Postoperative MRI features of cerebellar mutism syndrome: a retrospective cohort study

Wei YangDepartments of Neurosurgery and

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Hong ZhangRadiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing;

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Yingjie CaiDepartments of Neurosurgery and

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Xiaojiao PengDepartments of Neurosurgery and

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Hailang SunDepartments of Neurosurgery and

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Jiashu ChenDepartments of Neurosurgery and

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Zesheng YingDepartments of Neurosurgery and

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Kaiyi ZhuDepartment of Cardiology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan; and
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

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Yun PengRadiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing;

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Ming GeDepartments of Neurosurgery and

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OBJECTIVE

In this study, the authors aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome.

METHODS

A retrospective cohort of patients who underwent tumor resection from July 2013 to March 2021 for midline posterior fossa tumors was investigated. All patients were followed up at least once. Clinical data were extracted from medical records and follow-up databases. Two neuroradiologists independently reviewed preoperative and postoperative MRI. Univariable and multivariable analyses were performed to compare the postoperative cerebellar mutism syndrome (pCMS) and non-pCMS groups. Correlation analysis was performed using the Spearman correlation coefficient analysis.

RESULTS

Of 124 patients, 47 (37.9%) developed pCMS. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months. The median duration of mutism was 45 days. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm. In the univariable analysis, abnormal T2-weighted signal of the left dentate nucleus (DN) (74.5% in the pCMS group vs 36.4% in the non-pCMS group, p < 0.001), right DN (83.0% vs 40.3%, p < 0.001), left superior cerebellar peduncle (SCP) (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left middle cerebellar peduncle (MCP) (51.1% vs 26.0%, p = 0.008), and right MCP (61.7% vs 26.0%, p < 0.001); male sex (83.0% vs 45.5%, p < 0.001); vermis 3 impairment (49.4% vs 19.1%, p = 0.002); solid tumor (91.5% vs 72.7%, p = 0.022); and hydrocephalus (72.3% vs 45.5%, p = 0.006) were more frequent in the pCMS group than in the non-pCMS group. Multivariable logistic analysis showed that male sex (adjusted OR 4.08, p = 0.010) and the cerebro-cerebellar circuit score of T2-weighted images (adjusted OR 2.15, p < 0.001) were independent risk factors for pCMS. The cerebro-cerebellar circuit score positively correlated with the duration of mutism. In Cox regression analysis, the cerebro-cerebellar integrated circuit injury score of T2 (adjusted HR 0.790, 95% CI 0.637–0.980; p = 0.032) and injury of vermis 3 (adjusted HR 3.005, 95% CI 1.197–7.547; p = 0.019) were independently associated with the duration of mutism.

CONCLUSIONS

Male sex and cerebro-cerebellar circuit damage are independent risk factors for pCMS. The cerebro-cerebellar circuit score indicates the duration of mutism.

ABBREVIATIONS

ADC = apparent diffusion coefficient; CIS = circuit injury score; DN = dentate nucleus; DWI = diffusion-weighted imaging; iCIS = integrated CIS; MCP = middle cerebellar peduncle; pCMS = postoperative cerebellar mutism syndrome; SCP = superior cerebellar peduncle; VP = ventriculoperitoneal.

OBJECTIVE

In this study, the authors aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome.

METHODS

A retrospective cohort of patients who underwent tumor resection from July 2013 to March 2021 for midline posterior fossa tumors was investigated. All patients were followed up at least once. Clinical data were extracted from medical records and follow-up databases. Two neuroradiologists independently reviewed preoperative and postoperative MRI. Univariable and multivariable analyses were performed to compare the postoperative cerebellar mutism syndrome (pCMS) and non-pCMS groups. Correlation analysis was performed using the Spearman correlation coefficient analysis.

RESULTS

Of 124 patients, 47 (37.9%) developed pCMS. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months. The median duration of mutism was 45 days. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm. In the univariable analysis, abnormal T2-weighted signal of the left dentate nucleus (DN) (74.5% in the pCMS group vs 36.4% in the non-pCMS group, p < 0.001), right DN (83.0% vs 40.3%, p < 0.001), left superior cerebellar peduncle (SCP) (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left middle cerebellar peduncle (MCP) (51.1% vs 26.0%, p = 0.008), and right MCP (61.7% vs 26.0%, p < 0.001); male sex (83.0% vs 45.5%, p < 0.001); vermis 3 impairment (49.4% vs 19.1%, p = 0.002); solid tumor (91.5% vs 72.7%, p = 0.022); and hydrocephalus (72.3% vs 45.5%, p = 0.006) were more frequent in the pCMS group than in the non-pCMS group. Multivariable logistic analysis showed that male sex (adjusted OR 4.08, p = 0.010) and the cerebro-cerebellar circuit score of T2-weighted images (adjusted OR 2.15, p < 0.001) were independent risk factors for pCMS. The cerebro-cerebellar circuit score positively correlated with the duration of mutism. In Cox regression analysis, the cerebro-cerebellar integrated circuit injury score of T2 (adjusted HR 0.790, 95% CI 0.637–0.980; p = 0.032) and injury of vermis 3 (adjusted HR 3.005, 95% CI 1.197–7.547; p = 0.019) were independently associated with the duration of mutism.

CONCLUSIONS

Male sex and cerebro-cerebellar circuit damage are independent risk factors for pCMS. The cerebro-cerebellar circuit score indicates the duration of mutism.

In Brief

Postoperative cerebellar mutism syndrome (pCMS) is a common complication of posterior fossa surgery. This study aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome. The results showed that damage to the cerebro-cerebellar circuit was associated with pCMS. Furthermore, the extent of damage to the cerebro-cerebellar circuit was related to the duration of mutism. These results help in understanding the mechanism of pCMS and the variation of the duration of mutism.

