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Diagram showing the dentato-thalamo-cortical pathway (blue) and the Guillain and Mollaret triangle (red). DN, dentate nucleus; RN, red nucleus; ION, inferior olivary nucleus; SCP, superior cerebellar peduncle; CTT, central tegmental tract; ICP, inferior cerebellar pathway.
Source publication
Background:
The dentato-thalamo-cortical (DTC) pathway is recognized as the anatomical substrate for postoperative pediatric cerebellar mutism (POPCMS), a well-recognized complication affecting up to 31% of children undergoing posterior fossa brain tumour resection. The proximal structures of the DTC pathway also form a segment of the Guillain and...
Contexts in source publication
Context 1
... is growing consensus on the anatomical substrates involved in the causation of POPCMS and interruption of the dentato-thalamo-cortical (DTC) pathway has been attributed to its aetiology ( Figure 1) (5-7). The proximal efferent cerebellar pathway (pECP), which forms the proximal segment of the DTC, has been attributed as the region of primary post surgical insult (8)(9)(10)(11)(12)(13)(14). ...
Context 2
... red nucleus is connected to the ipsilateral ION by the central tegmental tract and receives afferents from the contralateral DN through the SCP. The triangle is completed by efferent fibers connecting the ION to the contralateral DN through the inferior cerebellar peduncle (Figure 1). Disruption of the triangle results in hypertrophic degeneration of the ION, which is thought to represent retrograde trans-synaptic degeneration of the ION. ...
Context 3
... of these patients showed HOD on radiological assessment (9 bilateral and 4 unilateral). Binary classification using the entire feature set showed that Feature 1, the mean gradient of contrast in the left ION obtained the highest score for all feature selection techniques ( Table 3) (18,19). Feature 4, the variance in the area of the left ION also showed a high score in relation to development of PPCMS (18). ...
Citations
... Collaborative articles between Gajjar, A. and Mabbott, D.J. in subsequent years focused on neurobehavioral outcomes and cognitive impairments associated with ppCMS, emphasizing the clinical aspect [12,[45][46][47]. Kumar, R. and Pizer, B. through seven co-published papers, delved into the mechanisms and pathophysiology of ppCMS, elucidating aspects such as the bilateral involvement of the proximal efferent cerebellar pathway and perfusion de cits [13,38,43,[48][49][50][51]. The review conducted in 2020 by Kumar, R. et al [52] underscored the importance of comprehensive rehabilitation plans for ppCMS. ...
... Moreover, the proximal efferent cerebellar pathway is also a part of the dentato-rubro-olivary pathway (Guillain-Mollaret triangle), which is comprised of the contralateral dentate nucleus, the red nucleus, and the ipsilateral inferior olivary nucleus (ION) [13]. Disruption to any part of this triangle, especially the dentate nucleus, may cause hypertrophic olivary degeneration (HOD). ...
... Disruption to any part of this triangle, especially the dentate nucleus, may cause hypertrophic olivary degeneration (HOD). Two research found that the presence of bilateral HOD was signi cantly associated with ppCMS occurrence [13,60], while the association between unilateral HOD and ppCMS appearance is not always signi cant [13]. For example, a paper published in 2021 did not nd such a correlation between HOD and ppCMS [61]. ...
Background
Post-operative pediatric cerebellar mutism syndrome (ppCMS) is a common neurological complication characterized by delayed onset mutism, emotional lability, hypotonia, and oropharyngeal dysfunction following resection of a posterior fossa tumor in children. The objective of this study is to visually depict the knowledge structure and pinpoint research hotspots within the field using bibliometric analysis.
Method
Publications related to ppCMS from 1999 to 2022 were searched on the Web of Science Core Collection (WoSCC) database. VOSviewer, R package, “bibliometrix”, and CiteSpace were used to draw and analyze corresponding visualization maps.
Results
410 articles from 52 countries led by the United States of America (USA) and England were included. The number of published papers is on the rise in general. Hospital for Sick Children (Canada), St. Jude Children’s Research Hospital (USA), University Toronto (Canada), Texas Children’s Hospital (USA), and Children’s National Hospital (USA) are the main research institutions. Child’s Nervous System is the most popular and the most co-cited journal in this domain. These publications come from 2091 authors. Gajjar, A. has published the most papers, and the papers authored by Schmahmann, J.D. have been co-cited the most. The mechanisms, risk factors, and clinical manifestations of ppCMS occurrence and development are the main topics in this field. The most commonly used keywords are medulloblastoma, posterior fossa syndrome, cerebellar mutism, cerebellum, and children.
