National multicentered retrospective review of clinical and intraoperative factors associated with the development of cerebellar mutism after pediatric posterior fossa tumor resection

doi:10.21203/rs.3.rs-3152670/v1

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Research Article

National multicentered retrospective review of clinical and intraoperative factors associated with the development of cerebellar mutism after pediatric posterior fossa tumor resection

https://doi.org/10.21203/rs.3.rs-3152670/v1

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Background

Cerebellar mutism (CM) is characterized by a significant loss of speech in children following posterior fossa (PF) surgery. The biological origin of CM remains unclear and is the subject of ongoing debate. Significant recovery from CM is less likely than previously described despite rigorous multidisciplinary neuro-rehabilitational efforts.

Methods

A national multi-centered retrospective review of all children undergoing PF resection in 4 midsized Canadian academic pediatric institutions was undertaken. Patient, tumor, and surgical factors associated with the post-operative development of CM were reviewed. Retrospective identification of PF surgery patients including those developing and those that did not (internal control).

Results

The study identified 258 patients across the 4 centers between 2010–2020 (mean age 6.73 years; 42.2 female). Overall, CM was experienced in 19.5% of patients (N = 50). Amongst children who developed CM histopathology included medulloblastoma (35.7%), pilocytic astrocytoma (32.6%), and ependymoma (17.1%). Intraoperative impression of adherence to the floor of the 4th ventricle was positive in 36.8%. Intraoperative abrupt changes in blood pressure and/or heart rate were identified in 19.4% and 17.8% of cases. The clinical resolution of CM was rated to be complete, significant resolution, slight improvement, no improvement, and deterioration in 56.0%, 8.0%, 20.0%, 14.0%, 2.0%, respectively. In the cohort of children who experienced post-operative CM as compared to their no-CM counterpart, proportionally more tumors were felt to be adherent to the floor of the 4th ventricle (56.0% vs 49.5%), intraoperative extent of resection was a GTR (74% vs 68.8%), and changes in heart rate were noted (≥ 20% from baseline) (26.0% vs 15.9%). However, a logistic regression for experiencing CM identified only intraoperative impression of adherence to the floor of the 4th ventricle (OR 2.32, p = 0.011), abrupt changes in intraoperative HR (> 20% from baseline) (OR 2.34, p = 0.028), and medulloblastoma histology (OR 3.77, p = 0.001) to significantly associated with development of post-operative CM.

Conclusion

As a devastating surgical complication, identifying and understanding the biological origin of CM is the first step to complication avoidance. Maximal safe resection irrespective of intraoperative pathology remains the strategy to minimize the devastating post-operative development of CM.

Cerebellar mutism

cerebellar mutism syndrome

pediatric posterior fossa surgery

medulloblastoma

Cerebellar mutism (CM) is a condition characterized by a significant lack or loss of speech in children following posterior fossa (PF) surgery[1, 2]. Cerebellar mutism (CM), also known as posterior fossa syndrome, occurs in a subset of children after posterior fossa tumor resection. The incidence of CM in children in the literature varies from 8–47% of children following PF surgery[2–30]. This condition is part of a larger constellation of symptoms included in the definition of post-operative pediatric cerebellar mutism syndrome (CMS) in the 2016 consensus paper, characterized by delayed onset of mutism or reduced speech and emotional lability after cerebellar or 4th ventricular tumor surgery in children [17]. These central features may also be accompanied by cerebellar motor syndrome (i.e., ataxia/regression in walking, horizontal nystagmus, dysmetria, neck stiffness/torticollis)[31], cerebellar cognitive affective syndrome (i.e., reduced IQ, neuropsychological and social deficits)[32, 33] brain stem dysfunction including long tract signs[34] and cranial neuropathies. CM often manifests in the first couple of days to one week following PF surgery and has historically been described to have a limited duration of weeks to months with significant dysarthria during the recovery period[2].

