key cognitive and social context provided by telencephalic structures is relayed through the basis pontis to the cerebellum, where the information is used for regulation. The modulation of expressions by the cerebellum to social context is a learned pattern of behaviour. Subsequently, this information is relayed back to telencephalic inductor and effector sites in cortical and subcortical regions of the brain, leading to context-appropriate laughter and crying. To contextualize the brainstem compression findings herein, we propose that disruption of the pons, in this case due to compression from mass lesion, leads to deafferentation of the cerebellum from cortical and limbic structures through the basis pontis in a manner consistent to the model proposed by Parvizi and colleagues. Ultimately, this impairs modulation of emotional responses to contextual information, rendering patients unable to control their laughter and/or crying. The study results suggest that compression onto the pons inhibits control over involuntary, stereotyped expression of emotion.      26 In this investigation, we did not analyze tumour compression of the brainstem in the anterior-posterior direction. Tumours generally have a sidedness and the lateral scale was sufficient to capture the degree of compression at each brainstem level. An anterior-posterior compression analysis would be useful for truly midline clival tumours, which are rare. Furthermore, none of the tumours in our study were pure midline clival tumours.  4.1.2 Cerebellar Findings  Compared to control patients, EL patients more commonly have motor cerebellar findings pre-operatively during a standard neurological exam. Greater disruption of EL tracts is correlated with greater disruption of motor tracts to the cerebellum. EL patients more frequently present with dysmetria, clumsiness, and slowness when asked to complete coordinated movements. This is likely because motor tracts communicating to the cerebellum may also be affected by the increasingly compressed basis pontis. While EL is a motor response, it is stipulated that the EL-related circuitry involves different tracts from those engaged in “non-EL” motor responses. This may explain why patients with cerebellar findings, like dyscoordination, commonly don’t exhibit EL symptoms and inversely, why not all EL patients in our cohort had cerebellar findings during their neurological exam.          27 4.1.3 Brainstem Compression Scale Application The novel brainstem compression scale used for project can be used for future investigations since there is no published scale currently for brainstem compression. This scale would be beneficial to quantify otherwise nebulous qualitative characterizations of compression (ex. “moderate”, “severe”, “marked”, etc.). To this end, our scale has wide implications beyond this current investigation.   4.1.4 Limitations & Future Direction  The main limitation for this section of the study was the lack of prospective data due to the rarity of this condition. Future research should aim to perform comparative analysis with prospectively collected diffusion tensor imaging (DTI) studies so that affected brainstem regions can be mapped pre- and post-operatively for a better understanding of the tracts involved in the regulation of emotional expression.  4.2 Quality of Life Findings This section of the study aimed to investigate change in quality of life after surgery. We compared prospectively collected pre-operative survey scores to post-operative scores at three timepoints: a) the first post-op follow-up appointment, b) the last follow-up appointment within a 1-year post-op period, and c) the most recent post-op neurosurgical appointment. For patients with limited post-op surveys, there was overlap in the surveys included for each of these three timepoints.  For all three analyses, the median was used to describe the time      28 between two events because outlier data points skew the mean values, rendering the mean an ineffective tool for analyzing this data set.  4.2.1 First Post-Operative QOL Survey Using the first post-operative survey scores demonstrate the acute change in QOL. This is reflective of the immediate cessation of EL symptoms post-operatively per our hypothesis. In support of our hypothesis, it was found that EL patients experience greater acute improvement post-operatively in the “Health Change” metric, which ascertains perception of health. In six of the eight SF36v1 subsections, EL patients experienced improvement post-operatively. While none of these sub score changes were statistically greater than the improvement of control patients, the EL group perceived their health to be improved to a greater degree than the control patients perceived their health change. This finding on perceived health change augments the benefits of obtaining EL-alleviating surgery for patients.  