Postoperative cerebellar mutism syndrome (pCMS), a well-known neurological complication, is characterized by transient mutism or reduced speech following surgery for tumors arising in the posterior fossa, especially medulloblastoma.1 Patients can develop mutism immediately or 1–7 days after surgery.2 Some patients experience reduced speech, which can only be invoked with strong stimulation.1 Apart from language impairment, patients with pCMS can also present with emotional liability, hypotonia, apraxia, ataxia, and cognitive impairment.3,4 Commonly, mutism lasts for 1–3 months after surgery. However, patients can experience long-term linguistic impairments such as low speech speed, and dysarthria and motor impairment.

The reported incidence of pCMS varies widely, ranging from 8% to 39%.5 However, the underlying etiology of pCMS remains unclear. The most prevalent hypothesis is that cerebro-cerebellar diaschisis plays a crucial role in pCMS development.6,7 Previous studies have extensively investigated the radiological characteristics of tumors, and the only reproducible features were midline location and radiological diagnosis of medulloblastoma.8 Invasive compression of the superior cerebellar peduncles (SCPs), middle cerebellar peduncles (MCPs), and brainstem has also been reported but is not consistent across all reports.9 Some diffusion tensor imaging studies have reported decreases in fractional anisotropy in the cerebellar peduncles.6,1012 However, there is controversy regarding the laterality and involvement of the cerebellar peduncles, and the relationship between the cerebellar peduncles and pCMS remains unclear. Previous studies have reported that incision of the cerebellar vermis precipitates pCMS and that the telovelar approach can reduce the occurrence of pCMS.13,14 However, a recent meta-analysis found no association between pCMS and surgical route,15 and the relationship between pCMS and vermis incision remains controversial. Moreover, studies that have systemically evaluated the postsurgical MRI of patients with pCMS are scarce.

To better understand the relationship between pCMS and surgical damage to cerebellar efferent elements, we investigated the postsurgical MRI features of pCMS in a retrospective cohort of patients with posterior fossa tumors in the midline position. Two neuroradiologists independently reviewed the highly associated structures on MRI. This study aimed to explore the association between surgical damage and the occurrence and duration of pCMS.

Methods

Patients

This retrospective cohort study included patients diagnosed with a midline tumor in the posterior fossa and who underwent craniotomy between July 2013 and March 2021 at Beijing Children’s Hospital. The inclusion criteria were patients 1) with a diagnosis of a posterior fossa tumor located at the midline position, 2) aged 1 to 18 years, and 3) who received craniotomy treatment. The exclusion criteria included lack of preoperative or postoperative MRI data, no pCMS status assessment because of tracheotomy or missing clinical records, and presurgical abnormal speech as reported by the parents. Patients were followed up on an outpatient basis or by telephone every 6–12 months. The Ethics Committee of the Beijing Children’s Hospital approved this study.

Definition of pCMS

According to the consensus from the Delphi conference, pCMS is a complete loss of the ability to speak or markedly reduced speech. The diagnosis was based on medical records or neurological examinations by a senior neurosurgeon. Mutism status was further confirmed by follow-up of the duration of mutism by telephone interviews or outpatient interviews. Other symptoms, such as dysphagia, hypotonia, and emotional irritability, were also retrieved or recorded. Speech restoration was the ability to speak at least one Chinese word. The duration of mutism was calculated according to the start day and the day of speech restoration. Because of the retrospective design, some of the records were not completed. For missing records, we queried the parents by telephone.

Definition of Variables

MRI was performed on a Philips 1.5T, 3.0T, or GE 3.0T scanner. T1-weighted, T2-weighted, FLAIR, and diffusion-weighted imaging (DWI) sequences were obtained pre- and postoperatively. DWI sequences (b = 1000) were reviewed alongside derived apparent diffusion coefficient (ADC) maps to corroborate positive findings, and tumor diameter was determined by measuring the largest diameter on the three planes. The Evans’ index was measured and calculated on preoperative axial T1-weighted MRI. Hydrocephalus was defined as an Evans’ index ≥ 0.3. Paraventricular edema was evaluated on presurgical FLAIR MRI. Tumor consistency was dichotomized as solid and nonsolid. Tumors with solid substances in more than half of their volume were determined to be solid. Surgeries were completed by three different surgeons (M.G., H.S., or Yuanqi Ji), and they were labeled as "G," "S," and "J," respectively. Based on anatomical landmarks, the cerebellar vermis was divided into three parts: vermis 1, vermis 2, and vermis 3, as shown in Fig. 1. To investigate impairment of the SCPs, MCPs, dentate nucleus (DN), and cerebellar vermis, postsurgical T1-weighted, T2-weighted, FLAIR, DW, and ADC MR images were independently reviewed by two pediatric neuroradiologists (H.Z. and Y.P.), who were blinded to the diagnosis of pCMS. T1-weighted MRI was used to evaluate the integrity of these structures. Integrity was categorized as normal (score 0) and abnormal (score 1). T2-weighted and ADC MR images were used to identify abnormal signals in these structures. The signal variable was categorized as normal (score 0) and abnormal (score 1). T1-weighted and T2-weighted images were used to exclude hemorrhage signals. When reviewing postsurgical MRI, presurgical MRI was employed as a reference to identify the damage from operations. The left or right cerebro-cerebellar circuit injury score (CIS) was calculated using the sum of the scores of the corresponding lateral MCP, SCP, and DN. The cerebro-cerebellar integrated CIS (iCIS) is the sum of the left and right CISs. The iCIS and CIS were calculated for each modality of MRI. Mutism duration was categorized as 0 (no mutism), 1 (< 30 days), 2 (30–90 days), or 3 (> 90 days). For patients with reduced speech, the duration of mutism was not applicable. The median interval between the postsurgical MRI and surgery date was 8 (Q1: 6, Q3: 13) days.