Recently however, it has been noted that children developing post-operative CM experience persistent dysarthria, altered prosody of speech, and neurological impairments despite rehabilitation. With an emphasis on quality of life for childhood survivors of brain cancer and the substantial acute complications and the pervasive chronic sequelae of CMS, clinicians are focussing on preventative steps and subsequent treatment options to optimize both short- and long-term adverse outcomes[32]. In efforts to identify the biological substrate in addition to predict the development of CMS in children, many authors have analyzed both clinical and radiological (pre-operative and post-operative) features to inform neurosurgical management[4, 6, 35–39]. Cues intraoperatively to inform the neurosurgeon of maneuvers risking the development of CMS present critical feedback to revising the intraoperative approach and/or plan for extent of resection. To determine the presence of intraoperative cues in conjunction with clinical features of a posterior fossa tumor, a multicentered retrospective analysis of clinical and intraoperative features associated with the post-operative development of CM was undertaken.

A multicentered retrospective review of children experiencing CM after posterior fossa tumor resection was conducted through a multicentered research ethics board (REB) lead from McMaster University and the data securely uploaded and stored on the McMaster server RedCap database. Sources of data included electronic or physical medical records. Pediatric patients treated within our 4 Canadian mid-sized pediatric neurosurgical centers who were <18 years of age at the time of surgery, who have undergone a surgical resection of a posterior fossa lesion were included in the study.

The primary outcome measure was the occurrence of CM. We adhered to a strict definition of CM as a significant lack of speech or loss of speech in children following posterior fossa surgery. Secondary outcome measures included potential predictors of CM data pertaining to patient demographics, tumor features, and intraoperative findings (Table 1). The clinical course of CM was defined as improving (documented subjective improvement in cerebellar mutism, i.e., verbal spontaneity and fluency), stable (no clinical change since diagnosis of cerebellar mutism) or deteriorating (documented subjective worsening of cerebellar mutism, (i.e., verbal spontaneity and fluency)). The follow-up time was defined as 4 months or longer.

Sociodemographic and clinical characteristics were summarized using means, standard deviations or median and interquartile range for continuous data, and frequencies and percentages for categorical data. The chi-square or Fisher’s exact test was used for the comparison of categorical data and t-test or one-way ANOVA were used for the comapriosn of the continuous data. For the primary outcome, the proportion of CM with 95% CI was reported. The logistic regression analysis was used to explore which factors were associated with children experiencing CM. Odds ratios (OR) with 95% CI s and Hosmer-Lemeshow goodness of fit p-value were reported. To assess the discrimination ability of the regression model, the operating receiving curve (ROC) of the predicted probabilities and observed occurrence of CM was plooted. The area under the curve with 95 % CI was reported as measure of accuracy. The data was analyzed at the McMaster University, Department of Surgery using SPSS software (www.ibm.com). A p-value of 0.05 was considered for statistical significance.

In total, 258 consecutive patients undergoing management for a posterior fossa tumor across the 4 centers over a 10-year period (2010-2020) were included (Table 1). The average age of the cohort was 6.73 years (SD 4.60 years) and 42.2% of children were female. Frozen section was available in 91.5% of cases. Most of the final tumor histology in children developing CM was medulloblastoma (35.7%), pilocytic astrocytoma (32.6%), ependymoma (17.1%) and exophytic glioma (1.2%). The most frequent WHO grade of the lesion was IV (41.4%) followed by I (34.9%). Cerebellar mutism (CM) was experienced in 19.5% of patients (N=50) within the cohort between post-operative day 1 to greater than 1 week post-operatively. The clinical resolution of CM as mainly assessed by a neurosurgeon (86%) and was classified as complete, significant resolution, slight improvement, no improvement, and deterioration in 56.0%, 8.0%, 20.0%, 14.0%, 2.0% respectively.

