Independent Validation of the Colloid Cyst Risk Score to Predict Symptoms and Hydrocephalus in Patients with Colloid Cysts of the Third Ventricle

Independent Validation of the Colloid Cyst Risk Score to Predict Symptoms and Hydrocephalus in Patients with Colloid Cysts of the Third Ventricle

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Journal Pre-proof Independent Validation of the Colloid Cyst Risk Score to Predict Symptoms and Hydrocephalus in Patients with Colloid Cysts of the Third Ventricle Elizabeth N. Alford, M.D., Lauren E. Rotman, M.D., Christopher D. Shank, MD, MBA, Bonita S. Agee, Ph.D., James M. Markert, M.D., M.P.H. PII:

S1878-8750(19)32826-8

DOI:

https://doi.org/10.1016/j.wneu.2019.10.188

Reference:

WNEU 13659

To appear in:

World Neurosurgery

Received Date: 2 July 2019 Revised Date:

29 October 2019

Accepted Date: 30 October 2019

Please cite this article as: Alford EN, Rotman LE, Shank CD, Agee BS, Markert JM, Independent Validation of the Colloid Cyst Risk Score to Predict Symptoms and Hydrocephalus in Patients with Colloid Cysts of the Third Ventricle, World Neurosurgery (2019), doi: https://doi.org/10.1016/ j.wneu.2019.10.188. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Independent Validation of the Colloid Cyst Risk Score to Predict Symptoms and Hydrocephalus in Patients with Colloid Cysts of the Third Ventricle

Elizabeth N. Alford, M.D., Lauren E. Rotman, M.D., Christopher D. Shank, MD, MBA, Bonita S. Agee, Ph.D., James M. Markert, M.D., M.P.H.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama

Corresponding Author: Dr. Elizabeth Alford 1720 2nd Ave South FOT 1057 Birmingham, AL 35294 Phone: (205) 934-3546 Fax: (205) 934-6507 [email protected]

Key Words: colloid cyst, validation study, reproducibility of results, forecasting Short Title: Independent Validation of the CCRS

The authors have no financial or material disclosures to report. No portions of this work have been previously presented. Acknowledgments: Dr. Alford completed this work as a UAB Women’s Leadership Council Clinical Research Scholar.

1 2

Abstract

3

Background

4

The Colloid Cyst Risk Score (CCRS) was devised to identify symptomatic colloid cyst patients

5

and stratify risk of hydrocephalus. The CCRS considers patient age, presence of headache,

6

colloid cyst diameter, fluid-attenuated inversion recovery (FLAIR) hyperintensity, and location

7

within the third ventricle.

8 9 10

Objective The purpose of this study was to independently evaluate the validity of the CCRS.

11 12

Methods

13

Patients with a colloid cyst of the third ventricle were identified retrospectively from institutional

14

billing records and radiology report archives. Patients without a confirmed diagnosis of colloid

15

cyst of the third ventricle or magnetic resonance imaging (MRI) of the brain were excluded. Data

16

were collected via retrospective chart review.

17 18

Results

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One hundred fifty-six patients met inclusion and exclusion criteria. In our cohort, the CCRS

20

stratified symptomatic patients and patients with hydrocephalus across all scores (p<0.001).

21

From CCRS two to five, the percentage of symptomatic patients increased from 13% to 100%,

22

while the percentage of patients with hydrocephalus increased from 8% to 83%. Simple logistic

23

regression showed that total CCRS, headache, axial diameter, FLAIR hyperintensity, and risk

24

zone were all highly predictive of symptomatic status and hydrocephalus (p<0.001). Logistic

25

regression with receiver operator curves for the CCRS demonstrated an area under the curve

26

(AUC) of 0.914 for symptomatic colloid cysts and an AUC of 0.892 for colloid cysts with

27

hydrocephalus.

28 29

Conclusion

1

30

Our data analysis validates the predictive value of the CCRS for both symptomatic status and

31

hydrocephalus and supports the use of the CCRS in risk-stratification and clinical decision-

32

making.

33 34

Running Title: Independent validation of the CCRS

35

Keywords: colloid cyst, validation study, reproducibility of results, forecasting

36

2

37

Introduction

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Symptomatic colloid cysts often present with headache, nausea, vomiting, blurred vision, ataxia,

39

and encephalopathy.1–3 Colloid cysts may cause obstructive hydrocephalus, which can cause

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precipitous neurologic decline, or even, sudden death. However, many colloid cysts are

41

asymptomatic, and are discovered incidentally after neuroimaging for another indication. Other

42

patients with colloid cysts present with symptoms that are exceedingly common in the general

43

population (such as headache and vertigo), and differentiating whether these symptoms are

44

attributable to the colloid cyst can be very difficult. Among incidental colloid cysts, there is an

45

estimated 5-15% 5-year risk of progression necessitating operative intervention.3 Identifying

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those patients who are at highest risk of being symptomatic from their colloid cyst would enable

47

physicians to make more nuanced clinical management recommendations.