Unexpectedly, the control group experienced a greater improvement post-operatively in the “Role Limitations Due to Physical Health” subsection. This can be attributed to one outlier patient in the EL group whose deterioration post-operatively skewed the small data set. This patient suffered from prolonged diplopia and was undergoing outpatient rehabilitation during the time of his first post-op follow-up. Of note, the diplopia resolved completely by his second follow-up appointment and his QOL survey scores normalized to be consistent with his pre-operative scores. Even with the outlier EL patient, the sum of all sub-scores demonstrates that EL patients experience greater average improvement compared to the control group.       29 The expected timeline for this follow-up was regularly met. Routine follow-up appointments are typically booked for approximately 6-8 weeks after surgery. We found that the median time between the surgery and the first post-operative survey was 9.8 weeks (range 5.9 – 72.9 weeks) for EL patients and 8.6 weeks (range 5.9 – 35.6 weeks) for control patients.    4.2.2 One-year Post-Operative QOL Survey The purpose of analysis at this timepoint was to ascertain the QOL status of patients within a 1-year post-operative period. This timepoint provides long-term data for “Health Change” since this metric is measured in a 1-year timeframe (“compared to one year ago, how would you rate your health in general now?”). In order to effectively assess QOL at this timepoint, we excluded patients who did not have at least one post-op survey within the first year after surgery. To this end, 2 EL patients and 6 of their matched controls were removed from the analysis. Finally, 6 EL patients and 14 controls were included in this analysis; this sample size was the smallest of the three analyses.  It was found that EL patients experience greater improvement post-operatively in the subsection “Health Change” at this timepoint. As noted in the previous section, this metric assesses how patients perceive their health status. These findings are additionally in support of our hypothesis, further strengthening the benefits of obtaining EL-alleviating surgery since health change continues to be greater for the EL group than for the control group within the 1-year post-op window.       30 Of note, it was found that at this timepoint, control patients experience greater mean improvement in total SF36v1 score, though the difference does not reach statistical significance. In the other two QOL analyses, EL patients have a greater mean improvement in SF36v1 total score. This is the sole analysis where this finding was reversed, one of two phenomenon are thought to be responsible for this outcome: a) this is a function of the reduced sample size for this analysis (EL n=6, controls n=14) or b) at this timepoint, the control patients truly have a greater improvement than EL patients. The evidence towards the former rationale is superior, there was a reduced sample size in this specific analysis due to the nature of the 1-year timeline. As we reduce the sample size, the effect of outlier data points on the mean total score increases. Since no specific SF36v1 subsection demonstrated a statistically significant difference between the control population and the EL population, the greater total score change for the control group can be attributed mostly to the reduced sample size.  The expected timeline for the follow-ups that are scheduled within the 1-year post-op period was largely met. Patients are normally seen in the clinic at approximately 6 months after surgery, then again at the 1-year post-op mark depending on ongoing symptoms. The median time between the surgery and the post-operative survey was 23.8 weeks (range 10.3 – 43.9 weeks) for EL patients and 24.5 weeks (range 7.3 – 43.9 weeks) for control patients.            31 4.2.3 Last Available Post-Operative QOL Survey This analysis includes the change in long-term quality of life for patients who were seen over an extended period of time by the treating neurosurgeon. Patients are typically seen by their surgeon until improvements and ongoing symptoms plateau after surgery, this can take up to one year in some cases. Follow-up appointments are made at the surgeon’s discretion; patients may also request an appointment if they have new or ongoing concerns about their post-operative neurological health status.   