Intraoperative impression of adherence to the floor of the 4th ventricle was noted to be positive in 36.8% and negative in 47.7% of cases (Table 2). The surgeon’s assessment as gross total resection at the end of surgery occurred in 69.8% of cases. There was a note that specifically mentioned leaving behind tumor to prevent CM in 7% of cases. During the surgery, abrupt changes (>20% from baseline) in blood pressure and/or heart rate was identified in 19.4% and 17.8% of cases. In the cohort of children who experienced post-operative CM as compared to their no-CM counterpart, proportionally more tumors were felt to be adherent to the floor of the 4^th ventricle (56.0% vs 49.5%), intraoperative extent of resection was a gross total resection (74% vs 68.8%), and changes in heart rate (>20% from baseline) were noted (26.0% vs 15.9%).

However, a univariate logistic regression (Table 3) for experiencing CM identified only intraoperative impression of adherence to the floor of the 4^th ventricle (OR 2.32, p=0.011), abrupt changes in intraoperative HR (>20% from baseline) (OR 2.34, p=0.028), medulloblastoma histology (OR 3.77, p=0.001) and WHO grade IV (OR 4.06, p<0.001) to be significantly associated with children experiencing CM.

Historically, research and management of CMS in children were limited by ambiguity introduced by inconsistent nomenclature, poorly defined diagnostic criteria, and uncertainty surrounding risk factors and etiology. Consequently, the significant variance in range of incidence in the literature is likely secondary to the lack of consensus in definition of CMS. The largest prospective study to date incorporating patients from 2 large cooperative group medulloblastoma treatment trials (CCG9931 and POG A9961) surveyed 450 children undergoing posterior fossa resection of medulloblastoma. These authors defined PFS as mutism, ataxia, hypotonia, irritability or emotional lability and observed CM to occur in 24% (107 children developing CM) of their cohort[8]. Since, an Icelandic group published their Delphi consensus results for the definition of CMS (synonym: PFS) to be “characterized by delayed onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricular tumor surgery in children. Additional common features include hypotonia and oropharyngeal dysfunction/dysphagia. It may be frequently accompanied by cerebellar motor syndrome[31], cerebellar cognitive affective syndrome[33] and brainstem dysfunction including long tract signs and cranial neuropathies[34]. The mutism is always transient and language my not return to normal, and other cognitive, affective and motor function often persist”[17].

Many studies, though in small cohorts, have identified risk factors for CM. And from these, many theories to explain the postoperative paucity of speech have been postulated including: bilateral destruction or edema of the cerebellar nuclei[40], vasospasm, post-operative meningitis, unrecognized hydrocephalus, and psychiatric origin[5]. Risk factors most commonly associated with development of CMS include midline tumor location[14], surgical approach[3, 25, 41–46], brain stem invasion or compression[8, 14, 47–49], tumor size[3, 26, 38], diagnosis of medulloblastoma[3, 21, 50, 50–53] and specific tumor subtype[20, 50], younger age at diagnosis[22, 23] and preoperative language impairment[39], lower volume centers[22], male gender[23, 54], left handedness[38, 55]. Other authors failed to find an association between age[22], ventricular size[19, 22], extent of resection[8, 19, 22], tumor size[22], handedness³⁵, surgical approach[41], location in the cerebellar hemisphere[8], ultrasonic aspirator use[19], low volume center[19] nor second surgery[56]. Furthermore, advances in imaging techniques have shed some light onto the anatomical substrate(s) of CMS with a proposed etiology of CMS which includes disruption of the cerebellar outflow tracts (i.e., dentothalamocortical tract)[6, 35, 37, 57], with changes radiologically identified in the supplementary motor area[24, 36, 58–61], the cerebellar nuclei (i.e., fastigial nucleus)[36, 57], periaqueductal gray matter[62], and their efferent projections through the superior cerebellar peduncle[4, 37, 48].