Conclusion
This is the first bibliometric analysis to comprehensively overview the active research areas and development of ppCMS, which will provide a reference for scholars studying this field.
... The entire segmentation process was repeated three times for each set of imaging. These same authors utilized the aforementioned "seed growing" technique to demonstrate a significant association between bilateral hypertrophic olivary degeneration and pediatric cerebellar mutism following posterior fossa tumor resection in another study [37]. A neuroradiologist validated and edited the results of segmentation ( Table 2). ...
Background
Segmentation tools continue to advance, evolving from manual contouring to deep learning. Researchers have utilized segmentation to study a myriad of posterior fossa-related conditions, such as Chiari malformation, trigeminal neuralgia, post-operative pediatric cerebellar mutism syndrome, and Crouzon syndrome. Herein, we present a summary of the current literature on segmentation of the posterior fossa. The review highlights the various segmentation techniques, and their respective strengths and weaknesses, employed along with objectives and outcomes of the various studies reported in the literature.
Methods
A literature search was conducted in PubMed, Embase, Cochrane, and Web of Science up to November 2023 for articles on segmentation techniques of posterior fossa. The two senior authors searched through databases based on the keywords of the article separately and then enrolled joint articles that met the inclusion and exclusion criteria.
Results
The initial search identified 2205 articles. After applying inclusion and exclusion criteria, 77 articles were selected for full-text review after screening of titles/abstracts. 52 articles were ultimately included in the review. Segmentation techniques included manual, semi-automated, and fully automated (atlas-based, convolutional neural networks). The most common pathology investigated was Chiari malformation.
Conclusions
Various forms of segmentation techniques have been used to assess posterior fossa volumes/pathologies and each has its advantages and disadvantages. We discuss these nuances and summarize the current state of literature in the context of posterior fossa-associated pathologies.
... Whether the mere fact of midbrain dysfunction leads to maladaptive changes in intact areas of the cerebellum remains to be explored, but it is tempting to consider similarities between cerebellar activation during verb generation 25 and the map of cortico-dentato abnormalities found here, and to hypothesize that synaptic efficacy has been meaningfully shifted in the cerebellar modules responsible for speech-related planning. It is also interesting that inferior olivary hypertrophy has a well-established association with CMS, 33,34 given that the inferior olive is considered the last common source in the pathway that provides teaching signals to the cerebellar cortex. Specific pathogenic mechanisms for this trans-synaptic injury remain obscure, but we would predict hyper-activation of inferior olivary neurons in the current framing, which could possibly contribute. ...
Background
Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology.
Methods
We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury.
Results
CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere.
Conclusions
The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal gray and other critical midbrain targets.
... Abnormalities in this network have been linked to a variety of neurological conditions, including ataxia, dystonia, and dysarthria [3]. Hypertrophic olivary degeneration (HOD) is a degenerative condition that affects the ION in the brainstem, which is involved in motor coordination and learning that occurs as a result of damage to the DROP [5][6][7][8]. Understanding the role of GMT is important because damage to this area can lead to HOD [4]. A better understanding of this triangle could lead to improved treatment options for movement disorders. ...
... The authors also noted that the clinical symptoms varied depending on the underlying cause of HOD [5,6]. Avula et al. [7] conducted a retrospective study focusing on 15 children diagnosed with PMCMS. The results of their analysis indicated that the primary cause of PMCMS in their study population was predominantly attributed to brain tumors (60%) [58], followed by vascular malformations (20%) and infections (20%) [7]. ...
... Avula et al. [7] conducted a retrospective study focusing on 15 children diagnosed with PMCMS. The results of their analysis indicated that the primary cause of PMCMS in their study population was predominantly attributed to brain tumors (60%) [58], followed by vascular malformations (20%) and infections (20%) [7]. Moreover, the researchers postulated that PMCMS may arise from ION, and/or GMT lesions. ...
