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Cerebellum (London, England) Jun 2016The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of... (Review)
Review
The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello-thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops.
Topics: Cerebellar Diseases; Cerebellum; Humans
PubMed: 26105056
DOI: 10.1007/s12311-015-0687-3 -
JAMA Oncology Nov 2016Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR)... (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR) and outcome remains undefined, notwithstanding many relevant studies.
OBJECTIVE
To determine whether greater EOR is associated with improved 1- and 2-year overall survival and 6-month and 1-year progression-free survival in patients with GBM.
DATA SOURCES
Pubmed, CINAHL, and Web of Science (January 1, 1966, to December 1, 2015) were systematically reviewed with librarian guidance. Additional articles were included after consultation with experts and evaluation of bibliographies. Articles were collected from January 15 to December 1, 2015.
STUDY SELECTION
Studies of adult patients with newly diagnosed supratentorial GBM comparing various EOR and presenting objective overall or progression-free survival data were included. Pediatric studies were excluded.
DATA EXTRACTION AND SYNTHESIS
Data were extracted from the text of articles or the Kaplan-Meier curves independently by investigators who were blinded to each other's results. Data were analyzed to assess mortality after gross total resection (GTR), subtotal resection (STR), and biopsy. The body of evidence was evaluated according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria and PRISMA guidelines.
MAIN OUTCOME AND MEASURES
Relative risk (RR) for mortality at 1 and 2 years and progression at 6 months and 1 year.
RESULTS
The search produced 37 studies suitable for inclusion (41 117 unique patients). The meta-analysis revealed decreased mortality for GTR compared with STR at 1 year (RR, 0.62; 95% CI, 0.56-0.69; P < .001; number needed to treat [NNT], 9) and 2 years (RR, 0.84; 95% CI, 0.79-0.89; P < .001; NNT, 17). The 1-year risk for mortality for STR compared with biopsy was reduced significantly (RR, 0.85; 95% CI, 0.80-0.91; P < .001). The risk for mortality was similarly decreased for any resection compared with biopsy at 1 year (RR, 0.77; 95% CI, 0.71-0.84; P < .001; NNT, 21) and 2 years (RR, 0.94; 95% CI, 0.89-1.00; P = .04; NNT, 593). The likelihood of disease progression was decreased with GTR compared with STR at 6 months (RR, 0.72; 95% CI, 0.48-1.09; P = .12; NNT, 14) and 1 year (RR, 0.66; 95% CI, 0.43-0.99; P < .001; NNT, 26). The quality of the body of evidence by the GRADE criteria was moderate to low.
CONCLUSION AND RELEVANCE
This analysis represents the largest systematic review and only quantitative systematic review to date performed on this subject. Compared with STR, GTR substantially improves overall and progression-free survival, but the quality of the supporting evidence is moderate to low.
Topics: Brain; Brain Neoplasms; Disease-Free Survival; Glioblastoma; Humans; Risk; Treatment Outcome
PubMed: 27310651
DOI: 10.1001/jamaoncol.2016.1373 -
Brain Pathology (Zurich, Switzerland) Jul 2022Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal... (Review)
Review
Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal cord. Clinically, ependymomas represent a very heterogeneous group of tumors from rather benign subependymomas to very aggressive and often deadly childhood ependymomas of the posterior fossa. Newly identified biological markers and classification schemes, e. g. based on global DNA methylation profiling, have led to the definition of 10 types of ependymal tumors and an improved prediction of patients' outcome by applying the new classification system. While the exact genetic basis for several ependymoma types still remains unclear, the knowledge about ependymoma driving events has significantly increased within the last decade and contributed to a classification based on molecular characteristics and localization rather than histological features alone. Convincing evidence is now pointing towards gene fusions involving ZFTA or YAP1 causing the development of supratentorial ependymomas. Also, H3, EZHIP, or TERT mutations have been detected in a fraction of infratentorial ependymal tumors. Finally, MYCN amplifications have recently been identified in spinal ependymomas, in addition to the previously known mutations in NF2. This review summarizes how recent findings regarding biology, molecular tumor typing, and clinical outcome have impacted the classification of ependymomas as suggested by the updated 2021 WHO CNS tumor classification system. We focus on changes compared to the previous classification of 2016 and discuss how a formal grading could evolve in the future and guide clinicians to treat ependymoma patients.
Topics: Brain Neoplasms; Child; Ependymoma; Humans; Infratentorial Neoplasms; Supratentorial Neoplasms; World Health Organization
PubMed: 35307892
DOI: 10.1111/bpa.13068 -
Stroke Jun 2023Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the...