48 49

The Colloid Cyst Risk Score (CCRS), developed by Beaumont et al.1, is a five-category measure

50

intended to predict symptomatic clinical status and stratify risk for hydrocephalus in patients

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presenting with colloid cyst of the third ventricle (Table 1). The CCRS is intended for use by

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neurosurgeons. The CCRS assigns one point if the patient is <65 years old, one point if headache

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is present, one point if the colloid cyst measures ≥7mm in maximum axial diameter, one point if

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the cyst is hyperintense on FLAIR imaging, and one point if the cyst is located in one of two

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anatomical “risk zones.” Three anatomical zones have been defined (Figure 1). Zone I is

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anterior to the mammillary bodies and massa intermedia, and a colloid cyst in this location can

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cause obstructive hydrocephalus by obstruction of the foramen on Monro. Zone III extends from

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the inlet of the cerebral aqueduct to the posterior limit of the third ventricle, and a colloid cyst in

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this location can cause obstructive hydrocephalus via aqueductal stenosis/obstruction. Zone II,

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which lies between Zones I and II, is a comparatively more favorable location as a colloid cyst in

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Zone II is less likely to cause hydrocephalus or other symptoms.1 Collectively, Zones I and III

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comprise the “risk zones”. Of note, a point is given for non-traumatic headache on presentation,

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but that headache does not necessarily have to be related to the colloid cyst. A patient with

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chronic migraines would, therefore, receive one point, but a patient with a head injury would not

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receive any points. The total CCRS ranges from 0 to 5 with higher scores indicating a higher

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likelihood of hydrocephalus and symptomatic clinical status. The CCRS is not intended to

3

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supplant a physician’s clinical decision-making, but to provide additional evidence-based

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guidance for consideration.

69 70

The CCRS seems to have significant potential in identifying high-risk colloid cysts (cysts likely

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to cause symptoms and/or hydrocephalus) and aiding in clinical management decisions;

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however, it must be externally validated before its widespread use is justified. To date, no study

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has performed any external validation of the CCRS. The purpose of this study, therefore, is to

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test the validity of the CCRS in an independent population of patients with colloid cysts of the

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third ventricle. The interrater and intrarater reliability of the CCRS is evaluated and discussed in

76

a companion manuscript.

77 78

Methods

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Study Population

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Patients with a diagnosis of colloid cyst at the authors’ institution were identified using billing

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records. The search was restricted to the time period January 1, 1995 – December 31, 2015.

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These patients were identified using ICD-9 codes 225, 331.4 and ICD-10 code Q04.6.

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Additionally, all radiology reports from this time period were queried for the term “colloid cyst.”

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This generated a total of 1102 potential patients. Duplicates (n=392) were removed. All results

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were screened by the clinical investigators for inclusion in the study. Patients without a

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confirmed or confirmable diagnosis of colloid cyst of the third ventricle were excluded from

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further analyses (n=554). The majority of those excluded at this stage were patients with thyroid

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colloid cysts that were identified by radiology reports. There were 156 patients remaining that

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met inclusion and exclusion criteria and ultimately comprised the study sample. There were no

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significant differences in setting, eligibility criteria, outcome, or predictors between this study

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and the initial description of the CCRS by Beaumont et al.1 The final sample size was a

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“convenience sample” in that it was determined by the number of available patients that met all

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inclusion and exclusion criteria, as opposed to a formal sample size calculation.

94 95

Data Collection

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The following data were collected via retrospective chart review: age, cyst diameter (mm),

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presence/absence of headache, presence/absence of cyst-related symptoms, and presence/absence

4

98

of hydrocephalus. Patients were excluded if a preoperative magnetic resonance image (MRI) of

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the brain was not available. Using the methods described by Beaumont et al., the Colloid Cyst

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Risk Score (CCRS) was calculated for each patient. FLAIR hyperintensity was evaluated

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qualitatively as either present or absent. For a subset of the sample (n=53), the CCRS was

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calculated independently by three senior neurosurgery residents (E.A., J.L., L.R.) and the mode

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of their ratings was used. Given good interrater reliability (data presented in companion

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publication), a single rater (E.A.) determined the remaining CCRS scores. Since some clinical

105

details were required to perform the CCRS rating, raters could not be blinded.

106 107 108

The two outcomes of interest were: 1) presence of hydrocephalus, and 2) clinical status

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(symptomatic versus incidental), both assessed at initial presentation. There were no missing

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data. The clinical status (ie. Whether the colloid cyst was symptomatic or incidental) was

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determined by review of the medical records. The criteria for a colloid cyst to be symptomatic

112

were as follows:

113



114 115

Presence of one or more symptoms of elevated intracranial pressure, including headache, nausea, vomiting, blurred vision or diplopia, dizziness, ataxic gait, or syncope; AND



Absence of an alternative cause for symptoms (eg. Stroke, sinusitis, migraine headaches).