The median time between the surgery and the last available post-operative survey was 71.9 weeks (range 27.9 – 426.9 weeks) for EL patients and 35.6 weeks (range 7.4 – 262.1 weeks) for control patients. Patients who presented with EL have a longer median follow-up period, this can be attributed to the complicated nature of their surgery. As noted in the brainstem compression findings, patients with EL have greater compression in this highly complex region of the brain. Greater brainstem compression makes surgery more complicated, rendering ongoing post-operative follow-ups essential for symptom monitoring. The need for further long-term follow-up in the EL population alludes to the severity of these cases.  We found no statistically significant difference in QOL sub-scores between the EL and control groups in this analysis. This finding suggests that the diminished outcomes for the EL group in the “Role Limitations Due to Physical Health” subsection during the acute post-op phase stabilized over time. As noted earlier, this is expected since acute complications, such as diplopia, improve with time and rehabilitation. EL patients were found to have greater mean      32 improvement in the total survey score (141-point improvement) compared to the control patients (132-point improvement) at this timepoint.   We found that there is no difference between the two groups in the long-term analysis of “Health Change”. This is due to the nature of the “Health Change” metric (“compared to one year ago, how would you rate your health in general now?”). The timeline for the aforementioned question no longer holds value in a long-term analysis because patients who are seen more than one year after their surgery are comparing their health to a post-operative timepoint when answering this question. Consequently, this metric at this specific timepoint does not reveal any insights about whether or not alleviation of EL symptoms improves QOL.  It can be concluded that in the long term, the metrics scored by the SF36v1 survey stabilize between both groups as patients generally experience long-term improvements post-operatively. Due to the nature of the brainstem-compressing tumour resection surgery, this conclusion is highly dependent on whether patients suffer from lasting or disabling post-operative complications, which were very rare in our patient population.              33 4.2.4 Limitations & Future Direction This series was retrospective and thus has all the limitations inherent to this study design. One such limitation is potential information bias since we were unable to obtain QOL scores for all 11 EL and 33 control patients. The small size of the cohort was additionally limiting, leading to the potential for data to be skewed and analysis to be biased. Reducing the sample size further for the ‘One-year Post-Operative QOL Survey’ analysis limited the extent to which it could be compared to the other QOL analyses. The lack of data for all patients at all data points was largely because this study is based on data collected for standard of care hence there was no regimented research timeline. While uncommon, some patients did not complete the QOL survey either because they refused to fill out the form or because they were occupied by their appointment and subsequently forgot to fill out the form.  Future studies reporting quality of life changes should consider utilizing prospective data collection methods to follow patients over an extended period of time in order to maximize and standardize data points collected for each patient. To improve generalizability and shorten accrual timelines, a multicenter study is suggested. Lastly, the SF36v1 health survey is a broad quality of life assessment. A brain tumour specific QOL survey (ex. Functional Assessment of Cancer Therapy-Meningioma survey) ought to be considered for future prospective studies to ascertain QOL as it relates to neurological status in addition to metrics measured by general health surveys.         34 5. CONCLUSION This retrospective study is the largest case series to date that investigates adult extra-axial posterior fossa tumours that cause emotional lability. This study strengthens the body of evidence that EL may be attributed to deafferentation of the cerebellum from cortical and limbic structures through the basis pontis, leading to impaired modulation of emotional response. The clinical and image analysis results suggest that compression onto the pons inhibits control over involuntary, stereotyped expression of emotion. The quality of life results indicate that increased improvement in health perception post-operatively for EL patients augment the benefits of obtaining EL-alleviating surgery. 