Neuropsychiatric Symptoms in Rhombencephalosynapsis: A Clinical Report.

Rhombencephalosynapsis (RES) is a hindbrain malformation characterized by a missing cerebellar vermis with apposition or fusion of the cerebellar hemispheres. The present clinical case report provides a comprehensive, longitudinal overview of cognitive and affective manifestations in a 22-year-old patient with RES. The patient shows clinical signs of emotional reactivity and dysregulation, impulsivity, and impairments in executive functioning since early childhood. These features fit the constellation of neuropsychiatric symptoms observed in patients with congenital and acquired abnormalities of the posterior vermis. It is proposed that patients with RES may show affective and cognitive difficulties which increase their vulnerability to psychological stress and risk of developing mental health issues.

Non-motor role of the cerebellum: Cerebellar mutism syndrome in a child with a small hemorrhagic contusion in the dentate nucleus: A case report and literature review.

Key Clinical Message: Our case report highlights that Prompt recognition of cerebellar mutism syndrome (CMS) is critical in clinical practice, as it is often misdiagnosed as just being reduction in the level of consciousness, particularly in pediatrics trauma patients. Abstract: Cerebellar mutism syndrome is defined as transient mutism following posterior fossa surgery, hemorrhage or traumatic insults involving the cerebellum. Cerebellar mutism syndrome (CMS) is now recognized as a form of cerebellar cognitive affective syndrome (CCAS/Schmahmann syndrome). CMS following head injury is exceedingly rare with very few cases reported. Five years old boy with normal developmental milestones and no significant medical history, sustained closed head injury following road traffic accident, the clinical scenario in addition to the radiological findings led to the diagnosis of cerebellar mutism syndrome. CMS is defined as of neurologic and cognitive disorders, mainly speech disorder. Patient non-motor signs recovered in a period of few weeks from the mutism syndrome with remaining mild motor deficit. CMS is a set of neurologic and cognitive disorders, the most distinct of which is speech disorder (usually reversible), what is unique about this case is the selective site of the contusion at the region of the dentate nucleus and superior cerebellar peduncle. Such cases offer a better understanding to the function of the cerebellum and its role in cognition. Additionally, the knowledge of this aspect of cerebellar function helps in better predicting the clinical course of such lesions which in turn helps in communication and explanation to patient's families.

A Comparative Study on Cognitive Assessment in Cerebellar and Supratentorial Stroke.

This study aims to understand the cognitive profiles of cerebellar infarction patients and compare them to those with supratentorial infarctions, particularly frontal infarctions. This current study also aims to find reliable assessment tools for detecting cognitive impairment in cerebellar infarction patients. A total of fifty cerebellar infarction patients, sixty supratentorial infarction patients, and thirty-nine healthy controls were recruited. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Addenbrooke's Cognitive Examination III (ACE-III), and Cerebellar Cognitive Affective Syndrome scale (CCAS-s) were used to assess global cognitive function. An extensive neuropsychological assessment battery was also tested to evaluate the characteristics of each cognitive domain. To assess the features of cognitive function, a comprehensive neuropsychological evaluation tool was also utilized. The cerebral infarction patients demonstrated cognitive impairment comparable to those with frontal infarcts, notably characterized by disturbance in attention and executive function. However, the degree of cognitive impairment was comparatively milder in cerebellar infarction patients. Furthermore, the patients in the cerebellar group had worse scores in the ACE-III and CCAS-s compared to healthy controls. The two assessments also demonstrated a significant area under the curve values, indicating their effectiveness in distinguishing cognitive impairment in cerebellar infarctions. In conclusion, cognitive impairment in a cerebellar infarction resembles frontal lobe dysfunction but is generally mild. It can be accurately assessed using the ACE-III and CCAS-s scales.

Neuroanatomy of cerebellar mutism syndrome: the role of lesion location.

Approximately 25% of paediatric patients who undergo cerebellar tumour resection develop cerebellar mutism syndrome. Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with an increased risk of cerebellar mutism syndrome. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of cerebellar mutism syndrome in an observational study of 56 paediatric patients ranging from five months to 14 years of age who underwent cerebellar tumour resection. We hypothesized that individuals who developed cerebellar mutism syndrome after surgery, relative to those who did not, would have lesions that preferentially intersect with: (i) the cerebellar outflow pathway and (ii) a previously generated 'lesion-symptom map' of cerebellar mutism syndrome. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). We found supporting evidence for both hypotheses. Compared to patients who did not develop cerebellar mutism syndrome, patients with cerebellar mutism syndrome (n = 10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen's d = 0.73, P = 0.05), and the cerebellar mutism syndrome lesion-symptom map (Cohen's d = 1.1, P = 0.004). These results strengthen the association of lesion location with the risk of developing cerebellar mutism syndrome and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to paediatric cerebellar tumours.