FIG. 1.
FIG. 1.

The vermis was divided into three parts: vermis 1, vermis 2, and vermis 3. The primary fissure and prepyramidal fissure serve as the boundary lines. Figure is available in color online only.

Consistency Analysis

Postoperative MRI data were independently reviewed by two experienced pediatric neuroradiologists who were blinded to pCMS status. Cohen’s kappa was used to evaluate interobserver variations.

Statistical Analysis

Statistical analysis was performed using Python 3.7. The study population was characterized by descriptive parameters of mean ± SD, median (Q1, Q3), and number (percentage). The two-sample t-test, Kruskal-Wallis test, chi-square test, or Fisher’s exact test was used for comparisons between the pCMS and non-pCMS groups. Variables that were significant in the comparison at the p < 0.05 level were included in the multivariable logistic analysis. Correlation analysis was conducted using the Spearman test. Risk factors of mutism duration were analyzed with backward stepwise Cox regression. Interreviewer reliability of post-MRI features was measured using the kappa test.

Results

Summary of Patient and Tumor Characteristics

Between July 2013 and March 2021, 225 patients underwent posterior fossa surgery at our hospital, of whom 124 patients with midline tumors in the posterior fossa were included in this study. Forty-nine patients were excluded because of loss to follow-up or loss of medical records, and 52 patients were excluded because their tumors were located in the cerebellar hemisphere. The mean age at surgery was 5.9 ± 3.3 years, and males composed 59.7% of the cohort. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm, with 55.6% of the patients presenting with hydrocephalus and 10.5% receiving a ventriculoperitoneal (VP) shunt before surgery. Medulloblastoma accounted for 52.4% of all tumors, and ependymoma accounted for 16.1%; 31.5% of tumors were classified as other. Of 124 patients, 47 (37.9%) were diagnosed with cerebellar mutism syndrome after surgery. Additional detailed information is provided in Table 1.

TABLE 1.

Patient characteristics

VariableNo. of Patients (%)
Total124
No. of patients w/ pCMS47 (37.9)
Male sex74 (59.7)
Age >3 yrs93 (75.0)
Hydrocephalus present69 (55.6)
Paraventricular edema present88 (71.0)
Preop VP shunt present13 (10.5)
Solid tumor100 (80.6)
Tumor >5 cm69 (55.6)
Surgeon
 G67 (54.0)
 S36 (29.0)
 J21 (16.9)
Surgical route
 Unknown57 (46.0)
 Transvermis approach35 (28.2)
 Telovolar approach20 (16.1)
 Other12 (9.7)
GTR109 (87.9)
Pathology
 MB65 (52.4)
 EP20 (16.1)
 Other39 (31.5)
Histological classification
 Other64 (51.6)
 Classic44 (35.5)
 DP8 (6.5)
 MBEN4 (3.2)
 LCA4 (3.2)
Abnormal vermis 11 (0.8)
Abnormal vermis 210 (8.1)
Abnormal vermis 377 (62.1)
Abnormal SCP (T1WI)2 (1.6)
Abnormal SCP (T2WI)72 (58.1)
Abnormal SCP (ADC)35 (28.2)
Abnormal MCP (T1WI)2 (1.6)
Abnormal MCP (T2WI)73 (58.9)
Abnormal MCP (ADC)2 (1.6)
Abnormal DN (T1WI)0 (0)
Abnormal DN (T2WI)86 (69.4)
Abnormal DN (ADC)6 (4.8)

DP = desmoplastic; EOR = extent of resection; EP = ependymoma; GTR = gross-total resection; LCA = large cell/anaplastic; MB = medulloblastoma; MBEN = MB with extensive nodularity; T1WI = T1-weighted imaging; T2WI = T2-weighted imaging.

Summary of Patients With pCMS

Of the 47 patients with pCMS, the starting and ending days of mutism were missed in 2 patients. Reduced speech was diagnosed in 4 patients, and the duration of mutism could not be defined. The latency to the onset of mutism after posterior fossa surgery varied from 0 to 7 days, with a median 0 days. The duration of mutism ranged from 7 to 469 days, with a median of 45 days. The duration of hypotonia ranged from 42 to 469 days (median 75 days). Of the 47 patients, 26 (55.3%) presented with oropharyngeal dysfunction and 36 (76.6%) presented with emotional liability. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months.

Baseline Comparison Between the pCMS and Non-pCMS Groups

Univariable analysis demonstrated that patients with pCMS were significantly more likely to be male (83.0% vs 45.5%), have hydrocephalus (72.3% vs 45.5%), and have a solid tumor (91.5% vs 72.7%) than non-pCMS patients (p < 0.05). There were significant differences in the distribution of pathology and surgical routes between the two groups (p < 0.05). No significant differences were found in age at surgery, diagnosis of medulloblastoma, paraventricular edema, tumor size, presurgical VP shunt, extent of resection, or surgeon (p > 0.05) between the two groups (Table 2). Figure 2 illustrates examples of cases with varying damage patterns on the MR images.

TABLE 2.