The dentato-rubro-olivary pathway, also known as the Guillain-Mollaret triangle (GMT) or myoclonic triangle, consists of the dentate nucleus, the red nucleus, and the inferior olivary nucleus (ION). GMT is important for motor coordination and control, and abnormalities in this network can lead to various neurological disorders. The present study followed a systematic approach in conducting a review on GMT studies. The inclusion criteria were limited to human subjects with primary objectives of characterizing and evaluating GMT syndromes, and the methodology used was not a determining factor for eligibility. The search strategy used MeSH terms and keywords relevant to the study's objective in various databases until August 2022. A total of 76 studies were included in the review after assessing 527 articles for eligibility based on the final inclusion criteria. Most of the studies evaluated the GMT in human subjects, with the majority utilizing magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), or combination of them. The review found that Hypertrophic olivary degeneration (HOD), a common consequence of GMT damage, has diverse underlying causes, including stroke, brainstem cavernous malformations, and structural impairments. Palatal tremor, ocular myoclonus, ataxia, nystagmus, and vertigo were frequently reported symptoms associated with HOD. This systematic review provides comprehensive insights into the association between GMT and various neurological syndromes, shedding light on the diagnostic, etiological, and prognostic aspects of GMT dysfunction. Understanding the role of the GMT and its implications in movement disorders could pave the way for improved treatment options and better management of neurological conditions related to this critical brainstem pathway.
... The midline location has anatomical structures considered relevant for CM, such as the vermis, fastigial nuclei, and parts of the DTC pathway. [17][18][19][20] The DTC pathway also passes through the brainstem and, as such, is at risk of damage caused by brainstem infiltration and resection. ...
Objective:
Cerebellar mutism syndrome (CMS) is a well-known complication following posterior fossa tumor surgery in pediatric patients. We evaluated the incidence of CMS in our institute and analyzed association with multiple risk factors, such as tumor entity, surgical approach, and hydrocephalus.
Methods:
All pediatric patients who received an intra-axial tumor resection in the posterior fossa between January 2010 and March 2021 were included for retrospective analysis. Various data points, including demographic, tumor-associated, clinical, radiological, surgery associated, complications and follow-up data were collected and statistically evaluated for association with CMS.
Results:
63 surgeries in 60 patients were included with a median age of 8 years. Pilocytic astrocytoma was mostly represented by 50%, followed by medulloblastoma in 28%, and ependymomas in 10%. Complete resection was achieved in 67% versus subtotal in 23%, and partial resection in 10%. Telovelar approach was the most used in 43 % compared to transvermian in 8%. 10 children (17%) developed CMS and showed marked improvement but with residual deficits. Significant risk factors were transvermian approach (p=0.03), vermian splitting whenever added to other approach (p=0.002), initial presentation with acute hydrocephalus (p=0.02), and remaining hydrocephalus after tumor surgery (p=0.004).
Conclusion:
Our CMS rate compares to those described in literature. Despite the limitations of our study as a retrospective one, we found CMS was not only associated with a transvermian approach, but also occurs after using a telovelar approach, however to a lesser extent. Acute hydrocephalus at initial presentation necessitating urgent management was significantly associated with higher incidence of CMS.
... Less frequently, cerebellar speech disorders or ataxia has been reported (17). Specifically in children, there is also a correlation with the posterior fossa syndrome, manifesting as cerebellar mutism subsequent to the resection of a cerebellar tumor (7,18). Yet, HOD can also appear without clinical symptoms (19), and the exact underlying mechanisms remain unclear. ...
... In previous studies, the diagnosis of HOD is usually based on T2 and/or fluid-attenuated inversion recovery (FLAIR) hyperintensity of the ION identified by one or more radiologists (5,(23)(24)(25). While HOD can easily be identified if a distinct hypertrophy is present, the mere T2 hyperintensity can be diffuse and subtle (2, 18,26). Furthermore, most studies were retrospective studies and were not optimized for imaging of the brain stem, and the readers were not blinded to the patients' symptoms or causative lesions. ...
... Although there are reports of HOD without visible causative lesions on MRI (36), the correlation of HOD development with preceding lesions in the GMT is undoubtedly proven, and for a circumscribed lesion within the GMT, the side of HOD occurrence is well-predictable (2, 10). While the actual etiology of the underlying index lesion seems to be non-relevant (18,26,37,38), our study focused on stroke patients, because this allowed for both a precise localization of the index lesion on MRI and a precise determination of the index lesion onset. Nevertheless, it is yet unknown how frequently a lesion within the GMT causes a HOD and to what extent the anatomical structures in the GMT must be affected. ...