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J Neurol Psychopathol, IV, 299–333.                 39 APPENDICES APPENDIX 1: STATISTICS CODE AND OUTPUT The RStudio code used to complete statistical analysis of the data and the resulting output have been outlined here. To ensure that the correct choice of statistical model was made, we consulted with consultants in UBC Department of Statistics.   Clinical Characteristics:  Glm (formula = EL ~ Gender + Age + Handedness + Laterality + Size + CerebellarFindings, family = "binomial", data = dataframe)  Table 7. Deviance residuals of the binomial logistic regression model of clinical characteristics. Min 1Q Median 3Q Max -1.7282 -0.5026 -0.4307 -0.1460 2.4585  Table 8. Coefficients of the binomial logistic regression model of clinical characteristics.   Estimate Std. Error z value Pr(>|z|) (Intercept) -1.85561 3.37850 0.549 0.58284 Gender M 0.41601 1.12425 0.370 0.71136 Age 0.01726 0.04541 0.380 0.70394 Handedness R -0.23762 2.29949 -0.103 0.91770 Laterality R -0.79457 1.02540 -0.775 0.43840 Size   -0.01914 0.04896 -0.391 0.69592 Cerebellar Findings 4.42997 1.49352 2.966 0.00302**  Cerebellar findings include dysmetria, clumsiness, and slowness when tested during a standard neurological exam. These findings were documented by the treating neurosurgeon in the patient’s clinical notes.       40 Compression Scale Scores:  Glm (formula = EL ~ Medulla + Pons + Midbrain, family = "binomial", data = dataframe)  Table 9. Deviance residuals of the binomial logistic regression model of lateral brainstem compression score. Min 1Q Median 3Q Max -1.3821 -0.6914 -0.3954 0.1398 1.7598  Table 10. Coefficients of the binomial logistic regression model of lateral brainstem compression.  Estimate Std. Error z value Pr(>|z|) (Intercept) -4.04256 1.38549   -2.918   0.00353 ** Medulla -0.08228     0.40111   -0.205   0.83747    Pons 1.44884     0.61003    2.375   0.01755 * Midbrain - 0.42780     0.42026   -1.018   0.30871                      41 Quality of Life: First Post-Operative QOL Survey The following analysis examines the first post-operative survey available for each patient to their respective pre-operative survey. EL status was converted from a binomial output to a linear one using the log of odds conversion.   Fixed effects: EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC   > library(nlme) > # Read data > Orthodont <- read.csv('SF36 R Worksheet 22Jan2020 Clean.csv', header = TRUE ) >  > # Fit model > model <- lme(EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC , data=Orthodont, random = ~1| Ptn ) > # ˜ 1| Subject means add random intercept ( random shift in outcome ) for each subject > # Call model summary > summary(model)  Table 11. First Post-Operative QOL Survey: coefficients for the linear mixed-effects model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change).   Value Std. Error DF t-value p-value (Intercept) 0.26454832 0.08766186 18 3.0178268   0.0074 PF -0.00576359 0.00399362 18 -1.4431985   0.1661 RP -0.00544636 0.00218727 18 2.4900215  0.0228* RE 0.00217569 0.00231069 18 0.9415769   0.3589 EF 0.00393646 0.00523445 18 0.7520291   0.4618 EW 0.00351025 0.00612149 18 0.5734315   0.5734 SF -0.00238557 0.00400325 18 -0.5959096   0.5587 BP 0.00189870 0.00428469 18 0.4431369   0.6629 GH -0.00219893 0.00600670 18 -0.3660786   0.7186 HC 0.00428056 0.00200629 18 2.1335746   0.0469*      42 One-year Post-Operative QOL Survey  The following analysis examines the last available survey within the first post-op year available for each patient to their respective pre-operative survey. EL status was converted from a binomial output to a linear one using the log of odds conversion.   Fixed effects: EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC   > library(nlme) > # Read data > Orthodont <- read.csv('SF36 1 Year R Worksheet 25Mar2020 TO USE.csv', header = TRUE ) >  > # Fit model > model <-  lme(EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC, data=Orthodont, random = ~1| Ptn ) > # ˜ 1| Subject means add random intercept ( random shift in outcome ) for each subject > # Call model summary > summary(model)  Table 12. One-year Post-Operative QOL Survey: coefficients for the linear mixed-effects model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change).   