Despite many of these observations, there is little consensus on the preventative steps that can be taken to minimize the risk of CM occurrence. Armed with the knowledge that brainstem infiltration, and disruption of adjacent structures such as the superior cerebellar peduncle andperiaqueductal gray matter, we hypothesized that there are intraoperative physiological prompts to notify a neurosurgeon of operative maneuvers that may place the child at an increased risk of developing CM. Nearby structures such as locus caeruleus, a neuromodulator of norepinephrine in the brain, if disrupted may provide feedback to neuroanaesthetists and neurosurgeons with respect to limits of brainstem manipulation in efforts to dissect or resect the tumor lesion. In this multicenter cohort, we identified an association with abrupt changes, defined as ≥ 20% from baseline, in heart rate but not blood pressure to be significantly associated with the development of post-operative CM. These cues should be carefully considered and integrated into an active revision to the intraoperative microsurgical plan.

Contemporary treatment for CMS remains supportive as attempts to provide adjuncts such as fluoxetine[63], zolpidem[64], bromocriptine[65, 66], and midazolam[67] have in a small case reports and series shown efficacy but remain off-licence in their use. Recently, it has been observed that despite multidisciplinary interventions, the functional outcome in these children is less favorable than previously described[68]. Resolution of symptoms occurred at a median of 16 days after which a plateau in improvement has been described[22]. The resolution of symptoms is also heterogeneous with description of children experiencing complete CM (also known as posterior fossa syndrome 1) in whom 25% of children never regain independent ambulation[22]. Objectively, Cámara and colleagues found gender matched children who developed CMS after a posterior fossa tumor resection performed less well in neuropsychological assessment[47, 69] exacerbated by the provision of adjuvant therapy[7]

The current study has certain methodological strengths compared to the published literature The study population is vulnerable, and CM is a rare event. The multicentre nature of the study provided larger sample increasing study power. To the best of our knowledge, it is largest study to date. There is also increased generalisability of the findings to the wider populations. There are however inherent limitations to the study design. Firstly, it is a retrospective design prone to data inaccuracy and missing data. We used complete set analysis to avoid inaccurate imputation of missing data such as undetermined or not mentioned in intraoperative decisions. Secondly, the sample size is likely small and the stuyd is underpowered to draw definite conclusion from the findings. The findings should be interpreted with caution.

Due to the treatment-refractory nature of CM and the devastating sequelae for children and families experiencing the surgical complication, understanding the factors associated with its post-operative development is paramount. High grade lesions with infiltration into deep structures, finding adherence to the floor of the fourth ventricle and abrupt changes in vital signs intraoperatively should alert the surgeon to pause and re-review the operative strategy to prevent the devastating sequalae of CMS.

Ethics approval and consent to participate

Ethics approval has been acquired at the coordinating site (McMaster University) and rolled out and is currently at various stages of approval at the collaborating sites.

Competing interests

The authors declare that they have no competing interests.

Funding

Funding for the project was acquired through the McMaster University New Investigator Fund ($30,000, January 2017) for 1) the development and maintenance of the secure online database (RedCap), 2) service fees associated with a) the provision of anonymized patient images from the local radiology departments, b) secure courier service to the coordinating center for central radiological review, and 3) Biostatistical analysis. Additional funding was also provided by the University of Alberta Clinical Research Grant (CE/VM).

Authors’ contributions

MKS is the coordinating lead author who developed the concept for the study, set up and manage the RedCap database, received the hardcopy images, coordinated final data analysis and wrote the final manuscript. MR input the data from the coordinating centers, CE, VM, LB, HM, AD, MA, MKT, NS coordinated and inputted data from the collaborating centers in addition to the review of final manuscript. MKS, MA and FF analysed the data. OA, BY, AF, FF, SKS supervised the project and reviewed the final submitted manuscript.

Acknowledgements

Funding provided by Hamilton Health Sciences (HHS) Research, University of Alberta Clinical Research and HHS Foundation through the HHS New Investigator Fund (NIF) program.

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Table 1: Descriptive statistics for clinical variables (N=258).