Purpose
Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking a diagnostic gold standard, diagnosis is usually based on T2 or FLAIR imaging and expert rating. To facilitate precise HOD diagnosis in future studies, we assessed the reliability of this rater-based approach and explored alternative, quantitative analysis.
Methods
Patients who had suffered strokes in the GMT and a matched control group prospectively underwent an MRI examination including T2, FLAIR, and proton density (PD). Diffusion tensor imaging (DTI) was additionally performed in the patient group. The presence of HOD was assessed on FLAIR, T2, and PD separately by 3 blinded reviewers. Employing an easily reproducible segmentation approach, relative differences in intensity, fractional anisotropy (FA), and mean diffusivity (MD) between both IONs were calculated.
Results
In total, 15 patients were included in this study. The interrater reliability was best for FLAIR, followed by T2 and PD (Fleiss κ = 0.87 / 0.77 / 0.65). The 3 raters diagnosed HOD in 38–46% (FLAIR), 40–47% (T2), and 53–67% (PD) of patients. False-positive findings in the control group were less frequent in T2 than in PD and FLAIR (2.2% / 8.9% / 6.7%). In 53% of patients, the intensity difference between both IONs on PD was significantly increased in comparison with the control group. These patients also showed significantly decreased FA and increased MD.
Conclusion
While the rater-based approach yielded the best performance on T2 imaging, a quantitative, more sensitive HOD diagnosis based on ION intensities in PD and DTI imaging seems possible.
... However, despite its potential advantages, advanced neuroimaging can also introduce further bias and difficulties in comparing results across studies [20]. At least two similar studies conclude that bilateral HOD could serve as an indicator of CMS [3,23]. However, the authors also encountered limitations with regard to imaging protocols and data on laterality in a retrospective study design [23]. ...
... However, the authors also encountered limitations with regard to imaging protocols and data on laterality in a retrospective study design [23]. Laterality is an important aspect, as a predilection of damage to the right efferent cerebellar pathways and HOD in the left ION have been implicated in CMS, correlating with left cerebral hemisphere dominance for language in most humans [3]. The incidence of right hemisphere language dominance is 30% in left-handed humans, highlighting the importance of laterality and left/right handedness in future studies on the pathophysiology of CMS [17]. ...
Cerebellar mutism syndrome (CMS) occurs in one out of four children after posterior fossa tumor surgery, with open questions regarding risk factors, pathophysiology, and prevention strategies. Because of similarities between several cerebellar syndromes, a common pathophysiology with damage to the dentato-thalamo-cortical and dentato-rubro-olivary pathways has been proposed. Hypertrophic olivary degeneration (HOD) is an imaging correlate of cerebellar injury observed for instance in stroke patients. Aim of this study was to investigate whether the occurrence and severity of CMS correlates with the extent of damage to the relevant anatomical structures and whether HOD is a time-dependent postoperative neuroimaging correlate of CMS. We performed a retrospective single center study of CMS patients compared with matched non-CMS controls. CMS occurred in 10 children (13% of the overall cohort) with a median age of 8 years. Dentate nucleus (DN) injury significantly correlated with CMS, and superior cerebellar peduncle (SCP) injury was associated by tendency. HOD was observed as a dynamic neuroimaging phenomenon in the postoperative course and its presence significantly correlated with CMS and DN injury. Children who later developed HOD had an earlier onset and tended to have longer persistence of CMS. These findings can guide surgical measures to protect the DN and SCP during posterior fossa tumor resections and to avoid a high damage burden (i.e., bilateral damage). Development of intraoperative neuromonitoring of the cerebellar efferent pathways as well as improved preoperative risk stratification could help to establish a patient-specific strategy with optimal balance between degree of resection and functional integrity.
... It remains to be examined how disruption of this circuit could affect the function of ancillary structures and circuits, including the dentato-rubro-olivary circuitry that shows clear signs of dysfunction and degeneration in this and other studies. 33,34 The overlapping structure and complimentary function of these circuits undoubtedly make their individual contribution to CMS difficult to discern. ...
Background
Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS.
Methods
Children with Mb deemed high-risk for CMS based on intraventricular location of the tumor had T1 images analyzed for location(s) of surgical damage using a specially developed algorithm. We used three complementary methods of spatial analysis to identify surgical damage linked to CMS diagnosis. Magnetization transfer ratio (MTR) images were analyzed for evidence of demyelination in anatomic regions downstream of the cerebellum, indicating neuronal dysfunction.
