Defects in diffusion barrier function of ciliary transition zone caused by ciliopathy variations of TMEM218.

Primary cilia are antenna-like structures protruding from the surface of various eukaryotic cells, and have distinct protein compositions in their membranes. This distinct protein composition is maintained by the presence of the transition zone (TZ) at the ciliary base, which acts as a diffusion barrier between the ciliary and plasma membranes. Defects in cilia and the TZ are known to cause a group of disorders collectively called the ciliopathies, which demonstrate a broad spectrum of clinical features, such as perinatally lethal Meckel syndrome (MKS), relatively mild Joubert syndrome (JBTS), and nonsyndromic nephronophthisis (NPHP). Proteins constituting the TZ can be grouped into the MKS and NPHP modules. The MKS module is composed of several transmembrane proteins and three soluble proteins. TMEM218 was recently reported to be mutated in individuals diagnosed as MKS and JBTS. However, little is known about how TMEM218 mutations found in MKS and JBTS affect the functions of cilia. In this study, we found that ciliary membrane proteins were not localized to cilia in TMEM218-knockout cells, indicating impaired barrier function of the TZ. Furthermore, the exogenous expression of JBTS-associated TMEM218 variants but not MKS-associated variants in TMEM218-knockout cells restored the localization of ciliary membrane proteins. In particular, when expressed in TMEM218-knockout cells, the TMEM218(R115H) variant found in JBTS was able to restore the barrier function of cells, whereas the MKS variant TMEM218(R115C) could not. Thus, the severity of symptoms of MKS and JBTS individuals appears to correlate with the degree of their ciliary defects at the cellular level.

Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7.

Biallelic TOE1 variants can cause pontocerebellar hypoplasia type 7 (PCH7), a condition characterized by pontocerebellar hypoplasia with genital abnormality. TOE1 is a 3'-exonuclese for 3'-end maturation in small nuclear RNA. TOE1 pathogenic variants have been reported at the DEDD catalytic domain and zinc finger motif. Here, we describe a PCH7 patient with novel compound heterozygous TOE1 variants and a detailed clinical course. The patient was a 3-year-old female and showed developmental delay without cerebellar ataxic behavior. Head MRI revealed delayed myelination without pontocerebellar hypoplasia at 9 months of age. Progressive pontocerebellar atrophy was prominent at follow-up MRI. Cerebral abnormalities are characteristic features of PCH7 before pontocerebellar atrophy is observed. One variant, p.Arg331*, was located at the nuclear localization motif (NLM) and partially escaped from nonsense-mediated decay. This variant affected nuclear localization in mutant expressing cells, thus, the TOE1 variant at NLM leads to TOE1 dysfunction associated with nuclear mis-localization.

Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT): A Preventable Cerebellar Disorder.

We report a case study of a 60-year-old man with bipolar disorder on stable lithium treatment who developed severe toxicity while admitted to ICU with sepsis and multiorgan failure. Despite unchanged lithium administration, his serum levels escalated due to renal dysfunction, resulting in lithium toxicity. After regaining consciousness, he exhibited a cerebellar syndrome marked by ataxia, tremor, and scanning speech. MRI revealed cerebellar atrophy. Following discontinuation of lithium and hemodialysis, the patient's symptoms remained static. The patient was diagnosed with syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), a chronic cerebellar disorder characterized by persistent ataxia, nystagmus, and gait abnormalities extending beyond two months post-lithium exposure. The disorder has a predilection for cerebellar and basal ganglia dysfunction. MRI findings include cerebellar gliosis and atrophy and leptomeningeal enhancement. This case report highlights that SILENT is both preventable and permanent, urging heightened awareness among clinicians to facilitate early detection and intervention. Patients on lithium with compromised renal function or fever necessitate vigilant lithium level monitoring, dose adjustment, or cessation, to forestall enduring morbidity. This case emphasizes the significance of recognizing and managing SILENT, particularly in critical care settings, to mitigate long-term cerebellar impairment and optimize patient outcomes.

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.

Prevalence, recovery and phenotype of dysphagia in patients with ischaemic cerebellar stroke.