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Other radiographic factors, such as degree of cortical atrophy, presence or absence of sulcal

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effacement, effacement of basal cisterns, and periventricular T2 hyperintensity were used to aid

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in distinguishing hydrocephalus from benign ventriculomegaly (ie. Hydrocephalus ex vacuo). A

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patient with effacement of sulci and/or basal cisterns, periventricular T2 hyperintensity, and no

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cortical atrophy was felt to have hydrocephalus. Prominent cortical atrophy with large sulci and

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patent basal cisterns were considered indicative of benign (ex vacuo) ventricular dilatation.

122 123

This study was approved by the Institutional Review Board. Patient consent was waived, as this

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is a minimal risk retrospective chart review. This manuscript was prepared using the TRIPOD

125

Checklist for Prediction Model Validation.

126 127

Statistical Analysis

5

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Frequency distributions of both the composite CCRS score and the individual CCRS

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components, age < 65 years, headache, axial diameter, FLAIR hyperintensity and risk zone, were

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obtained. Chi-square and Fisher’s exact tests were used to assess statistical significance of

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differences according to presence/absence of hydrocephalus and symptomatic clinical status. As

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previously suggested by Beaumont et al., the low-risk group was defined as CCRS ≤2, while the

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high-risk group was defined as CCRS ≥4, and CCRS equal to 3 was the intermediate-risk group.1

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Logistic regression models of CCRS as a predictor of either hydrocephalus or symptomatic

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status were used to generate receiver operating characteristic (ROC) curves as an assessment of

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the ability of CCRS to correctly classify those patients with and without the event. The area

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under the ROC curve, known as the AUC or C-statistic, is an effective tool for determining the

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validity of CCRS as a diagnostic test. A perfect diagnostic test would have an AUC of 1.00,

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while a test with an AUC of 0.50 represents random chance. An AUC is typically characterized

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as excellent with a value between 0.90 and 0.99, good with an AUC range of 0.80 – 0.89, fair

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with an AUC range of 0.70-0.79, and poor with an AUC range of 0.51-0.69.

142 143

Results

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Cohort Characteristics

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A total of 156 patients met all inclusion and exclusion criteria. One hundred-thirty-three patients

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(85%) were less than 65 years old and 74 patients (47%) reported a headache. The colloid cyst

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diameter was >7mm for 82 patients (53%) and the cyst demonstrated FLAIR hyperintensity in 44

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patients (28%). Ninety-five patients (61%) had a cyst located in a risk zone, all of which were

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located in Zone I. There were no missing data. The distribution of total CCRS was as follows: 5

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(3%) had a total score of 0, 31 (20%) had a total score of 1, 38 (24%) had a total score of 2, 30

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(19%) had a total score of 3, 29 (19%) had a total score of 4, and 23 (15%) had a total score of 5.

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Compared to the cohort used to develop the CCRS, our cohort had significantly more patients

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<65 years old (85% vs. 73%; p=0.0069) and significantly fewer patients with cyst diameter ≥7

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mm (53% vs. 68%; p=0.0046), but was otherwise similar (Table 2).

155 156

A total of 49 (31%) patients underwent surgical intervention at a mean 6.3 months (range: 0-

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108.7 months) from initial evaluation. The majority (n=41, 84%) of patients who underwent

6

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surgery did so within one month of initial presentation, while four patients (8%) underwent

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surgery 1-3 months after presentation and four patients (8%) had surgery in a significantly

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delayed fashion. Considering all patients who had surgery, endoscopic resection was performed

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in 37 patients (76%), while microsurgical transcallosal resection was performed in six patients

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(12%), microsurgical transcortical resection was performed in five patients (10%), and one

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patient (2%) underwent bilateral ventriculoperitoneal shunt placement. In our cohort, no patients

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with a CCRS Score 0 or 1 received surgical treatment. Four patients (11%) with a CCRS Score

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2, 5 patients (17%) with a CCRS Score 3, 19 (66%) with a CCRS Score 4, and 21 (91%) with a

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CCRS Score 5 underwent surgical treatment (Table 3).

167 168

For those patients that did not require surgical intervention at the time of presentation, 72

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patients had at least 6 months of clinical and/or radiographic follow-up. Among patients

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followed for at least 6 months (n=72), median follow-up was 42.3 months (IQR 18.7 – 75.2

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months). Four patients ultimately required surgical intervention at 2.7, 4.9, 8.0, and 9.1 years

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after initial diagnosis, respectively. The first patient presented at 36 years of age with a many

173

year history of worsening headaches and was found to have a 5mm FLAIR-hyperintense cyst in

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Zone I (CCRS 4). After approximately two years, the cyst had grown to 13mm in size and her

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headaches continued to worsen. The second patient was diagnosed with a small colloid cyst