Baseline comparison between pCMS and non-pCMS patients

VariableOverall (n = 124)Non-pCMS (n = 77)pCMS (n = 47)p Value
Sex<0.001
 Female50 (40.3)42 (54.5)8 (17.0)
 Male74 (59.7)35 (45.5)39 (83.0)
Hydrocephalus0.006
 Yes69 (55.6)35 (45.5)34 (72.3)
 No55 (44.4)42 (54.5)13 (27.7)
Tumor consistency0.022
 Cystic25 (20.2)21 (27.3)4 (8.5)
 Solid99 (79.8)56 (72.7)43 (91.5)
Pathology0.026
 MB65 (52.4)35 (45.5)30 (63.8)
 Other39 (31.5)31 (40.3)8 (17.0)
 EP20 (16.1)11 (14.3)9 (19.1)
Op route0.035
 Other12 (9.7)12 (15.6)0 (0)
 Unknown57 (46.0)32 (41.6)25 (53.2)
 Transvermis approach35 (28.2)22 (28.6)13 (27.7)
 Telovolar approach20 (16.1)11 (14.3)9 (19.1)
MB0.071
 Yes65 (52.4)35 (45.5)30 (63.8)
 No59 (47.6)42 (54.5)17 (36.2)
Paraventricular edema0.091
 Yes88 (71.0)50 (64.9)38 (80.9)
 No36 (29.0)27 (35.1)9 (19.1)
Preop VP shunt0.237*
 No111 (89.5)71 (92.2)40 (85.1)
 Yes13 (10.5)6 (7.8)7 (14.9)
Tumor size0.323
 ≤5 cm69 (55.6)46 (59.7)23 (48.9)
 >5 cm55 (44.4)31 (40.3)24 (51.1)
Surgeon0.601
 G67 (54.0)44 (57.1)23 (48.9)
 S36 (29.0)20 (26.0)16 (34.0)
 J21 (16.9)13 (16.9)8 (17.0)
EOR0.916
 GTR109 (87.9)68 (88.3)41 (87.2)
 Non-GTR15 (12.1)9 (11.7)6 (12.8)
Age at op, mean (SD)5.9 (3.3)5.9 (3.6)5.8 (2.9)0.947

Values represent the number of patients (%) unless stated otherwise.

Fisher exact test.

Two-sample t-test.

FIG. 2.
FIG. 2.

Typical postoperative MR images obtained in 2 patients. A–J: MR images obtained 5 days after tumor resection in a 7-year-old boy. Axial T1-weighted (A), T2-weighted (B), FLAIR (C), DW (D), and ADC map (E) images demonstrate surgical damage to the bilateral SCP (white arrows). The DW and ADC map images showing restricted diffusion, consistent with cytotoxic edema. This finding was interpreted as permanent damage to the bilateral SCPs. Axial T1-weighted (F), T2-weighted (G), FLAIR (H), DW (I), and ADC map (J) images. The T2-weighted (G) image shows a high signal in the bilateral MCPs and DNs (open arrows). DW and ADC map images showing slight restricted diffusion because of hemorrhage (high signal on the T1-weighted image). This finding was interpreted as postsurgical vasogenic edema in the bilateral MCPs and DNs. K–T: MR images obtained 5 days after tumor resection in a 2-year-old girl. Axial T1-weighted (K), T2-weighted (L), FLAIR (M), DW (N), and ADC map (O) images demonstrating no damage to the SCPs (white arrows). Axial T1-weighted (P), T2-weighted (Q), FLAIR (R), DW (S), and ADC map (T) images demonstrating no damage to the MCPs and DNs (open arrows).

Comparison of Postoperative MRI Features

The proportions of vermis 3 impairment (80.9% in the pCMS group vs 50.6% in the non-pCMS group, p = 0.002); and abnormal T2-weighted signal in the left SCP (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left MCP (51.1% vs 26.0%, p = 0.008), right SCP (61.7% vs 26.0%, p < 0.001), left DN (74.5 vs 36.4%, p < 0.001), and right DN (83.0% vs 40.3%, p < 0.001) were significantly higher in the pCMS group than in the non-pCMS group (p < 0.05). The pCMS group had a higher proportion of abnormal ADC signals in the right SCP than the non-pCMS group (34.0% vs 13.0%, p = 0.01). There were no significant differences in the other postoperative features between the pCMS and non-pCMS groups (Table 3).

TABLE 3.

Comparison of postoperative MRI features between pCMS and non-pCMS patients

Location & ModalityMRI FeatureNo. of Patients (%)p Value
Overall (n = 124)Non-pCMS (n = 77)pCMS (n = 47)
DN
 T1WI, ltNormal124 (100.0)77 (100.0)47 (100.0)>0.99
 T1WI, rtNormal124 (100.0)77 (100.0)47 (100.0)>0.99
 T2WI, ltNormal61 (49.2)49 (63.6)12 (25.5)<0.001
Abnormal63 (50.8)28 (36.4)35 (74.5)
 T2WI, rtNormal54 (43.5)46 (59.7)8 (17.0)<0.001
Abnormal70 (56.5)31 (40.3)39 (83.0)
 ADC, ltNormal121 (97.6)76 (98.7)45 (95.7)0.557*
Abnormal3 (2.4)1 (1.3)2 (4.3)
 ADC, rtNormal119 (96.0)75 (97.4)44 (93.6)0.366*
Abnormal5 (4.0)2 (2.6)3 (6.4)
SCP
 T1WI, ltNormal124 (100.0)77 (100.0)47 (100.0)>0.99
 T1WI, rtNormal122 (98.4)76 (98.7)46 (97.9)>0.99*
Abnormal2 (1.6)1 (1.3)1 (2.1)
 T2WI, ltNormal68 (54.8)56 (72.7)12 (25.5)<0.001
Abnormal56 (45.2)21 (27.3)35 (74.5)
 T2WI, rtNormal76 (61.3)59 (76.6)17 (36.2)<0.001
Abnormal48 (38.7)18 (23.4)30 (63.8)
 ADC, ltNormal98 (79.0)65 (84.4)33 (70.2)0.097
Abnormal26 (21.0)12 (15.6)14 (29.8)
 ADC, rtNormal98 (79.0)67 (87.0)31 (66.0)0.010
Abnormal26 (21.0)10 (13.0)16 (34.0)
MCP
 T1WI, ltNormal123 (99.2)76 (98.7)47 (100.0)>0.99*
Abnormal1 (0.8)1 (1.3)
 T1WI, rtNormal123 (99.2)77 (100.0)46 (97.9)0.379*
Abnormal1 (0.8)0 (0)1 (2.1)
 T2WI, ltNormal80 (64.5)57 (74.0)23 (48.9)0.008
Abnormal44 (35.5)20 (26.0)24 (51.1)
 T2WI, rtNormal75 (60.5)57 (74.0)18 (38.3)<0.001
Abnormal49 (39.5)20 (26.0)29 (61.7)
 ADC, ltNormal123 (99.2)76 (98.7)47 (100.0)>0.99*
Abnormal1 (0.8)1 (1.3)0 (0)
 ADC, rtNormal123 (99.2)76 (98.7)47 (100.0)>0.99*
Abnormal1 (0.8)1 (1.3)0 (0)
 Vermis 1Normal123 (99.2)76 (98.7)47 (100.0)>0.99*
Abnormal1 (0.8)1 (1.3)0 (0)
 Vermis 2Normal114 (91.9)71 (92.2)43 (91.5)>0.99*
Abnormal10 (8.1)6 (7.8)4 (8.5)
 Vermis 3Normal47 (37.9)38 (49.4)9 (19.1)0.002
Abnormal77 (62.1)39 (50.6)38 (80.9)