BACKGROUND AND PURPOSE: Swallowing is a complex task, moderated by a sophisticated bilateral network including multiple supratentorial regions, the brainstem and the cerebellum. To date, conflicting data exist about whether focal lesions to the cerebellum are associated with dysphagia. Therefore, the aim of the study was to evaluate dysphagia prevalence, recovery and dysphagia pattern in patients with ischaemic cerebellar stroke. METHODS: A retrospective analysis of patients consecutively admitted to an academic stroke centre with ischaemic stroke found only in the cerebellum was performed. The presence of dysphagia was the primary end-point and was assessed by a speech-language pathologist, according to defined criteria. Dysphagia pattern was evaluated by analysing the videos of the flexible endoscopic evaluation of swallowing. Brain imaging was used to identify lesion size and location associated with dysphagia. RESULTS: Between January 2016 and December 2021, 102 patients (35.3% female) with a mean age of 52.8 ± 17.3 years were included. Thirteen (12.7%) patients presented with dysphagia. The most frequently observed flexible endoscopic evaluation of swallowing phenotype was premature spillage (n = 7; 58.3%), whilst significant residues or aspiration did not occur. One patient died (7.7%); the other patients showed improvement of dysphagia and one patient (7.7%) was discharged with dietary restrictions. CONCLUSIONS: Although the involvement of the cerebellum in deglutition has become increasingly evident, isolated lesions to the cerebellum are less likely to cause clinically relevant and persisting dysphagia compared to other brain regions. The observed dysphagia pattern shows a lack of coordination and control, resulting in premature spillage or fragmented bolus transfer in some patients.

High blood glucose variability may predict poor outcomes in patients with spontaneous cerebellar hemorrhage undergoing surgical operation: a retrospective study.

BACKGROUND: Elevated blood glucose (BG) variability has been reported as an independent risk factor for poor prognosis in a variety of diseases. This study aimed to investigate the association between BG variability and clinical outcomes in patients with spontaneous cerebellar hemorrhage (SCH) undergoing surgical operation. METHODS: This retrospective cohort study of the consecutive patients admitted to the department of Neurosurgery, the Affiliated Hospital of Qingdao University between January 2014 and June 2022 with the diagnosis of SCH underwent surgical intervention. BG analysis was continuously and routinely performed. BG variability was represented by the standard deviation (SD) of the serial measurements within the first 7 days. The general characteristics, imageological information, blood glucose level, and surgical information were reviewed and compared through medical records. RESULTS: A total of 115 patients (65 male and 50 female) were enrolled. Out of all 115 patients, the overall clinical outcomes according to the modified Rankin Scale (mRS) were poor (mRS 3-6) in 31 patients (26.96%) and good (mRS 0-2) in 84 patients (73.04%). Twelve of the 115 patients died during hospitalization, and the mortality rate was 10.43%. Multivariate logistic regression analysis showed that SD of BG (odds ratio (OR), 4.717; 95% confidence interval (CI), 1.054-21.115; P = 0.043), GCS (OR, 0.563; 95% CI, 0.330-0.958; P = 0.034), and hematoma volume (OR, 1.395; 95% CI, 1.118-1.748; P = 0.003) were significant predictors. The area under the ROC curve of SD of BG was 0.911 (95% CI, 0.850-0.973; P < 0.001) with a sensitivity and specificity of 90.3% and 83.3%, respectively, and the cut-off value was 1.736. CONCLUSIONS: High BG Variability is independently correlated with the 6-month poor outcomes in patients with SCH undergoing surgical operation.

Bimanual coordinated motor skill learning in patients with a chronic cerebellar stroke.

Cerebellar strokes induce coordination disorders that can affect activities of daily living. Evidence-based neurorehabilitation programs are founded on motor learning principles. The cerebellum is a key neural structure in motor learning. It is unknown whether and how well chronic cerebellar stroke individuals (CCSIs) can learn to coordinate their upper limbs through bimanual motor skill learning. The aim was to determine whether CCSIs could achieve bimanual skill learning through a serious game with the REAplan® robot and to compare CCSIs with healthy individuals (HIs). Over three consecutive days, sixteen CCSIs and eighteen HIs were trained on an asymmetric bimanual coordination task ("CIRCUIT" game) with the REAplan® robot, allowing quantification of speed, accuracy and coordination. The primary outcomes were the bimanual speed/accuracy trade-off (BiSAT) and bimanual coordination factor (BiCo). They were also evaluated on a bimanual REACHING task on Days 1 and 3. Correlation analyses between the robotic outcomes and clinical scale scores were computed. Throughout the sessions, BiSAT and BiCo improved during the CIRCUIT task in both HIs and CCSIs. On Day 3, HIs and CCSIs showed generalization of BiSAT, BiCo and transferred to the REACHING task. There was no significant between-group difference in progression. Four CCSIs and two HIs were categorized as "poor learners" according to BiSAT and/or BiCo. Increasing age correlated with reduced BiSAT but not BiCo progression. Over three days of training, HIs and CCSIs improved, retained, generalized and transferred a coordinated bimanual skill. There was no between-group difference, suggesting plastic compensation in CCSIs. Clinical trial NCT04642599 approved the 24th of November 2020.