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(4.5mm) in Zone I at 38 years of age (CCRS 2) during work-up for sinusitis and parotid

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enlargement. After nearly five years of follow-up, her colloid cyst had enlarged to 8mm and

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there was interval enlargement in her ventricular size. The third patient presented at 46 years of

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age with headaches, temporomandibular joint pain, hearing loss, and tinnitus, and was found to

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have an 8mm FLAIR-hyperintense cyst in Zone 1 (CCRS 5). Seven years after initial

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presentation, she developed worsening headache, blurred vision, and intermittent diplopia;

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imaging was relatively unchanged and surgery was recommended. The fourth patient presented

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as a 16-year old with chronic headaches and a 12mm Zone I cyst (CCRS 4). She initially was not

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interested in surgery, but her cyst enlarged to 16mm on follow-up 9 years later and ultimately

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agreed to surgery.

186 187

Predictive Ability of CCRS Score

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In our cohort, the CCRS stratified symptomatic patients across all scores (p<0.001); percentage

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of symptomatic patients increased from 13% to 100% from CCRS two to five (Table 3).

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Frequencies of CCRS criteria by clinical status are shown in Table 4. Proportions of all criteria,

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except age, differed significantly between the symptomatic and asymptomatic groups (p<0.001).

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Simple logistic regression showed that total CCRS (OR=6.00, 95% CI: 3.51 – 10.29), headache

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(OR=32.08, 95% CI: 11.49 – 89.59), axial diameter (OR=16.83, 95% CI: 6.55 – 43.26), FLAIR

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hyperintensity (OR=6.40, 95% CI: 2.98 – 13.70), and risk zone (OR=7.88, 95% CI: 3.25 –

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19.07) were all highly predictive of symptomatic status (p<0.001; Table 5). Logistic regression

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with receiver operator curves for the CCRS demonstrated an area under the curve (AUC) of

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0.914 for symptomatic colloid cysts (Figure 2).

198 199

CCRS also stratified risk of hydrocephalus across all scores (p<0.001); percentage of patients

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with hydrocephalus increased from 8% to 83% from CCRS two to five (Table 3). Frequencies of

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CCRS criteria by presence of hydrocephalus are shown in Table 6. Again, proportions of all

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criteria, except age, differed significantly between the group of patients with hydrocephalus and

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the group without hydrocephalus (p<0.001). Simple logistic regression showed that total CCRS

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(OR=4.59, 95% CI: 2.80 – 7.51), headache (OR=14.59, 95% CI: 5.30 – 40.17), axial diameter

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(OR=14.39, 95% CI: 4.80 – 43.11), FLAIR hyperintensity (OR=5.72, 95% CI: 2.63 – 12.44),

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and risk zone (OR=43.61; 95% CI: 5.80 – 327.82) were all highly predictive of hydrocephalus

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(p<0.001; Table 5). Logistic regression with receiver operator curves for the CCRS

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demonstrated an AUC of 0.892 for colloid cysts with hydrocephalus (Figure 2).

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Subgroup Classification

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Beaumont et al. proposed that CCRS ≥4 represents the high-risk subgroup, while CCRS ≤2

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represents the low-risk subgroup. CCRS equal to 3 was considered an intermediate risk

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subgroup. Using these subgroup definitions, the CCRS has 89.6% sensitivity and 88.5%

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specificity for symptomatic status. Similarly, the CCRS has 91.9% sensitivity and 79.8%

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specificity for hydrocephalus.

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Discussion

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Clinical or operative management decisions for patients with colloid cysts are dependent on cost-

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benefit analyses comparing he risk of observation alone (ie., doing nothing) with the risk of the

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surgical intervention. Resection of intraventricular masses, including colloid cysts of the third

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ventricle, can carry high morbidity, particularly with a transcallosal approach.4,5 While

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endoscopic resection may be safer than microsurgical approaches, it can carry risk of subtotal

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resection and/or recurrence.6–8 A meta-analysis of 1,278 patients reported overall morbidity of

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10.5% with an endoscopic approach, 14.4% with a transcortical approach, and 24.5% with a

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transcallosal approach; however, microsurgical techniques had significantly greater rates of gross

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total resection (96.8% vs. 58.2%) and lower rates of recurrence (1.48% vs. 3.91%).8

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A more recently published meta-analysis examined the risk of colloid cyst progression requiring

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operative intervention.3 The meta-analysis included four retrospective studies that included 128

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patients followed for a median of 61.2 months. In this combined cohort, 8.6% of patients went on

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to require surgical intervention. Only one patient (0.8%) experienced sudden neurologic

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deterioration related to obstructive hydrocephalus, and no sudden deaths were reported. With

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regard to radiographic evolution, 86.7% of colloid cysts remained radiographically stable, while

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11.2% progressed, and 2.0% regressed.3 Other studies have reported a 3-45% risk of acute

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neurologic deterioration and a 5-38% risk of death.1,2,8–11 These findings are consistent with our

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data showing 5.6% risk of progression. The long interval between diagnosis and surgery in these

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patients (5-10 years or more) underscores the importance of continued clinical and radiographic

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follow-up. Furthermore, it highlights that published studies, including this one, may suffer from

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inadequate follow-up. Taking the extant literature in toto, there is remarkably limited and low

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quality evidence on the natural history or risk of progression of colloid cysts.