BACKGROUND
Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes.
METHODS
We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0-2], poor [modified Rankin Scale score 4-6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes.
RESULTS
Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all <0.05). Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5 mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all <0.05). Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule, and 21 mL for internal capsule/globus pallidus (all <0.001). All receiver operating characteristic models for location-specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for cerebellum.
CONCLUSIONS
ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.
Topics: Humans; Retrospective Studies; Cerebral Hemorrhage; Stroke; Globus Pallidus; Hematoma
PubMed: 37216445
DOI: 10.1161/STROKEAHA.122.041246 -
Journal of Clinical Oncology : Official... Mar 2023Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging....
PURPOSE
Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL.
PATIENTS AND METHODS
We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL.
RESULTS
Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, < .0001, log-rank test) and overall survival (OS, = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, = .0002; OS, = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value.
CONCLUSION
We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL.
UNLABELLED
[Media: see text].
Topics: Humans; Circulating Tumor DNA; Prognosis; Lymphoma, Non-Hodgkin; Supratentorial Neoplasms; Risk Assessment; Brain; Biomarkers, Tumor; Mutation
PubMed: 36542815
DOI: 10.1200/JCO.22.00826 -
JAMA Neurology May 2019Various signs may be observed on brain magnetic resonance imaging (MRI) in patients with spontaneous intracranial hypotension (SIH). However, the lack of a...
IMPORTANCE
Various signs may be observed on brain magnetic resonance imaging (MRI) in patients with spontaneous intracranial hypotension (SIH). However, the lack of a classification system integrating these findings limits decision making in clinical practice.
OBJECTIVE
To develop a probability score based on the most relevant brain MRI findings to assess the likelihood of an underlying spinal cerebrospinal fluid (CSF) leak in patients with SIH.
DESIGN, SETTING, AND PARTICIPANTS
This case-control study in consecutive patients investigated for SIH was conducted at a single hospital department from February 2013 to October 2017. Patients with missing brain MRI data were excluded. Three blinded readers retrospectively reviewed the brain MRI scans of patients with SIH and a spinal CSF leak, patients with orthostatic headache without a CSF leak, and healthy control participants, evaluating 9 quantitative and 7 qualitative signs. A predictive diagnostic score based on multivariable backward logistic regression analysis was then derived. Its performance was validated internally in a prospective cohort of patients who had clinical suspicion for SIH.
MAIN OUTCOMES AND MEASURES
Likelihood of a spinal CSF leak based on the proposed diagnostic score.
RESULTS
A total of 152 participants (101 female [66.4%]; mean [SD] age, 46.1 [14.3] years) were studied. These included 56 with SIH and a spinal CSF leak, 16 with orthostatic headache without a CSF leak, 60 control participants, and 20 patients in the validation cohort. Six imaging findings were included in the final scoring system. Three were weighted as major (2 points each): pachymeningeal enhancement, engorgement of venous sinus, and effacement of the suprasellar cistern of 4.0 mm or less. Three were considered minor (1 point each): subdural fluid collection, effacement of the prepontine cistern of 5.0 mm or less, and mamillopontine distance of 6.5 mm or less. Patients were classified into groups at low, intermediate, or high probability of having a spinal CSF leak, with total scores of 2 points or fewer, 3 to 4 points, and 5 points or more, respectively, on a scale of 9 points. The discriminatory ability of the proposed score could be demonstrated in the validation cohort.
CONCLUSIONS AND RELEVANCE
This 3-tier predictive scoring system is based on the 6 most relevant brain MRI findings and allows assessment of the likelihood (low, intermediate, or high) of a positive spinal imaging result in patients with SIH. It may be useful in identifying patients with SIH who are leak positive and in whom further invasive myelographic examinations are warranted before considering targeted therapy.
Topics: Adolescent; Adult; Aged; Brain; Case-Control Studies; Cerebrospinal Fluid Leak; Cranial Sinuses; Dura Mater; Female; Humans; Intracranial Hypotension; Logistic Models; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Myelography; Subdural Space; Tomography, X-Ray Computed; Young Adult
PubMed: 30776059
DOI: 10.1001/jamaneurol.2018.4921 -
Acta Neuropathologica May 2023Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these...
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
Topics: Humans; Young Adult; Biomarkers, Tumor; Brain; Brain Neoplasms; Central Nervous System Neoplasms; Gene Fusion; Neoplasms, Neuroepithelial; Receptor Protein-Tyrosine Kinases; X-linked Nuclear Protein
PubMed: 36933012
DOI: 10.1007/s00401-023-02558-0