Hydrocephalus associated with a molar tooth sign: A distinct subtype of Joubert syndrome.

Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or potentially signifies a new phenotypic subtype. The databases of Wolfson Medical Center, Sourasky Medical Center, and EB's personal collection were reviewed. Records from an additional family were obtained from RG. The patients' medical records, prenatal ultrasounds, and magnetic resonance imaging were assessed. In addition, we reviewed the medical literature for the association of ventriculomegaly/hydrocephalus (VM/HC) in JBTS. Only seven cases (from five families) were found with prenatal onset of VM/HC, diagnosed during the second trimester; three pregnancies were terminated, one was stillborn and three were born, of which one died within a week, and another died at the age of 6 years. Additional central nervous system findings included dysgenesis of the corpus callosum, delayed sulcation, polymicrogyria, and pachygyria. We found 16 publications describing 54 patients with JBTS and VM/HC: only five were diagnosed at birth and three were diagnosed prenatally. Hydrocephalus is extremely rare in JBTS. The recurrence of this association, reported in several publications in multiple family members, suggests that it might represent a new phenotypic subtype of JBTS possibly associated with specific genes or variants. Further genetic studies are needed to confirm this hypothesis. WHAT THIS PAPER ADDS: The association of fetal hydrocephalus with Joubert-Boltshauser syndrome (JBTS) is very rare but not a chance association. This association represents a new phenotypic subtype of JBTS possibly linked to specific genes or variants.

Prenatal diagnosis of pontocerebellar hypoplasia with postnatal follow-up.

OBJECTIVE: To describe the MR features enabling prenatal diagnosis of pontocerebellar hypoplasia (PCH). METHOD: This was a retrospective single monocentre study. The inclusion criteria were decreased cerebellar biometry on dedicated neurosonography and available fetal Magnetic Resonance Imaging (MRI) with PCH diagnosis later confirmed either genetically or clinically on post-natal MRI or by autopsy. The exclusion criteria were non-available MRI and sonographic features suggestive of a known genetic or other pathologic diagnosis. The collected data were biometric or morphological imaging parameters, clinical outcome, termination of pregnancy (TOP), pathological findings and genetic analysis (karyotyping, chromosomal microarray, DNA sequencing targeted or exome). PCH was classified as classic, non-classic, chromosomal, or unknown type. RESULTS: Forty-two fetuses were diagnosed with PCH, of which 27 were referred for decreased transverse cerebellar diameter at screening ultrasound. Neurosonography and fetal MRI were performed at a mean gestational age of 29 + 4 and 31 + 0 weeks, respectively. Termination of pregnancy occurred. Pregnancy was terminated in 24 cases. Neuropathological examination confirmed the diagnosis in 24 cases and genetic testing identified abnormalities in 29 cases (28 families, 14 chromosomal anomaly). Classic PCH is associated with pontine atrophy and small MR measurements decreasing with advancing gestation. CONCLUSION: This is the first large series of prenatally diagnosed PCHs. Our study shows the essential contribution of fetal MRI to the prenatal diagnosis of PCH. Classic PCHs are particularly severe and are associated with certain MR features.

Cerebellar mutism syndrome caused by bilateral cerebellar hemorrhage in adults: a case report and review of the literature.