Fisher exact test.

Association Between Cerebro-Cerebellar Circuit Injuries and pCMS

We compared the cerebro-cerebellar CISs of the three modalities of MRI between the two groups. The Kruskal-Wallis test revealed significant differences in bilateral cerebro-cerebellar CISs on T2-weighted and ADC images, and in cerebro-cerebellar iCISs on T2-weighted and ADC images between patients with and those without pCMS. No significant difference was identified in cerebro-cerebellar circuit injuries on T1-weighted imaging (Supplementary Table 1).

Multivariable Analysis of pCMS

All significant variables in the univariable analysis were subjected to multivariable analysis. Given the association between cerebro-cerebellar CISs and postoperative MRI features, we conducted three separate multivariable analyses. In the first multivariable analysis, which included the postoperative MRI features, male sex (adjusted OR 3.39, p = 0.039), abnormal T2-weighted imaging findings of the right DN (adjusted OR 3.91, p = 0.036), and hydrocephalus (adjusted OR 3.38, p = 0.035) were independent risk factors for pCMS. The remaining variables that were significant prognostic factors in the univariable analysis were not significant in the multivariable analysis (Table 4).

TABLE 4.

Multivariable analysis of postoperative MRI features

OR95% CICoefficientp Value
LBUB
Intercept0.010.000.05−5.00<0.001
SCP (T2WI, lt)9.571.8051.052.260.008
Hydrocephalus3.381.0910.461.220.035
DN (T2WI, rt)3.911.0914.001.360.036
Sex (male)3.391.0610.801.220.039
MCP (T2WI, rt)3.650.8515.581.290.081
Tumor consistency2.760.5115.121.020.241
SCP (ADC, rt)0.400.081.89−0.930.245
Pathology (MB vs others)0.470.102.10−0.760.321
DN (T2WI, lt)2.000.488.400.690.342
MCP (T2WI, rt)0.510.122.29−0.660.383
SCP (T2WI, rt)1.740.427.270.550.448
Vermis 20.720.202.68−0.320.628
Pathology (EP vs others)1.410.209.940.350.728

LB = lower bound; UB = upper bound.

In the second multivariable analysis, which included the separated cerebro-cerebellar CISs on T2-weighted images, bilateral cerebro-cerebellar CISs on T2-weighted images (left: adjusted OR 2.06, p = 0.005; right: adjusted OR 2.24, p = 0.002), and male sex (adjusted OR 3.89, p = 0.016) were independent risk factors for pCMS. Hydrocephalus, pathology, cerebro-cerebellar CISs on ADC images, and vermis 3 abnormalities were not independent risk factors for pCMS (Table 5).

TABLE 5.

Multivariable analysis for risk factors of pCMS

OR95% CICoefficientp Value
LBUB
CIS w/ laterality included in analysis
 Intercept0.010.000.06−4.68<0.001
 CIS (T2WI, rt)2.241.333.770.810.002
 CIS (T2WI, lt)2.061.253.400.720.005
 Sex (male)3.891.2911.721.360.016
 Hydrocephalus2.580.947.100.950.066
 Pathology (EP vs others)2.280.4112.500.820.344
 Tumor consistency (solid)1.960.3810.070.670.420
 CIS (ADC, rt)0.840.203.60−0.170.820
 CIS (ADC, lt)0.680.172.74−0.390.587
 Pathology (MB vs others)0.940.243.65−0.070.923
 Vermis 31.030.303.490.030.960
iCIS included in analysis
 Intercept0.010.000.06−4.71<0.001
 iCIS (T2WI)2.151.493.080.76<0.001
 Sex (male)4.081.3911.981.410.010
 Hydrocephalus2.560.947.010.940.067
 Pathology (EP vs others)2.450.4712.880.900.289
 Tumor consistency (solid)1.930.389.820.660.428
 iCIS (ADC)0.760.371.54−0.280.443
 Pathology (MB vs others)0.930.243.62−0.070.919
 Vermis 31.040.313.500.040.953

In the third multivariable analysis, which included the cerebro-cerebellar iCISs, cerebro-cerebellar iCISs of T2-weighted images (adjusted OR 2.15, p < 0.001) and male sex (adjusted OR 4.08, p = 0.010) were independent risk factors for pCMS. Other factors were not independent risk factors for pCMS (p > 0.05) (Table 5).