Randomized double-blind placebo-controlled trial of the effects of oral trehalose in spinocerebellar ataxia type 3: An interim analysis.

INTRODUCTION: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease characterized by increasingly worsening ataxia and non-ataxia features, negatively impacting patients' quality of life. This study was designed to test formally evaluate whether oral trehalose was effective in SCA3 patients. METHODS: In this double-blind, randomized controlled trial, SCA3 patients received either 100 g oral trehalose or 30 g maltose to improve ataxia severity over six months. We also measured other clinical (non-ataxia), patient-reported (quality of life, motivations), and safety endpoints. An unscheduled interim analysis was conducted using two-way ANOVAs to analyze the interaction between time (baseline, 3-months, 6-months) and intervention (Trehalose vs. Placebo). RESULTS: Fifteen participants (Trehalose = 7 vs. Placebo = 8) completed the study at the time of interim analysis. There was no interaction effect on the ataxia severity, and available data suggested an estimated sample size of 132 (66 per arm) SCA3 patients required to demonstrate changes in a 6-month trial. There were significant interaction effects for executive function (ƞ2 = 0.28-0.43). Safety data indicated that 100 g oral trehalose was well-tolerated. CONCLUSION: We performed an unplanned interim analysis due to a slow recruitment rate. The new estimated sample size was deemed unfeasible, leading to premature termination of the clinical trial. In this small, current sample of SCA3 patients, 100 g oral trehalose did not differentially impact on ataxia severity compared to placebo. Interestingly, our findings may suggest an improvement in executive function. Future efforts will require a large multi-country, multi-center study to investigate the potential effect of trehalose.

Redefining cerebellar assessment: A comprehensive review of the cerebellum's cognitive and affective roles and the efficacy of CCAS scales.

Background: Emerging research expands our understanding of the cerebellum beyond motor control to include cognitive, emotional, and autonomic functions. This review examines the cerebellum's complex role, spotlighting Schmahmann's syndrome, or cerebellar cognitive affective syndrome (CCAS), which impairs executive functions, language, and spatial processing. It emphasizes advancements in diagnosing CCAS and the imperative of developing superior diagnostic tools for managing cerebellar pathologies effectively. Methods: A comprehensive literature search was performed using databases such as PubMed, OVID Embase, and OVID Medline. Using the keywords "cerebellar cognitive, affective syndrome" and "Schmahmann syndrome," the search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines for systemic review, in which the selection process narrowed down an initial set of 54 articles to 12, focusing on the impact of the CCAS scale on diagnosing and understanding Schmahmann's syndrome. Results: The review's analysis confirms the cerebellum's roles in motor and cognitive functions and underscores the CCAS scale as a significant advancement in detecting cerebellar deficits, surpassing traditional assessments such as the mini-mental state examination and Montreal cognitive assessment. Conclusion: This review emphasizes the importance of understanding the cerebellum's involvement in cognition and emotion and the crucial role of the CCAS scale for identifying cerebellar impairments. It calls for better diagnostic tools to assess CCAS accurately and suggests enhancing the CCAS Scale to reflect cultural and educational diversity. This will improve the diagnosis and treatment of cerebellar disorders, promoting a comprehensive neurological perspective on the cerebellum's functions.

Feasibility and Efficacy of a Virtual Reality Social Prediction Training in Children and Young Adults with Congenital Cerebellar Malformations.