Cerebellar mutism syndrome (CMS) is a frequent complication of surgical intervention on posterior fossa in children. It has been only occasionally reported in adults and its features have not been fully characterized. In children and in young adults, medulloblastoma is the main reason for neurosurgery. A single case of postsurgical CMS is presented in an adult patient with a cerebellar hemorrhage and a systematic review of the published individual cases of CMS in adults was done. Literature review of individual cases found 30 patients, 18/30 (60%) males, from 20 to 71 years at diagnosis. All but one case was post-surgical, but in one of the post-surgical cases iatrogenic basilar artery occlusion was proposed as cause for CMS. The causes were: primary tumors of the posterior fossa in 16/22 (72.7%) metastasis in 3/30 (10%), ischemia in 3/30 (10%) cerebellar hemorrhage in 3/30 (10%), and benign lesions in 2/30 (6.7%) patients. 8/30 patients (26.7%) were reported as having persistent or incomplete resolution of CMS within 12 months. CMS is a rare occurrence in adults and spontaneous cerebellar hemorrhage has been reported in 3/30 (10%) adult patients. The generally accepted hypothesis is that CMS results from bilateral damage to the dentate nucleus or the dentate-rubro-thalamic tract, leading to cerebro-cerebellar diaschisis. Several causes might contribute in adults. The prognosis of CMS is slightly worse in adults than in children, but two thirds of cases show a complete resolution within 6 months.

A rare case of acute cerebellitis due to enterovirus treated with therapeutic plasma exchange: Case report and review of the literature.

BACKGROUND: Acute cerebellitis is a rare complication of pediatric infections. There are many reports that viral infections lead to neurological manifestations, including acute cerebellitis. METHODS: A retrospective chart review was conducted for pediatric patients diagnosed with enterovirus cerebellitis between 2000 and 2024. The methods involved reviewing clinical and radiological records and assessing the treatment methods. RESULTS: Case Report We present the case of a 4-year-old immunocompetent child who initially presented with acute encephalopathy followed by truncal ataxia, and eventually received a diagnosis of postinfectious cerebellitis. Enterovirus real-time polymerase chain reaction were positive in the nasopharyngeal swab. Therapeutic plasma exchange (TPE) was started due to neurological deterioration despite IVIG treatment. She improved significantly with TPE, and methylprednisolone treatment and was discharged in good health status. The patient is being followed up as neurologically normal. CONCLUSION: Acute cerebellitis associated with enterovirus is a rare pediatric disorder. Early diagnosis and treatment with TPE in this severe case is thought to be preventive for the potentially fatal complications.

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.

Catatonia associated with pediatric postoperative cerebellar mutism syndrome.

OBJECTIVE: To ascertain the presence of catatonia in cases of pediatric postoperative cerebellar mutism syndrome (PPCMS). METHOD: A systematic review of PPCMS case reports of patients aged 0-17 years with sufficient clinical information to extract catatonic phenomena was undertaken following PRISMA guidelines. Standardized catatonia rating scales were applied to selected cases retrospectively to ascertain whether diagnostic criteria for catatonia were met. A case known to the authors is also presented. RESULTS: Two hundred twenty-one suitable full-text articles were identified. Following screening and application of inclusion criteria, 51 articles were selected plus seven more from their references, reporting on 119 subjects. All cases met Bush and Francis (BF) diagnostic criteria for catatonia, 92.5% Pediatric Catatonia Rating Scale (PCRS), 52.9% ICD-11, and 44.5% DSM-5. All patients presented with mutism. The next most frequent signs were immobility/stupor (77.3%), withdrawal (35.3%), mannerisms (23.5%), and excitement/agitation (18.5%). Most cases presented with stuporous catatonia (75.6%). Catatonia most frequently occurred following resection of medulloblastoma (64.7%). Preoperative hydrocephalus occurred in 89 patients (74.8%). CONCLUSION: Catatonia was frequent in this PPCMS sample, with a predominant stuporous variant; it should be considered in patients with PPCMS and assessed with reliable and validated instruments for prompt diagnosis and management.

Case of pediatric cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome in a 2-year-old girl.

Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a recently described entity that refers to a specific pattern of cerebellar edema with restricted diffusion and crowding of the fourth ventricle among other findings. The syndrome is commonly associated with toxic opioid exposure. While most commonly seen in adults, we present a case of a 2-year-old girl who survived characteristic history and imaging findings of CHANTER syndrome.

Risk factors of prognosis for spontaneous cerebellar hemorrhage: a systematic review and meta-analysis.