Association Between the Mutism Duration and Cerebro-Cerebellar Injuries

Spearman correlation analysis showed that the mutism duration was positively correlated with the degree of the cerebro-cerebellar iCIS (r = 0.535, p < 0.001), left cerebro-cerebellar CIS (r = 0.394, p < 0.001), and right cerebro-cerebellar CIS (r = 0.484, p < 0.001). Figure 3 shows the positive correlation between the mutism duration and the cerebro-cerebellar CIS. To further explore the risk factors of mutism duration, patients with pCMS (4 patients with reduced speech were excluded) were analyzed with a backward stepwise Cox regression. Finally, an iCIS of 2 on T2-weighted imaging (adjusted HR 0.790, 95% CI 0.637–0.980; p = 0.032), injury to vermis 3 (adjusted HR 3.005, 95% CI 1.197–7.547; p = 0.019), and age at surgery (adjusted HR 1.123, 95% CI 0.999–1.262; p = 0.051) were preserved in the model.

FIG. 3.
FIG. 3.

The correlation between CIS or iCIS on T2-weighted (T2w) imaging and duration of mutism. A and B: Positive correlation between the left and right CISs on T2-weighted imaging and duration of mutism. C: Positive correlation between the iCIS on T2-weighted imaging and duration of mutism. The higher the CIS or iCIS on T2-weighted imaging, the greater the likelihood of a longer duration of mutism. Figure is available in color online only.

Interobserver Agreement

Kappa statistics for interobserver variability ranged from −0.01 to 0.97, with a mean kappa of 0.73 ± 0.3. The kappa values for the DN on T1-weighted imaging were incalculable because of very small positive findings in the review (Supplementary Table 2).

Discussion

A midline tumor location has proven to be a reliable risk factor for pCMS, but not all patients with a tumor located at the midline will develop pCMS. Previous studies on pCMS included all posterior fossa tumors when investigating the risk factors of pCMS, which identified the midline location as an independent risk factor for pCMS. However, these studies did not fully answer the question of why some patients with midline tumors did not develop pCMS. In fact, few studies have investigated posterior midline tumors alone. Diaschisis of the cerebrum and cerebellum has been theorized to cause pCMS. Numerous studies have investigated impairment of the DN, SCP, and cerebellar vermis in pCMS. However, these studies were based on presurgical MRI, in which the impairment was caused by the tumor itself.1517 Herein, we investigated the features of postsurgical MRI in patients with a midline posterior fossa tumor.

In the baseline comparison, tumor size, age at surgery, extent of resection, surgeon, and presurgical VP shunt were not associated with pCMS. This finding is consistent with the results of several previous studies.5,8,18,19 Hydrocephalus was a significant risk factor, whereas paraventricular edema was not. Further multivariable analysis revealed that hydrocephalus was not a stable independent factor of pCMS. This is consistent with previous studies2,9,19,20 in which whether hydrocephalus is a risk factor of pCMS remains controversial. However, the mechanism by which hydrocephalus increases the risk of pCMS remains unclear. Zhang et al.20 considered that a rapid drop in intracranial pressure causes damage to neuronal fibers and leads to pCMS. If so, a presurgical shunt might decrease the risk of pCMS. However, this was not observed in this study. Hence, more compelling evidence is required to clarify the association between pCMS and hydrocephalus. Tumor consistency, tumor pathology, and surgical route were significantly associated with pCMS in univariable analysis but were not significant in multivariable analysis. The surgical route was not incorporated into the multivariable analysis because there were many cases in which the route was unknown. Given that most midline posterior tumors are solid, it is reasonable to presume that solid tumor could not be an independent risk factor for pCMS. Medulloblastoma was not a significant risk factor for pCMS in the univariable analysis, which differs from previous perceptions.8,15 This result indicates that medulloblastoma is not a repeatable risk factor. A previous conclusion was drawn in the entire posterior fossa tumor cohort, in which there was an association between medulloblastoma and the midline location. Therefore, it is acceptable to find no significant association between medulloblastoma and pCMS in the midline posterior fossa tumor cohort.

Sex was an independent risk factor for pCMS in the univariable and multivariable analyses. Gora et al.21 also found a significant association between pCMS and male sex. Other studies found a higher or lower proportion of males in the pCMS group than in the non-pCMS group, but the difference was not significant.8,2224 Linguistic studies have found that males lag behind females in early language development and are more vulnerable to language deficits than females.2527 We presume that the cerebellum may play an indispensable role in early language learning, especially for the Chinese language. Considering the different linguistic processing mechanisms among different languages, we believe that more effort is needed to clarify this issue.

In the univariable analysis, the rates of abnormal signals on T2-weighted images in the bilateral DNs, SCPs, and MCPs in pCMS were significantly higher (p < 0.05) than in the non-pCMS group. This is consistent with previous studies23,28 and supports the hypothesis that impairment of the cerebro-cerebellar circuit causes pCMS. Wells et al.23 also found trends for more MCP and SCP edema in patients with pCMS. Boisgontier et al.19 demonstrated a similar result that patients with pCMS were more likely to present with T2 hyperintensities in the right DN. However, whether lateral6 or bilateral29 damage to the DN is associated with pCMS remains debatable.30 An abnormal signal on T2-weighted MRI indicates tissue edema and can return to normal within a certain period. This might explain the phenomenon in which mutism can be restored after a while. ADC can distinguish cytotoxic edema (showing restricted diffusion) from vasogenic edema (showing unrestricted diffusion). Notably, an abnormal signal in the right SCP on ADC was significantly associated with pCMS. The other postoperative features were not significantly associated with pCMS. Theoretically, an abnormal signal on the ADC image and structural deficiency on the T1-weighted image indicate irreversible damage. To better understand such results and avoid confounding effects, we introduced the cerebro-cerebellar CIS to replace the single image feature. Two separate multivariable analyses were conducted. The first introduced the cerebro-cerebellar CIS as left and right features, and the second introduced the cerebro-cerebellar CIS as an integrated feature (iCIS). Our data showed that both the lateral and integrated cerebro-cerebellar CISs were significantly associated with pCMS. This indicates that damage to any lateral cerebro-cerebellar circuit can lead to pCMS.