Variable

N (%)

Age (years)

6.73 + 4.60

Gender

Female

Male

109 (42.2%)

149 (57.8%)

Intraoperative frozen section pathology available

Yes

22 (8.5%)

236 (91.5%)

Intraoperative pathology

AT/RT

Choroid plexus papilloma

Ependymoma

Exophytic glioma

Medulloblastoma

Not applicable

Pilocytic astrocytoma

Missing

6 (2.3%)

4 (1.6%)

34 (13.2%)

7 (2.7%)

90 (34.9%)

22 ( 8.5%)

82 (31.8%)

13 ( 5.1%)

Tumor histology

AT/RT

Choroid plexus papilloma

Ependymoma

Exophytic glioma

Medulloblastoma

Pilocytic astrocytoma

Missing

6 (2.3%)

5 (1.9%)

44 (17.1%)

3 (1.2%)

92 (35.7%)

84 (32.6%)

24 ( 9.3%)

WHO grade?

III

N/A

90 (34.9%)

34 (13.2%)

25 (9.7%)

106 (41.1%)

3 (1.2%)

Cerebellar mutism experienced

Unable to determine

Yes

202 (78.3%)

6 (2.3%)

50 (19.4%)

Number of hours post-operative CM onset

Not applicable

On extubation post-op

POD1 when extubated

POD1 (normal post-op)

POD2

POD3

POD4

POD5

POD6

POD7

>1-week post-op

217 (84.1%)

10 (3.9%)

1 (0.4%)

6 (2.3%)

10 (3.9%)

3 (1.2%)

4 (1.6%)

1 (0.4%)

3 (1.2%)

1 (0.4%)

2 (0.8%)

Clinical course of CM

Complete resolution

Significant resolution

Slight improvement

No improvement

Deterioration

Not mentioned

Not applicable

28 (10.9%)

4 (1.6%)

8 (3.1%)

7 (2.7%)

1 (0.4%)

2 (0.8%)

208 (80.6%)

Table 2: Descriptive statistics for intraoperative variables

Variable

All (N=258)

N (%)

No CM* (n=208)

(n=50)

Intraoperative impression of adherence to floor of 4th ventricle

Yes

Unable to determine

123 (47.7%)

95 (36.8%)

40 (15.5%)

103 (49.5%)

67 (32.2%)

38 (18.3%)

28 (56.0%)

20 (40.0%)

2 (4.0%)

Intraoperative impression of extent of resection

Biopsy only

Gross total resection

Near total resection

Subtotal resection

Not mentioned in operative note

3 (1.2%)

180 (69.8%)

13 (5.0%)

60 (23.3%)

2 (0.8%)

3 (1.4%)

143 (68.8%)

13 (6.2%)

47 (22.6%)

2 (1.0%)

0 (0.0%)

37 (74.0%)

0 (0.0%)

13 (26.0%)

0 (0.0%)

Intraoperative decision to leave behind tumor to prevent CM

Yes

Not mentioned

67 (26.0%)

18 (7.0%)

173 (67.1%)

60 (28.8%)

14 (6.7%)

134 (64.4%)

7 (14.0%)

4 (8.0%)

39 (78.0%)

Abrupt change (>20%) intraoperative blood pressure

Yes

Unable to determine

191 (74.0%)

50 (19.4%)

17 (6.6%)

155 (74.5%)

41 (19.7%)

12 (5.7%)

36 (72.0%)

9 (18.0%)

5 (1.0%)

Abrupt change (>20%) intraoperative HR

Yes

Unable to determine

192 (74.4%)

46 (17.8%)

20 (7.8%)

162 (77.9%)

33 (15.9%)

13 (6.3%)

30 (60.0%)

13 (26.0%)

7 (14.0%)

*includes n=6 patients in which unable to determine if CM experienced

Table 3. Univariate logistic regression examining cerebellar mutism experienced for the clinical and intraoperative variables.