BACKGROUND: The most deadly type of spontaneous intracerebral hemorrhage is spontaneous cerebellar hemorrhage (SCH). The purpose of this meta-analysis was to investigate risk factors for prognosis in SCH patients to provide a basis for taking preventive and therapeutic measures. METHODS: Seven electronic databases were searched from inception to May 2023 for randomized controlled trial, cohort study, case control study and cross-sectional study on prognosis of spontaneous cerebellar hemorrhage. The quality of the selected studies were assessed by the American Agency for Healthcare Research and Quality (AHRQ). To assess the impact of the included risk factors on the prognosis of spontaneous cerebellar hemorrhage, combined odds ratios (ORs) with matching 95% confidence intervals (CIs) were combined. RESULTS: Eight studies were included, including 539 participants. And a total of 31 potentially associated risk factors were identified. Ultimately, 6 risk factors were included in the meta-analysis after assessing. The factors supported by moderate evidence include the hydrocephalus (OR = 4.3, 95% CI: 2.33 to 7.91) and drug-induced coagulopathy (OR = 2.74, 95% CI: 1.23 to 6.09). The factors supported by limited evidence include the intraventricular bleeding(OR = 1.86, 95% CI: 1.13 to 3.07) and hematoma size>3 cm(OR = 3.18, 95% CI: 1.87 to 5.39). Meta-analysis revealed no association between hypertension, diabetes mellitus and SCH prognosis. CONCLUSION: The current meta-analysis revealed obvious risk factors for prognosis in spontaneous cerebellar hemorrhage patients, including hydrocephalus, drug-induced coagulopathy, intraventricular bleeding and hematoma size>3 cm.

Gait Variability as a Potential Motor Marker of Cerebellar Disease-Relationship between Variability of Stride, Arm Swing and Trunk Movements, and Walking Speed.

Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 patients with spinocerebellar ataxia type 14 (SCA), 12 patients with essential tremor (ET), and 67 healthy elderly (HE). Using inertial sensors, recordings of gait performance were conducted at different subjective walking speeds to delineate gait parameters and respective coefficients of variability (CoV). Comparisons across cohorts and walking speed categories revealed slower stride velocities in SCA and ET patients compared to HE, which was paralleled by reduced arm swing range of motion (RoM), peak velocity, and increased CoV of stride length, while no group differences were found for trunk deflections and their variability. Larger arm swing RoM, peak velocity, and stride length were predicted by higher gait velocity in all cohorts. Lower gait velocity predicted higher CoV values of trunk sagittal and horizontal deflections, as well as arm swing and stride length in ET and SCA patients, but not in HE. These findings highlight the role of arm movements in ataxic gait and the impact of gait velocity on variability, which are essential for defining disease manifestation and disease-related changes in longitudinal observations.

Neuropeptides and Their Roles in the Cerebellum.

Although more than 30 different types of neuropeptides have been identified in various cell types and circuits of the cerebellum, their unique functions in the cerebellum remain poorly understood. Given the nature of their diffuse distribution, peptidergic systems are generally assumed to exert a modulatory effect on the cerebellum via adaptively tuning neuronal excitability, synaptic transmission, and synaptic plasticity within cerebellar circuits. Moreover, cerebellar neuropeptides have also been revealed to be involved in the neurogenetic and developmental regulation of the developing cerebellum, including survival, migration, differentiation, and maturation of the Purkinje cells and granule cells in the cerebellar cortex. On the other hand, cerebellar neuropeptides hold a critical position in the pathophysiology and pathogenesis of many cerebellar-related motor and psychiatric disorders, such as cerebellar ataxias and autism. Over the past two decades, a growing body of evidence has indicated neuropeptides as potential therapeutic targets to ameliorate these diseases effectively. Therefore, this review focuses on eight cerebellar neuropeptides that have attracted more attention in recent years and have significant potential for clinical application associated with neurodegenerative and/or neuropsychiatric disorders, including brain-derived neurotrophic factor, corticotropin-releasing factor, angiotensin II, neuropeptide Y, orexin, thyrotropin-releasing hormone, oxytocin, and secretin, which may provide novel insights and a framework for our understanding of cerebellar-related disorders and have implications for novel treatments targeting neuropeptide systems.

Influenza Cerebellitis in a 3-Year-Old Male.

Acute cerebellitis (AC) is often a para-infectious inflammatory process that usually presents with a variable clinical picture; often with fever, nausea, headache, altered mental status, gait abnormalities, and coordination defects. It is usually a complication of an infectious process or as a result of post-infectious autoimmune mechanisms. We report a case of a 3 year old male with influenza A who presented with an acute encephalitic picture whose course and radiologic studies demonstrate cerebellar changes strongly compatible with AC.