This study tested the feasibility and efficacy of a Virtual Reality (VR) social prediction training (VR-Spirit) specifically designed for patients with congenital cerebellar malformation. The study is a randomised controlled trial in which 28 cerebellar patients aged 7-25 yo were randomly allocated to the VR-Spirit or to a control intervention in VR. The VR-Spirit required participants to compete with different avatars in scenarios that prompted them to form predictions about avatars' intentions. The control intervention consisted of games currently adopted for motor rehabilitation. Social prediction as well as secondary neuropsychological and behavioural outcomes were assessed at the beginning (T0), at the end (T2) and after 2 months (T3). The experimental group showed a significant increase, compared to the control participants, in social prediction assessed through a VR task. Moreover, at least at T3, the VR-Spirit enhanced the use of contextual predictions in a computer-based action prediction task. Importantly, these effects were generalized to secondary neuropsychological outcomes, specifically theory of mind and, only at T2, inhibition. No differences between the interventions were detected on emotional-behavioural problems. Lastly, both interventions showed high feasibility and acceptability. These findings confirm that it is possible to develop condition-specific rehabilitative training on the basis of neurocognitive functions impaired in case of congenital malformation. The VR-Spirit demonstrated to generalize its effects to theory of mind abilities, and it might be thus extended to other neurodevelopmental disorders that present social perception deficits and alterations of predictive processing.Trial registration: ISRCTN, ID: ISRCTN22332873. Retrospectively registered on 12 March 2018.

A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity. Here we studied the effect of long-term injections of SK channels activator chlorzoxazone (CHZ) together and separately with the folic acid (FA) on the cerebellar Purkinje cell (PC) firing and histology, and also on the motor and cognitive functions as well as mood alterations in SCA3-84Q hemizygous transgenic mice. We realized that both CHZ and CHZ-FA combination had similar positive effect on pure cerebellum impairments including PC firing precision, PC histology, and motor performance in SCA3-84Q mice. However, only the CHZ-FA combination, but not CHZ, had significantly ameliorated the signs of anxiety and depression, and also noticeably improved recognition memory in SCA3-84Q mice. Our results suggest that the combination therapy for both ataxia and non-motor symptoms is required for the complex treatment of ADCA.

Proceedings of the first global meeting of the Posterior Fossa Society: state of the art in cerebellar mutism syndrome.

PURPOSE: The Posterior Fossa Society, an international multidisciplinary group, hosted its first global meeting designed to share the current state of the evidence across the multidisciplinary elements of pediatric post-operative cerebellar mutism syndrome (pCMS). The agenda included keynote talks from world-leading speakers, compelling abstract presentations and engaging discussions led by members of the PFS special interest groups. METHODS: This paper is a synopsis of the first global meeting, a 3-day program held in Liverpool, England, UK, in September 2022. RESULTS: Topics included nosology, patient and family experience, cerebellar modulation of cognition, and cerebellar cognitive affective syndrome. In addition, updates from large-scale studies were shared as well as abstracts across neuroradiology, neurosurgery, diagnosis/scoring, ataxia, and rehabilitation. CONCLUSIONS: Based on data-driven evidence and discussions, each special interest group created research priorities to target before the second global meeting, in the spring of 2024.

Role of the Cerebellum in Bipolar Disorder: A Systematic Literature Review.

The aim of this systematic literature review was to investigate the role of the cerebellum in the affective symptoms observed in patients with bipolar disorder. The present systematic literature review included clinical studies conducted from 2013-2023 among adult populations with bipolar I and II disorders, along with their specifiers. With regard to cerebellar pathology, it was found that those with bipolar disorder performed worse than their healthy counterparts in their ability to comprehend the mental states of others and in identifying negative mental states. Additionally, individuals with bipolar disorder had reduced gray matter loss in regions such as lobules I-IX, crus I, and crus II, different functional activation patterns of the thalamus, striatum, and hippocampus on functional magnetic resonance imaging (fMRI), and increased cortical thickness. Cerebro-cerebellar functional connectivities were altered in patients with bipolar disorder. The effects of lamotrigine and lithium on cerebellar volume and abnormalities are also discussed in this paper. The present systematic literature review illustrates the emerging involvement of the cerebellum in bipolar disorder and its affective symptoms and paves the way for future research and a better understanding of bipolar disorder.

Reduced cerebral blood flow and cognitive dysfunction following isolated cerebellar infarction: two case reports.