Value Std. Error DF t-value p-value (Intercept) 0.13886091 0.12192603 10 1.1388948   0.2813 PF 0.0017387 0.00426548 10 0.4076268   0.6921 RP -0.0044228 0.00316709 10 -1.3964974   0.1928 RE 0.0018259 0.00377549 10 0.4836193   0.6391 EF -0.0074127 0.00601104 10 -1.2331875   0.2457 EW -0.0046298 0.00832174 10 -0.5563545   0.5902 SF 0.0051781 0.00452988 10 1.1430969   0.2796 BP -0.0120529 0.00609381 10 -1.9778935   0.0761 GH 0.0060701 0.00888663 10 0.6830589   0.5101 HC 0.0077317 0.00296266 10 2.6097038   0.0261*       43 Last Available Post-Operative QOL Survey The following analysis examines the last available post-operative survey available for each patient to their respective pre-operative survey. EL status was converted from a binomial output to a linear one using the log of odds conversion.   Fixed effects: EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC   > library(nlme) > # Read data > Orthodont <- read.csv('SF36 Last Survey R Worksheet 25Mar2020 Clean.csv', header = TRUE ) >  > # Fit model > model <-  lme(EL ~ PF + RP + RE + EF + EW + SF + BP + GH + HC, data=Orthodont, random = ~1| Ptn ) > # ˜ 1| Subject means add random intercept ( random shift in outcome ) for each subject > # Call model summary > summary(model)  Table 13. Last Available Post-Operative QOL Survey: coefficients for the linear mixed-effects model for changes in each SF36v1 sub-score and health change as a separate SF36v1 metric (PF: Physical functioning, RP: Role limitations due to physical health, RE: Role limitations due to emotional problems, EF: Energy/fatigue, EW: Emotional well-being, SF: Social functioning, BP: Bodily Pain, GH: General health, HC: Health Change).   Value Std. Error DF t-value p-value (Intercept) 0.20634447 0.12422610 18 1.6610396   0.1140 PF -0.00091016 0.00491090 18 -0.1853353  0.8550 RP -0.00351092 0.00257982 18 -1.3609196   0.1903 RE -0.00214683 0.00335018 18 -0.6408104   0.5297 EF 0.00705369 0.00544525 18 1.2953837   0.2116 EW 0.00218614 0.00684278 18 0.3194805   0.7530 SF 0.00098665 0.00503174 18 0.1960854   0.8467 BP 0.00089838 0.00463595 18 0.1937863   0.8485 GH -0.00515779 0.00573866 18 -0.8987793   0.3806 HC 0.00185906 0.00268557 18 0.6922387   0.4976      44 APPENDIX 2: SF36V1 SURVEY  Obtained from Dr. Ryojo Akagami’s neurosurgical office on April 01, 2020.       45        46        47        48        49 APPENDIX 3: SF36V1 SCORING GUIDE Obtained from “36-Item Short Form Survey (SF-36) Scoring Instructions.” RAND Corporation, www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html on April 05, 2020.  4/5/2020 36-Item Short Form Survey (SF-36) Scoring Instructions | RANDhttps://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 1/5RAND > RAND Health Care > Surveys > RAND Medical Outcomes Study > 36-Item Short Form Survey (SF-36) >HEALTH CARE     50   4/5/2020 36-Item Short Form Survey (SF-36) Scoring Instructions | RANDhttps://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 2/5Step 1: Recoding Items     51   4/5/2020 36-Item Short Form Survey (SF-36) Scoring Instructions | RANDhttps://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 3/5Item numbers Change originalresponse category *To recodedvalue of:1, 2, 20, 22, 34, 36 1 → 1002 → 753 → 504 → 255 → 03, 4, 5, 6, 7, 8, 9, 10, 11, 12 1 → 02 → 503 → 10013, 14, 15, 16, 17, 18, 19 1 → 02 → 10021, 23, 26, 27, 30 1 → 1002 → 803 → 604 → 405 → 206 → 024, 25, 28, 29, 31 1 → 02 → 203 → 404 → 605 → 806 → 10032, 33, 35 1 → 02 → 253 → 504 → 755 → 100Step 2: Averaging Items to Form Scales     52    4/5/2020 36-Item Short Form Survey (SF-36) Scoring Instructions | RANDhttps://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 4/5Scale Number of items After recoding per Table 1, average the following itemsPhysical functioning 10 3 4 5 6 7 8 9 10 11 12Role limitations due to physical health 4 13 14 15 16Role limitations due to emotional problems 3 17 18 19Energy/fatigue 4 23 27 29 31Emotional well-being 5 24 25 26 28 30Social functioning 2 20 32Pain 2 21 22General health 5 1 33 34 35 36Reliability, Central Tendency, and Variability of Scales in theMedical Outcomes StudyScale Items Alpha Mean SDPhysical functioning 10 0.93 70.61 27.42Role functioning/physical 4 0.84 52.97 40.78Role functioning/emotional 3 0.83 65.78 40.71Energy/fatigue 4 0.86 52.15 22.39Emotional well-being 5 0.90 70.38 21.97Social functioning 2 0.85 78.77 25.43Pain 2 0.78 70.77 25.46General health 5 0.78 56.99 21.11Health change 1 — 59.14 23.12ABOUT4/5/2020 36-Item Short Form Survey (SF-36) Scoring Instructions | RANDhttps://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/scoring.html 5/5

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