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It is critical to be able to identify those patients most likely to experience symptoms attributable

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to their colloid cyst, develop hydrocephalus, and those who are at higher risk for sudden

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neurologic decline/death. To this end, Beaumont et al. developed the CCRS based on their

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institutional experience. Our data analysis validates the predictive value of the CCRS for both

246

symptomatic status and hydrocephalus. To date, the CCRS has not been evaluated for its ability

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to predict sudden neurologic deterioration or death, largely because of the rarity of that event.

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Sudden neurologic decline or death is thought to be caused by CSF obstruction at the foramen of

9

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Munro. Though unproven, the same criteria that comprise the CCRS may be risk factors for

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sudden neurologic decline or death. Chronic headache may reflect intermittent CSF obstruction;

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large, Zone I cysts are structurally more likely to cause obstruction of the foramen of Munro;

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and, FLAIR hyperintense cysts (cysts that are more dense/solid) may cause more complete CSF

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flow obstruction.

254 255

Another challenge in the management of colloid cysts if predicting which patients who are

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asymptomatic or minimally symptomatic will require intervention in the future. To shed light on

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this particular question, we described the outcomes of the subgroup of patients who had at least 6

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months clinical and radiographic follow-up. Four patients ultimately underwent surgery from this

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group from 2-9 years after initial presentation. Three of these patients had high CCRS (4 or 5) so

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it may have been predicted that they were at higher risk of clinical or radiographic progression.

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The fourth patient, however, had a CCRS of 2, indicating that CCRS is imperfect or that the

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treating physician used a different framework for clinical decision making.

263 264

Presence of headache and axial cyst diameter were the strongest predictors of symptomatic

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clinical status (ORs of 32.1 and 16.8, respectively), a finding which is both intuitive and

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consistent with classical clinical decision making. Beaumont et al.’s description of their

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symptomatic and incidental cohorts indicates that significant headache, whether clearly referable

268

to the colloid cyst or not, warranted assigning one point on the CCRS. A patient with

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longstanding history of migraine headaches would receive a point, though a temporary trauma or

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procedure related headache would not.

271 272

We also found that location of the cyst in a “risk zone” (Zone I or III) was the strongest predictor

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of hydrocephalus (OR 43.6), replicating the finding by Beaumont et al. The relationship between

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risk zone and hydrocephalus is conceptually new and warrants highlighting. Zone I is the portion

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of the third ventricle anterior to a line drawn tangential to the anterior limit of the massa

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intermedia and directly communicates with the lateral ventricles through the foramina of Monro.

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Zone III is the posterior third ventricle and includes the inlet to the cerebral aqueduct. A colloid

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cyst located in Zone I or III, particularly if it projects rostrally into the foramen of Monro or

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caudally into the cerebral aqueduct, is more likely to cause obstructive hydrocephalus than a

10

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colloid cyst in the roof of the third ventricle (Zone II). Zone III cysts are quite uncommon, and

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the vast majority of patients with hydrocephalus have a cyst located in Zone I. If a colloid cyst is

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large and spans more than one zone, it should be treated based on the highest risk zone due to its

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potential for causing CSF flow obstruction.

284 285

Compared to the cohort in Beaumont et al., patients in our cohort were significantly younger and

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had smaller cysts. The difference in cohort ages may relate to different referral patterns,

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demographic variation and/or divergent indications for obtaining head imaging between

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institutions. There may also be a temporal difference – the Beaumont series included patients

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from 1996 – 2014, while 86% of our patients were diagnosed in 2010 or later. With increasing

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availability and use of head imaging, it is likely that more asymptomatic colloid cysts are being

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identified, potentially at younger ages and smaller sizes.

292 293

In our cohort, age <65 years was not predictive of symptomatic status or hydrocephalus. Pollock,

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Schreiner & Huston reported that symptomatic patients tended to be younger than their

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asymptomatic counterparts (44 vs 57 years).1212 It remains possible that a relationship exists

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between age and likelihood of developing symptoms and/or hydrocephalus, but that our study

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failed to identify it. This could be a result of our sample size and the fact that only 15% of our

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cohort was >65 years old. Alternatively, 65 years of age may not be the appropriate threshold.

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Dichotomization of continuous data results in loss of data detail; selecting the “incorrect” cut-

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point can either inappropriately identify a difference where none exists (Type I error) or fail to

301

identify an important difference (Type II error). In summary, the relationship between age and

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development of symptoms and/or hydrocephalus, remains unclear and should be explored in

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future studies. That being said, the relationship (if one exists) may be a moving target due to

304

ever-evolving imaging indications and techniques.