To further confirm the association between pCMS and cerebellar circuit damage, we calculated the correlation coefficients between the two variables. The results showed that the cerebro-cerebellar CISs and iCISs were significantly positively correlated with the extent of mutism. Cox regression analysis showed that an iCIS of 2 on T2-weighted imaging is a risk factor for speech restoration, whereas a vermis 3 incision is a protective factor, meaning that too much damage to the cerebro-cerebellar circuit will prolong the duration of mutism. In addition, whether younger age is associated with prolonged mutism still needs to be validated, despite it being reserved in the Cox regression model with p = 0.051 and an adjusted HR of 1.123 (95% CI 0.999–1.262). Younger age has been proven to be a risk factor for pCMS in recent studies.22,31 Moreover, Khan et al.24 found that the ataxia score was associated with the duration of mutism. Our study provides alternative risk factors that may be useful in clinical practice. These results also remind surgeons to avoid radical damage to cerebro-cerebellar structures during surgery.

Whether surgical damage to the vermis is related to pCMS remains controversial. A recent meta-analysis15 showed that a vermis incision was significantly associated with pCMS, but the transvermian approach did not increase the occurrence of pCMS in contrast to the telovelar approach. Therefore, it remains controversial whether a vermis incision gives rise to pCMS. Furthermore, the authors of that study did not report which part of the vermis is more important. In this study, we divided the cerebellar vermis into three segments (vermis 1, vermis 2, and vermis 3) to explore damage to which part of the vermis is more likely to result in pCMS. The univariable analysis showed that the pCMS group had a higher rate of vermis 3 damage than did the non-pCMS group, whereas damage to vermis 1 or vermis 2 was not significantly associated with pCMS, but this difference lost significance in the multivariable analysis because of the correlation with T2 signal of the DN. Toescu et al.32 also found no association between vermis incision and pCMS, which is in accordance with findings in a previous study.9,33 Functional MR mapping studies have indicated that the vermis is not involved in language processing.34,35 Hence, we believe that vermis damage is not an independent risk factor of pCMS, which we hope will be validated in future studies.

In the interobserver variability analysis, the kappa values of bilateral DN impairment on T1-weighted imaging and MCP on ADC were small. This is because the positive results of these features were fewer, which did not change the statistical results. Therefore, these are reliable features for the analysis. The kappa values of the other features (0.66–1.00) were highly reliable. These are rational and scientific bases for further statistical analyses.

The strength of this study is that only midline posterior fossa tumors were included, and tumors in the lateral position were excluded. This could minimize the confounding effect, as pCMS seldom occurs with resection of lateral tumors. Second, we reviewed postsurgical MRI to evaluate the surgical damage and innovatively divided the vermis into three segments to explore their relationship with pCMS. Multimodal MRI was employed to make the evaluation more comprehensive. Third, we found a correlation between the cerebro-cerebellar CIS and the duration of mutism.

However, our study has some limitations. First, the retrospective design inevitably has sample and recall bias, and the incidence of pCMS in our center is higher than those in previous reports. In our study, the definition of pCMS is consistent with the consensus of the Delphi conference in 2016.1 We acknowledge that this definition is subjective to some extent. As a previous study pointed out, there is no standardized clinical criterion for pCMS, so the rate of pCMS is varied in the literature.36 In our study, 52 patients were not included in the analysis because the tumors were located at the cerebellar hemisphere, and none of these patients were diagnosed with pCMS. When including them, the rate of pCMS was 26.7%. In addition, each mutism diagnosis was confirmed by medical records and follow-up, and the duration of mutism was well documented. Consequently, the diagnosis of pCMS in our study is reliable. Second, information regarding the surgical route was incomplete; therefore, it could not be analyzed further in this study. Third, although we have found that an iCIS of 2 on T2-weighted imaging was associated with mutism duration, the results were not tested on an internal or external validation set. In the future, prospective randomized controlled trials with interventions on avoiding cerebro-cerebellar circuit injuries are needed to validate our results.

Conclusions

For patients with midline posterior fossa tumors, male sex and abnormal cerebro-cerebellar circuits on T2-weighted images were found to be associated with pCMS. The cerebro-cerebellar CIS positively correlated with the duration of pCMS. Postoperative T2-weighted images have better predictive values for pCMS.

Acknowledgments

We thank Prof. Yaguang Peng for guiding us in statistical analysis. We also thank Prof. Yuanqi Ji for performing some of the surgeries before his retirement. Funding was provided by Beijing Hospital’s Authority Clinical Medicine Development of Special Funding Support (code: XMLX202144).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ge, Yang, Zhang, Y Peng. Acquisition of data: Ge, Yang, Zhang, Cai, Chen, Ying, Y Peng. Analysis and interpretation of data: Yang, Zhang, Cai, X Peng, Sun, Chen, Ying. Drafting the article: Ge, Yang, Zhang, X Peng, Sun. Critically revising the article: Ge, Yang, Zhang, Cai, Zhu. Reviewed submitted version of manuscript: Ge, Yang, Zhang, Cai, Ying, Zhu, Y Peng. Approved the final version of the manuscript on behalf of all authors: Ge. Statistical analysis: Yang, Cai, Ying, Zhu. Administrative/technical/material support: Ge, X Peng, Sun, Chen, Y Peng. Study supervision: Ge, Y Peng.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

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  • Collapse
  • Expand

Images from Chiang et al. (pp 595–601).