Cognitive impairment in focal cerebellar disorders has been widely recognized and is described as cerebellar cognitive affective syndrome (CCAS). However, the relationship between CCAS and crossed cerebello-cerebral diaschisis (CCD) has rarely been discussed. The present report describes the uncommon phenomenon of CCD in two cases with isolated cerebellar infarction, and discuss its contribution to cognitive impairment. Cognitive performance was examined using the CCAS scale and a battery of neuropsychological assessments. Moreover, the relative distribution of cerebral and cerebellar blood flow was measured using three-dimensional arterial spin labeling imaging. Case 1 showed deficits in general cognition and had impaired language, episodic memory, and executive function. Case 2 showed deficits in general cognition at baseline, and cognitive deterioration of visuospatial abilities, language, episodic memory, and executive function was observed at the 3-month follow-up. Both cases met the diagnosis criteria of CCAS. Reduced cerebral blood flow was observed in the cerebral hemisphere contralateral to the cerebellar infarction at baseline in Case 1, and at the 3-month follow-up in Case 2. The present report describes cognitive decline after isolated cerebellar infarction in combination with contralateral cerebral hypoperfusion, as measured using quantitative arterial spin labeling. One possible mechanism involves the functional depression of cerebello-cerebral pathways.

Vestibular Testing and Impairments in Postoperative Pediatric Cerebellar Mutism Syndrome: A Case Series.

BACKGROUND: Postoperative pediatric cerebellar mutism syndrome (CMS) may occur following a process affecting the posterior cranial fossa. Recent evidence demonstrates disabling and potentially lasting motor components of this syndrome, including ataxia, hemiparesis, and oculomotor dysfunction. These impairments may contribute to vestibular deficits. METHODS: This case series contributes data to quantify vestibular dysfunction in postoperative CMS. The pair consisted of one female and one male. RESULTS: Vestibular testing demonstrated both peripheral and central dysfunction. CONCLUSIONS: Given these findings, a thorough vestibular assessment may be indicated as part of a comprehensive evaluation following a postoperative CMS diagnosis. Further research is needed to understand the pathophysiology, treatment, and long-term outcomes of postoperative pediatric CMS.

Cerebellar cognitive affective syndrome with long-term features of autism spectrum disorder: evidence in a 9-year-old girl after vermian medulloblastoma surgery.

The time course of socio-communicative disturbances in children after posterior fossa tumor resection is variable in clinical reports, and its assessment may help to understand the role of the cerebellum in the pathogenesis of socio-communicative disorders and improve rehabilitation plans. We report the 3-year cognitive-behavioral follow-up of a female patient (LZ) who underwent surgical ablation of the vermis due to medulloblastoma at age 9. LZ developed a severe post-operative Cerebellar Cognitive Affective Syndrome (CCAS) with cognitive-executive dysfunctions and behavioral alterations resembling an Autism Spectrum Disorder (ASD)-like syndrome. The lack of empathy and reduced ability to recognize others' intentions and mental states persisted at follow-up evaluations, as did language alterations. The present case report evidenced that lesions affecting cerebellar and vermal lobules may cause severe CCAS and impairment of social skills overlapping with that observed in ASD. This case is significant in its clinical features, revealing long-term social impairment, while the cognitive, linguistic, and executive functioning improved over time. Prospective case studies should plan the evaluation of symptoms of ASD within the clinical longitudinal assessment.

The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Cerebellar-Induced Aphasia After Stroke: Evidence for the "Linguistic Cerebellum".

The cerebellum is traditionally known to subserve motor functions. However, for several decades, the concept of the "cerebellar cognitive affective syndrome" has evolved. Studies in healthy participants and patients have confirmed the cerebellar role in language. The exact involvement of the cerebellum regarding cerebellar aphasia remains uncertain. We included 43 cerebellar stroke patients who were tested at 3 months post-onset with the Boston Naming Test (BNT), the Token Test (TT), and the Diagnostic Instrument for Mild Aphasia (DIMA). Lesion side (left/right) and volume (cm3) were investigated. Patients significantly deviated on the following: BNT (p<0.001), TT (p<0.05), DIMA subtests: sentences repetition (p=0.001), semantic odd-picture-out (p<0.05), sentence completion (p<0.05) without an effect of lesion location (left/right) or volume (cm3) (p>0.05). Our clinical study confirms a non-lateralized cerebellar aphasia post-stroke, characterized by impairments in word retrieval, phonology, semantics, and syntax resembling cerebral-induced aphasia. The integral cerebellum appears to interact with eloquent cortico-subcortical language areas.