305 306

We found excellent sensitivity and specificity for both symptomatic status and hydrocephalus

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when defining the high-risk group as CCRS ≥4 and the low-risk group as CCRS ≤2. CCRS equal

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to 3 is an intermediate risk subgroup. As discussed above, the decision whether or not to operate

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on a patient with a colloid cyst is complex and includes consideration of symptom burden,

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probability of future symptoms, medical co-morbidities, and surgical risk. The CCRS was

11

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developed as an adjunct tool to aid this clinical decision making; surgical decisions should not be

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based on the CCRS alone. A patient with CCRS ≥4 may be “high risk” but that does not

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necessarily mean they require surgical treatment. Similarly, “low risk” patients with CCRS ≤2

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may warrant surgical treatment in some circumstances.

315 316

Like most other studies on natural history and/or progression of colloid cyst, this is a

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retrospective study and therefore is inherently limited by recording and recall bias and

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unintentional data entry errors. Additionally, determination of whether a patient’s symptoms are

319

referable to their colloid cyst is subjective. Given the relative rarity of colloid cysts of the third

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ventricle, natural history and outcomes data may be best gathered by a prospective, multi-center

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collaborative registry. Our results reflect only a single institution’s experience, though they are

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overwhelmingly similar to published results. A collaborative registry could better elucidate the

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role of age in colloid cyst management, as well as provide additional insights into other

324

subgroups. Finally, a registry would provide much needed statistical power to better understand

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rare events, like sudden death, in patients with colloid cysts.

326 327

Conclusion

328

Our results replicate the finding that headache and cyst diameter are the strongest predictors of

329

symptomatic clinical status, while location of a colloid cyst within a risk zone is the strongest

330

predictor of hydrocephalus. Our analysis of the CCRS in an independent population of patients

331

suggests its validity and generalizability to other patient populations. Our findings support that

332

CCRS ≥4 represents the most high-risk subgroup, while CCRS ≤2 represents the low-risk

333

subgroup, and CCRS equal to 3 is an intermediate-risk subgroup. These data support the use of

334

the CCRS in risk-stratification and clinical decision-making. A prospective, multi-center colloid

335

cyst registry can provide additional validation and address subgroup-specific questions.

336 337 338

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References

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1. Beaumont TL, Limbrick DD, Rich KM, Wippold FJ, Dacey RG. Natural history of colloid cysts of the third ventricle. J Neurosurg. 2016;125(6):1420-1430. doi:10.3171/2015.11.JNS151396 2. Little JR, MacCarty CS. Colloid cysts of the third ventricle. J Neurosurg. 1974;40(2):230-235. doi:10.3171/jns.1974.40.2.0230 3. O’Neill AH, Gragnaniello C, Lai LT. Natural history of incidental colloid cysts of the third ventricle: A systematic review. J Clin Neurosci Off J Neurosurg Soc Australas. 2018;53:122-126. doi:10.1016/j.jocn.2018.04.061 4. Hassaneen W, Suki D, Salaskar AL, et al. Immediate morbidity and mortality associated with transcallosal resection of tumors of the third ventricle. J Clin Neurosci Off J Neurosurg Soc Australas. 2010;17(7):830-836. doi:10.1016/j.jocn.2009.12.007 5. Milligan BD, Meyer FB. Morbidity of transcallosal and transcortical approaches to lesions in and around the lateral and third ventricles: a single-institution experience. Neurosurgery. 2010;67(6):1483-1496; discussion 1496. doi:10.1227/NEU.0b013e3181f7eb68 6. Brunori A, de Falco R, Delitala A, Schaller K, Schonauer C. Tailoring Endoscopic Approach to Colloid Cysts of the Third Ventricle: A Multicenter Experience. World Neurosurg. 2018;117:e457-e464. doi:10.1016/j.wneu.2018.06.051 7. Horn EM, Feiz-Erfan I, Bristol RE, et al. Treatment options for third ventricular colloid cysts: comparison of open microsurgical versus endoscopic resection. Neurosurgery. 2008;62(6 Suppl 3):1076-1083. doi:10.1227/01.neu.0000333773.43445.7b 8. Sheikh AB, Mendelson ZS, Liu JK. Endoscopic versus microsurgical resection of colloid cysts: a systematic review and meta-analysis of 1,278 patients. World Neurosurg. 2014;82(6):1187-1197. doi:10.1016/j.wneu.2014.06.024 9. de Witt Hamer PC, Verstegen MJT, De Haan RJ, et al. High risk of acute deterioration in patients harboring symptomatic colloid cysts of the third ventricle. J Neurosurg. 2002;96(6):1041-1045. doi:10.3171/jns.2002.96.6.1041 10. Greenberg MS. Handbook of Neurosurgery. 8th ed. Thieme; 2016. 11. Ryder JW, Kleinschmidt-DeMasters BK, Keller TS. Sudden deterioration and death in patients with benign tumors of the third ventricle area. J Neurosurg. 1986;64(2):216-223. doi:10.3171/jns.1986.64.2.0216 12. Pollock BE, Schreiner SA, Huston J. A theory on the natural history of colloid cysts of the third ventricle. Neurosurgery. 2000;46(5):1077-1081; discussion 1081-1083. 1. Beaumont TL, Limbrick DD, Rich KM, Wippold FJ, Dacey RG. Natural history of colloid cysts of the third ventricle. J Neurosurg. 2016;125(6):1420-1430. doi:10.3171/2015.11.JNS151396