Results
Spatial analyses highlighted damage to the fastigial nuclei and their associated cerebellar cortices as the strongest predictors of CMS. CMS-related MTR decrease was greatest in the ventral periaqueductal grey area (PAG) and highly consistent in the left red nucleus.
Conclusion
Our evidence points to disruption of output from the fastigial nuclei as a likely causal trigger for CMS. We propose that core CMS symptoms result from a disruption in the triggering of survival behaviors regulated by the PAG, including the gating of vocalization and volitional movement. The fastigial nuclei provide the densest output to the PAG from the cerebellum, thus sparing these structures may provide a greater likelihood of CMS prevention.
... This would be an example of diaschisis, a phenomenon whereby disruption in a linguistic/cognitive infratentorial area may affect the normal functioning of a linguistic/cognitive supratentorial area, and vice versa [35]. Other authors also reported this lateralization of functions in the cerebellum, identifying the right side as the one involved in language tasks for right-handed people [27,36,37]. ...
... As for the right MCP, its significant association with the onset of PFS seen in our sample of patients may be explained by the presence of the ascending fibers of the cortico-ponto-cerebellar tract on it, which may play a part in language function as well [22,24]. Our findings are partially consistent with the current literature, in which bilateral involvement of the SCP seems to have the main role, although a predominantly right lateralization of cerebellar language and associated right-sided findings have already been suggested [37]. The vermis is involved in the language pathways too, and its postero-inferior part seems to be implicated in the affective-behavioral sphere [28]. ...
Introduction
Posterior fossa syndrome (PFS) is a set of debilitating complications that can occur after surgery for posterior fossa tumors. This study aimed to assess the preoperative radiological and surgical risk factors for the onset of PFS in a histologically homogeneous population of children with medulloblastoma and compare it to a similar population of young adults.
Methods
Included patients underwent posterior fossa surgery for medulloblastoma at 11 Italian neurosurgical wards (2003–2019) and were referred to Fondazione IRCCS Istituto Nazionale dei Tumori in Milan (INT) for postoperative treatments. We collected patients’ pre- and post-operative clinical, surgical and radiological data from the INT charts. To compare the distribution of variables, we used the Mann–Whitney and Fisher tests for continuous and categorical variables, respectively.
Results
136 patients (109 children and 27 young adults) were included in the study. Among children, 29 (27%) developed PFS, and all of them had tumors at midline site with invasion of the fourth ventricle. Radiological evidence of involvement of the right superior (39% versus 12%; p = 0.011) or middle cerebellar peduncles (52% versus 18%; p = 0.002) seemed more common in children who developed PFS. Young adults showed an expected lower incidence of PFS (4 out of 27; 15%), that may be due to anatomical, physiological and oncological elements.
Conclusions
This study confirmed some factors known to be associated with PFS onset and shed light on other debated issues. Our findings enhance an already hypothesized role of cerebellar language lateralization. The analysis of a population of young adults may shed more light on the often-neglected existence of PFS in non-pediatric patients.
... Other areas of the cerebellar outflow pathway such as the fastigial nucleus and inferior vermis may also be involved (Albazron et al., 2019). At present, the role of the middle (MCP) and inferior cerebellar peduncles (ICP) in CMS is less clear, although there is some evidence of delayed structural changes in the inferior olivary nucleus following CMS (Avula et al., 2016). ...
Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome.
In this retrospective study, twenty-eight children with medulloblastoma (mean age 8.8 ± 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy (FA) at 30 nodes along each tract.
Thirteen patients developed cerebellar mutism syndrome. FA was significantly lower in the distal third of the left superior cerebellar peduncle pre-operatively in all patients compared to controls (FA in proximal third 0.228, middle and distal thirds 0.270, p=0.01, Cohen’s d=0.927). Pre-operative differences in FA did not predict cerebellar mutism syndrome. However, post-operative reductions in FA were highly specific to the distal left superior cerebellar peduncle, and were most pronounced in children with cerebellar mutism syndrome compared to those without at the 1-4 month follow up (0.325 vs 0.512, p=0.042, d=1.36) and at the 1-year follow up (0.342, vs 0.484, p=0.038, d=1.12).
High spatial resolution cerebellar profilometry indicated a site-specific alteration of the distal segment of the superior cerebellar peduncle seen in cerebellar mutism syndrome which may have important surgical implications in the treatment of these devastating tumours of childhood.