Cerebellar mutism experienced

Logistic Regression

Variable

No= 203

Yes= 50

Odds ratio (95% CI)

p-value

Mean Age (SD)

6.78 (4.83)

6.16 (3.42)

0.97 (0.90, 1.04)

0.396

Mean Length of follow up (SD)

41.54 (41.29)

49.71 (42.35)

1.0 (0.99, 1.01)

0.214

Gender

Female

Male

89 (44.1)

113 (55.9)

18 (36.0)

32 (64.0)

Ref

1.4 (0.73, 2.65)

0.303

Intraoperative frozen section pathology available

Yes

22 (10.9)

180 (89.1)

0 (0.0)

50 (100.0)

Intraoperative impression of adherence to floor of 4th ventricle

Unable to determine

Yes

103 (51.0)

37 (18.3)

62 (30.7)

20 (40.0)

2 (4.0)

28 (56.0)

Ref

0.27 (0.06, 1.24)

2.32 (1.20, 4.47)

0.095

0.011

Intraoperative decision to leave behind tumor to prevent CM

Not mentioned

Yes

60 (29.7)

129 (63.9)

13 (6.4)

7 (14.0)

39 (78.0)

4 (8.0)

Ref

2.59 (1.09, 6.12)

2.63 (0.67, 10.34)

0.030

0.164

Abrupt change (>20%) intraoperative blood pressure

Unable to determine

Yes

155 (76.7)

9 (4.5)

38 (18.8)

36 (72.0)

5 (10.0)

9 (18.0)

Ref

2.39 (0.75, 7.56)

1.02 (0.45, 2.29)

0.138

0.962

Abrupt change (>20%) intraoperative HR

Unable to determine

Yes

162 (80.2)

10 (5.0)

30 (14.9)

30 (60.0)

7 (14.0)

13 (26.0)

Ref

3.78 (1.33, 10.71)

2.34 (1.09, 4.99)

0.012

0.028

Intra operative pathology

AT/RT

Choroid plexus papilloma

Ependymoma

Exophytic glioma

Medulloblastoma

Not applicable

Pilocytic astrocytoma

5 (2.6)

4 (2.1)

25 (13.2)

7 (3.7)

56 (29.5)

22 (11.6)

71 (37.4)

1 (2.0)

0 (0.0)

8 (16.3)

0 (0.0)

30 (61.2)

0 (0.0)

10 (20.4)

1.42 (0.15, 13.42)

2.27 (0.80, 6.39)

3.80 (1.71 ,8.43)

Ref

0.760

0.120

0.001

Tumor histology

AT/RT

Choroid plexus papilloma

Ependymoma

Exophytic glioma

Medulloblastoma

Pilocytic astrocytoma

5 (2.8)

35 (19.6)

3 (1.7)

58 (32.4)

73 (40.8)

1 (2.0)

0 (0.0)

8 (16.3)

0 (0.0)

30 (61.2)

10 (20.4)

1.46 (0.15, 13.80)

1.66 (0.60, 4.59)

3.77 (1.70, 8.35)

Ref

0.741

0.322

0.001

WHO grade?

III

80 (40.2) 28

(14.1)

21 (10.6)

70 (35.2)

9 (18.0)

6 (12.0)

3 (6.0)

32 (64.0)

Ref

1.9 (0.62, 5.83)

1.27 (0.31, 5.1)

4.06 (1.8, 9.1)

0.259

0.737

<0.001

Intra operative impression of extent of resection

Biopsy only

Subtotal resection

Gross total resection

Near total resection

3 (1.5)

44 (22.0)

140 (70.0)

13 (6.5)

0 (0.0)

13 (26.0)

37 (74.0)

0 (0.0)

Ref

0.89 (0.43, 1.83)

0.761

No competing interests reported.

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National multicentered retrospective review of clinical and intraoperative factors associated with the development of cerebellar mutism after pediatric posterior fossa tumor resection

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