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2. Little JR, MacCarty CS. Colloid cysts of the third ventricle. J Neurosurg. 1974;40(2):230-235. doi:10.3171/jns.1974.40.2.0230 3. O’Neill AH, Gragnaniello C, Lai LT. Natural history of incidental colloid cysts of the third ventricle: A systematic review. J Clin Neurosci Off J Neurosurg Soc Australas. 2018;53:122-126. doi:10.1016/j.jocn.2018.04.061 4. Hassaneen W, Suki D, Salaskar AL, et al. Immediate morbidity and mortality associated with transcallosal resection of tumors of the third ventricle. J Clin Neurosci Off J Neurosurg Soc Australas. 2010;17(7):830-836. doi:10.1016/j.jocn.2009.12.007 13

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5. Milligan BD, Meyer FB. Morbidity of transcallosal and transcortical approaches to lesions in and around the lateral and third ventricles: a single-institution experience. Neurosurgery. 2010;67(6):1483-1496; discussion 1496. doi:10.1227/NEU.0b013e3181f7eb68 6. Brunori A, de Falco R, Delitala A, Schaller K, Schonauer C. Tailoring Endoscopic Approach to Colloid Cysts of the Third Ventricle: A Multicenter Experience. World Neurosurg. 2018;117:e457-e464. doi:10.1016/j.wneu.2018.06.051 7. Horn EM, Feiz-Erfan I, Bristol RE, et al. Treatment options for third ventricular colloid cysts: comparison of open microsurgical versus endoscopic resection. Neurosurgery. 2008;62(6 Suppl 3):1076-1083. doi:10.1227/01.neu.0000333773.43445.7b 8. Sheikh AB, Mendelson ZS, Liu JK. Endoscopic versus microsurgical resection of colloid cysts: a systematic review and meta-analysis of 1,278 patients. World Neurosurg. 2014;82(6):1187-1197. doi:10.1016/j.wneu.2014.06.024 9. de Witt Hamer PC, Verstegen MJT, De Haan RJ, et al. High risk of acute deterioration in patients harboring symptomatic colloid cysts of the third ventricle. J Neurosurg. 2002;96(6):1041-1045. doi:10.3171/jns.2002.96.6.1041 10. Greenberg MS. Handbook of Neurosurgery. 8th ed. Thieme; 2016. 11. Ryder JW, Kleinschmidt-DeMasters BK, Keller TS. Sudden deterioration and death in patients with benign tumors of the third ventricle area. J Neurosurg. 1986;64(2):216-223. doi:10.3171/jns.1986.64.2.0216 12. Pollock BE, Schreiner SA, Huston J. A theory on the natural history of colloid cysts of the third ventricle. Neurosurgery. 2000;46(5):1077-1081; discussion 1081-1083.

14

406

Figure 1. Anatomical risk zones for colloid cysts of the third ventricle

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The third ventricle was divided into three zones along the sagittal axis. Zone I, from the lamina

408

terminalis to a vertical line drawn from the mammillary body and tangential to the massa

409

intermedia; Zone II, from the posterior boundary of Zone I to the rostral apex of the midbrain

410

tegmentum at the inlet of the cerebral aqueduct; Zone III, from the posterior boundary of Zone II

411

to the posterior limit of the third ventricle. Copyright Thomas L. Beaumont. Published with

412

permission.

413 414

Figure 2. Receiver-operator curves for the Colloid Cyst Risk Score

415

ROC for CCRS showed AUC of 0.914 for symptomatic colloid cysts (left) and 0.892 for colloid

416

cysts with hydrocephalus (right).