  • View in gallery
    FIG. 1.

    The vermis was divided into three parts: vermis 1, vermis 2, and vermis 3. The primary fissure and prepyramidal fissure serve as the boundary lines. Figure is available in color online only.

  • View in gallery
    FIG. 2.

    Typical postoperative MR images obtained in 2 patients. A–J: MR images obtained 5 days after tumor resection in a 7-year-old boy. Axial T1-weighted (A), T2-weighted (B), FLAIR (C), DW (D), and ADC map (E) images demonstrate surgical damage to the bilateral SCP (white arrows). The DW and ADC map images showing restricted diffusion, consistent with cytotoxic edema. This finding was interpreted as permanent damage to the bilateral SCPs. Axial T1-weighted (F), T2-weighted (G), FLAIR (H), DW (I), and ADC map (J) images. The T2-weighted (G) image shows a high signal in the bilateral MCPs and DNs (open arrows). DW and ADC map images showing slight restricted diffusion because of hemorrhage (high signal on the T1-weighted image). This finding was interpreted as postsurgical vasogenic edema in the bilateral MCPs and DNs. K–T: MR images obtained 5 days after tumor resection in a 2-year-old girl. Axial T1-weighted (K), T2-weighted (L), FLAIR (M), DW (N), and ADC map (O) images demonstrating no damage to the SCPs (white arrows). Axial T1-weighted (P), T2-weighted (Q), FLAIR (R), DW (S), and ADC map (T) images demonstrating no damage to the MCPs and DNs (open arrows).

  • View in gallery
    FIG. 3.

    The correlation between CIS or iCIS on T2-weighted (T2w) imaging and duration of mutism. A and B: Positive correlation between the left and right CISs on T2-weighted imaging and duration of mutism. C: Positive correlation between the iCIS on T2-weighted imaging and duration of mutism. The higher the CIS or iCIS on T2-weighted imaging, the greater the likelihood of a longer duration of mutism. Figure is available in color online only.

  • 1

    Gudrunardottir T, Morgan AT, Lux AL, et al. Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results. Childs Nerv Syst. 2016;32(7):11951203.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Catsman-Berrevoets CE. Cerebellar mutism syndrome: cause and rehabilitation. Curr Opin Neurol. 2017;30(2):133139.

  • 3

    Lanier JC, Abrams AN. Posterior fossa syndrome: review of the behavioral and emotional aspects in pediatric cancer patients. Cancer. 2017;123(4):551559.

  • 4

    Catsman-Berrevoets CE, Aarsen FK. The spectrum of neurobehavioural deficits in the posterior fossa syndrome in children after cerebellar tumour surgery. Cortex. 2010;46(7):933946.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Robertson PL, Muraszko KM, Holmes EJ, et al. Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group. J Neurosurg. 2006;105(6 suppl):444451.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Morris EB, Phillips NS, Laningham FH, et al. Proximal dentatothalamocortical tract involvement in posterior fossa syndrome. Brain. 2009;132(Pt 11):30873095.

  • 7

    Grønbæk J, Molinari E, Avula S, Wibroe M, Oettingen G, Juhler M. The supplementary motor area syndrome and the cerebellar mutism syndrome: a pathoanatomical relationship? Childs Nerv Syst. 2020;36(6):11971204.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Toescu SM, Hales PW, Aquilina K, Clark CA. Quantitative MRI in post-operative paediatric cerebellar mutism syndrome. Eur J Radiol. 2018;108:4351.

  • 9

    Renne B, Radic J, Agrawal D, et al. Cerebellar mutism after posterior fossa tumor resection in children: a multicenter international retrospective study to determine possible modifiable factors. Childs Nerv Syst. 2020;36(6):11591169.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Vedantam A, Stormes KM, Gadgil N, Kralik SF, Aldave G, Lam SK. Association between postoperative DTI metrics and neurological deficits after posterior fossa tumor resection in children. J Neurosurg Pediatr. 2019;24(4):364370.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Ojemann JG, Partridge SC, Poliakov AV, et al. Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome. Childs Nerv Syst. 2013;29(11):20712077.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Avula S, Kumar R, Pizer B, et al. Diffusion abnormalities on intraoperative magnetic resonance imaging as an early predictor for the risk of posterior fossa syndrome. Neuro Oncol. 2015;17(4):614622.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Cobourn K, Marayati F, Tsering D, et al. Cerebellar mutism syndrome: current approaches to minimize risk for CMS. Childs Nerv Syst. 2020;36(6):11711179.

  • 14

    Ghali MGZ. Telovelar surgical approach. Neurosurg Rev. 2021;44(1):6176.

  • 15

    Pettersson SD, Kitlinski M, Miękisiak G, Ali S, Krakowiak M, Szmuda T. Risk factors for postoperative cerebellar mutism syndrome in pediatric patients: a systematic review and meta-analysis. J Neurosurg Pediatr. 2021;29(4):467475.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Liu JF, Dineen RA, Avula S, et al. Development of a pre-operative scoring system for predicting risk of post-operative paediatric cerebellar mutism syndrome. Br J Neurosurg. 2018;32(1):1827.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Dhaenens BAE, Van Veelen MLC, Catsman-Berrevoets CE. Preoperative prediction of postoperative cerebellar mutism syndrome. Validation of existing MRI models and proposal of the new Rotterdam pCMS prediction model. Childs Nerv Syst. 2020;36(7):14711480.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Ashida R, Nazar N, Edwards R, Teo M. Cerebellar mutism syndrome: an overview of the pathophysiology in relation to the cerebrocerebellar anatomy, risk factors, potential treatments, and outcomes. World Neurosurg. 2021;153:6374.

    • Crossref
    • Search Google Scholar
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  • 19

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