Memory decline, anxiety and depression in the mouse model of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the ataxin-3 protein. SCA3 symptoms include progressive motor decline caused by an atrophy of the cerebellum and brainstem. However, it was recently reported that SCA3 patients also suffer from the cerebellar cognitive affective syndrome. The majority of SCA3 patients exhibit cognitive decline and approximately half of them suffer from depression and anxiety. The necessity to find a combined therapy for both motor and cognitive deficits in a SCA3 mouse model is required for the development of SCA3 treatment. Here, we demonstrated that the SCA3-84Q transgenic mice exhibited anxiety over the novel brightly illuminated environment in the open field, novelty suppressed feeding, and light-dark place preference tests. Moreover, SCA3-84Q mice also suffered from a decline in recognition memory during the novel object recognition test. SCA3-84Q mice also demonstrated floating behavior during the Morris water maze that can be interpreted as a sign of low mood and aversion to activity, i.e. depressive-like state. SCA3-84Q mice also spent more time immobile during the forced swimming and tail suspension tests which is also evidence for depressive-like behavior. Therefore, the SCA3-84Q mouse model may be used as a model system to test the possible treatments for both ataxia and non-motor symptoms including depression, anxiety, and memory loss.

Cerebellar Cognitive Affective Syndrome in Mexican Pediatric Patients with Ataxia-Telangiectasia.

Ataxia-telangiectasia (A-T) is a disease caused by mutations in the ATM gene (11q22.3-23.1) that induce neurodegeneration Sasihuseyinoglu AS et al.  Pediatr Allergy Immunol Pulmonol 31(1):9-14, 2018, Teive HAG et al. Parkinsonism Relat Disord 46:3-8, 2018. Clinically, A-T is characterized by ataxia, mucocutaneous telangiectasia, immunodeficiency, and malignancy. Movement disorders have been the most described and well-studied symptoms of A-T. Other studies have reported visuospatial processing disorders, executive function disorders and emotional regulation disorders, which are clinical manifestations that characterize cerebellar cognitive affective syndrome (CCAS) Choy KR et al. Dev Dyn 247(1):33-46, 2018. To describe the neurocognitive and emotional state of pediatric patients with ataxia-telangiectasia and to discuss whether they have cerebellar cognitive affective syndrome. This observational, cross-sectional, and descriptive study included 9 patients with A-T from May 2019 to May 2021. A complete medical history was retrieved, and tests were applied to assess executive functions, visual-motor integration and abilities, language, psychological disorders, and ataxia. Six girls and 3 boys agreed to participate. The age range was 6 to 14 years. The participants included five schoolchildren and four teenagers. Eight patients presented impaired executive functioning. All patients showed some type of error in copying and tracing (distortion) in the performance of visual perceptual abilities. Emotional disorders such as anxiety and depression were observed in six patients. Eight patients presented with dyslalia and impairments in word articulation, all patients presented with ataxia, and seven patients used a wheelchair. All patients presented symptoms consistent with CCAS and had variable cognitive performance.

Left Cerebellar Lesions may be Associated with an Increase in Spatial Neglect-like Symptoms.

Each cerebellar hemisphere projects to the contralateral cerebral hemisphere. Previous research suggests a lateralization of cognitive functions in the cerebellum that mirrors the cerebral cortex, with attention/visuospatial functions represented in the left cerebellar hemisphere, and language functions in the right cerebellar hemisphere. Although there is good evidence supporting the role of the right cerebellum with language functions, the evidence supporting the notion that attention and visuospatial functions are left lateralized is less clear. Given that spatial neglect is one of the most common disorders arising from right cortical damage, we reasoned that damage to the left cerebellum would result in increased spatial neglect-like symptoms, without necessarily leading to an official diagnosis of spatial neglect. To examine this disconnection hypothesis, we analyzed neglect screening data (line bisection, cancellation, figure copying) from 20 patients with isolated unilateral cerebellar stroke. Results indicated that left cerebellar patients (n = 9) missed significantly more targets on the left side of cancellation tasks compared to a normative sample. No significant effects were observed for right cerebellar patients (n = 11). A lesion overlap analysis indicated that Crus II (78% overlap), and lobules VII and IX (66% overlap) were the regions most commonly damaged in left cerebellar patients. Our results are consistent with the notion that the left cerebellum may be important for attention and visuospatial functions. Given the poor prognosis typically associated with neglect, we suggest that screening for neglect symptoms, and visuospatial deficits more generally, may be important for tailoring rehabilitative efforts to help maximize recovery in cerebellar patients.