15

Table 1. Colloid Cyst Risk Score Criterion

Points

Age < 65 years Yes

1

No

0

Yes

1

No

0

Headache

Axial diameter ≥7mm Yes

1

No

0

FLAIR hyperintensity Yes

1

No

0

Yes

1

No

0

Risk zone

Table 2. Comparison of development and validation cohorts Characteristic Alford et al. Beaumont et al. No. of patients 156 163 Age <65 years, n (%) 133 (85.3%) 119 (73%) Female sex, n (%) 83 (52.5%) 71 (43.6%) Headache, n (%) 74 (47.4%) 81 (49.7%) Cyst diameter ≥7mm, 82 (52.6%) 101 (68.1%) n (%) T2 FLAIR 44 (28.2%) 44 (27%) hyperintensity, n (%) Risk zone, n (%) 95 (60.9%) 87 (53.4%) Obstructive 41 (25.9%) 30 (18.4%) hydrocephalus, n (%) Symptomatic, n (%) 55 (35.3%) 65 (39.9%)

p-Value 0.0069 0.11 0.68 0.0046 0.81 0.18 0.11 0.40

Table 3. Patient stratification by Colloid Cyst Risk Score CCRS

n

Symptomatic, n (%)

Hydrocephalus, n (%)

Surgical Treatment, n (%)

0

5

0 (0.0)

0 (0.0)

0 (0.0)

1

31

0 (0.0)

0 (0.0)

0 (0.0)

2

38

5 (13.2)

3 (7.9)

4 (10.5)

3

30

7 (23.3)

4 (13.3)

5 (16.7)

4

29

20 (69.0)

15 (51.7)

19 (65.5)

5

23

23 (100)

19 (82.6)

21 (91.3)

CCRS = Colloid Cyst Risk Score

Table 4. Frequencies of CCRS criteria by clinical status Symptomatic

Not Symptomatic

(n = 55)

(n = 101)

Age < 65 years, n (%)

50 (90.9)

83 (82.2)

0.14

Headache, n (%)

50 (90.9)

24 (23.8)

<0.0001*

Axial Diameter, n (%)

49 (89.1)

33 (32.7)

<0.0001*

FLAIR hyperintensity, n (%)

29 (52.7)

15 (14.9)

<0.0001*

Risk zone, n (%)

48 (87.3)

47 (46.5)

<0.0001*

Criterion

P value*

<0.0001*

CCRS, n (%) 0

0 (0.0)

5 (4.9)

1

0 (0.0)

31 (30.7)

2

5 (9.1)

33 (32.7)

3

7 (12.7)

23 (22.8)

4

20 (36.4)

9 (8.9)

5

23 (41.8)

0 (0.0)

*Statistically significant at p < 0.05 CCRS = Colloid Cyst Risk Score FLAIR = fluid-attenuated inversion recovery

Table 5. Simple logistic regression models predicted by CCRS criteria Clinically Symptomatic

Hydrocephalus

95% Criterion

Odds Ratio

Confidence

P value*

Interval

Odds Ratio

95% Confidence

P value*

Interval

Total CCRS

6.00

3.51 – 10.29

<0.0001*

4.59

2.80 – 7.51

<0.0001*

Age < 65 years

2.17

0.76 – 6.20

0.15

1.83

0.58 – 5.74

0.30

Headache

32.08

11.49 – 89.59

<0.0001*

14.59

5.30 – 40.17

<0.0001*

Axial Diameter

16.83

6.55 – 43.26

<0.0001*

14.39

4.80 – 43.11

<0.0001*

6.40

2.98 – 13.70

<0.0001*

5.72

2.63 – 12.44

<0.0001*

7.88

3.25 – 19.07

<0.0001*

43.61

5.80 - 327.82

0.0002*

FLAIR hyperintensity Risk zone

*Statistically significant at p < 0.05 CCRS = Colloid Cyst Risk Score; FLAIR = fluid-attenuated inversion recovery

Table 6. Frequencies of CCRS criteria by hydrocephalus status

Criterion

Hydrocephalus (n = 41)

No Hydrocephalus

P value*

(n = 117)

Age < 65 years, n (%)

37 (90.2)

96 (83.5)

0.29

Headache, n (%)

36 (87.8)

38 (33.0)

<0.0001*

Axial Diameter, n (%)

37 (90.2)

45 (39.1)

<0.0001*

FLAIR hyperintensity, n (%)

23 (56.1)

21 (18.3)

<0.0001*

Risk zone, n (%)

40 (97.6)

55 (47.8)

<0.0001*

<0.0001*

CCRS, n (%) 0

0 (0.0)

5 (4.3)

1

0 (0.0)

31 (27.0)

2

4 (9.8)

35 (30.4)

3

3 (7.3)

26 (22.6)

4

15 (36.6)

14 (12.2)

5

19 (46.3)

4 (3.5)

*Statistically significant at p < 0.05 CCRS = Colloid Cyst Risk Score FLAIR = fluid-attenuated inversion recovery

Abbreviations List: AUC – area under the curve CCRS – Colloid Cyst Risk Score CI – confidence interval CSF – cerebrospinal fluid FLAIR – Fluid-attenuate inversion recovery ICD-9 – International Classification of Diseases, 9th Revision ICD-10 – International Classification of Diseases, 10th Revision IQR – interquartile range MRI – magnetic resonance imaging OR – odds ratio ROC – receiver operating characteristic

Disclosures: The authors have no financial or material disclosures to report. No portions of this work have been previously presented.