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1.
Genes (Basel) ; 15(5)2024 May 11.
Article En | MEDLINE | ID: mdl-38790244

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.


Aspartate-tRNA Ligase , INDEL Mutation , Leukoencephalopathies , Humans , Aspartate-tRNA Ligase/genetics , Aspartate-tRNA Ligase/deficiency , Male , Leukoencephalopathies/genetics , Leukoencephalopathies/pathology , Female , Brain Stem/pathology , Brain Stem/diagnostic imaging , Child , Lactic Acid/blood , Russia , Adult , Spinal Cord/pathology , Spinal Cord/diagnostic imaging , Adolescent , Mitochondrial Diseases
2.
Front Immunol ; 15: 1388667, 2024.
Article En | MEDLINE | ID: mdl-38799430

Cerebellar ataxia is an uncommon and atypical manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient.


Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Autoantibodies , Brain Stem , Humans , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , Brain Stem/pathology , Autoantibodies/immunology , Autoantibodies/cerebrospinal fluid , Autoantibodies/blood , Female , Cerebellar Ataxia/etiology , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/immunology , Cerebellum/pathology , Cerebellum/diagnostic imaging , Receptors, N-Methyl-D-Aspartate/immunology , Adult , Immunotherapy , Male , Magnetic Resonance Imaging
3.
Neuropathol Appl Neurobiol ; 50(3): e12977, 2024 Jun.
Article En | MEDLINE | ID: mdl-38680020

AIM: Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS. METHODS: To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS. RESULTS: Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition. CONCLUSIONS: IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.


Disease Progression , Electron Transport Complex I , Interferon-gamma , Leigh Disease , Animals , Mice , Brain Stem/pathology , Brain Stem/metabolism , Disease Models, Animal , Electron Transport Complex I/genetics , Electron Transport Complex I/deficiency , Interferon-gamma/metabolism , Leigh Disease/pathology , Leigh Disease/genetics , Mice, Inbred C57BL , Mice, Knockout
4.
J Alzheimers Dis ; 99(1): 307-319, 2024.
Article En | MEDLINE | ID: mdl-38669537

Background: Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.


Aging , Alzheimer Disease , Brain Stem , Microglia , Positron-Emission Tomography , Receptors, GABA , Humans , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Microglia/metabolism , Microglia/pathology , Male , Aged , Female , Aging/pathology , Brain Stem/metabolism , Brain Stem/pathology , Receptors, GABA/metabolism , Aged, 80 and over , Middle Aged , Isoquinolines , Adult
5.
Radiol Artif Intell ; 6(3): e230151, 2024 May.
Article En | MEDLINE | ID: mdl-38506619

Purpose To develop a fast and fully automated deep learning (DL)-based method for the MRI planimetric segmentation and measurement of the brainstem and ventricular structures most affected in patients with progressive supranuclear palsy (PSP). Materials and Methods In this retrospective study, T1-weighted MR images in healthy controls (n = 84) were used to train DL models for segmenting the midbrain, pons, middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), third ventricle, and frontal horns (FHs). Internal, external, and clinical test datasets (n = 305) were used to assess segmentation model reliability. DL masks from test datasets were used to automatically extract midbrain and pons areas and the width of MCP, SCP, third ventricle, and FHs. Automated measurements were compared with those manually performed by an expert radiologist. Finally, these measures were combined to calculate the midbrain to pons area ratio, MR parkinsonism index (MRPI), and MRPI 2.0, which were used to differentiate patients with PSP (n = 71) from those with Parkinson disease (PD) (n = 129). Results Dice coefficients above 0.85 were found for all brain regions when comparing manual and DL-based segmentations. A strong correlation was observed between automated and manual measurements (Spearman ρ > 0.80, P < .001). DL-based measurements showed excellent performance in differentiating patients with PSP from those with PD, with an area under the receiver operating characteristic curve above 0.92. Conclusion The automated approach successfully segmented and measured the brainstem and ventricular structures. DL-based models may represent a useful approach to support the diagnosis of PSP and potentially other conditions associated with brainstem and ventricular alterations. Keywords: MR Imaging, Brain/Brain Stem, Segmentation, Quantification, Diagnosis, Convolutional Neural Network Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Mohajer in this issue.


Brain Stem , Deep Learning , Magnetic Resonance Imaging , Supranuclear Palsy, Progressive , Humans , Supranuclear Palsy, Progressive/diagnostic imaging , Supranuclear Palsy, Progressive/pathology , Magnetic Resonance Imaging/methods , Female , Retrospective Studies , Brain Stem/diagnostic imaging , Brain Stem/pathology , Male , Aged , Middle Aged , Reproducibility of Results , Cerebral Ventricles/diagnostic imaging , Cerebral Ventricles/pathology , Image Interpretation, Computer-Assisted/methods
6.
Orphanet J Rare Dis ; 19(1): 92, 2024 Feb 28.
Article En | MEDLINE | ID: mdl-38419071

BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported. METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays. RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease. CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.


Leigh Disease , Neurodegenerative Diseases , Humans , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Leigh Disease/genetics , Leigh Disease/metabolism , Electron Transport Complex I/metabolism , Brain Stem/pathology , Mutation/genetics , Molecular Chaperones/genetics , Molecular Chaperones/metabolism
7.
Int J Radiat Oncol Biol Phys ; 119(2): 655-668, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38300187

PURPOSE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. METHODS AND MATERIALS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/ß value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.


Brain Stem , Brain , Central Nervous System Neoplasms , Necrosis , Neoplasm Recurrence, Local , Re-Irradiation , Humans , Re-Irradiation/adverse effects , Necrosis/etiology , Child , Neoplasm Recurrence, Local/radiotherapy , Central Nervous System Neoplasms/radiotherapy , Central Nervous System Neoplasms/pathology , Adolescent , Brain/radiation effects , Brain/pathology , Brain Stem/radiation effects , Brain Stem/pathology , Ependymoma/radiotherapy , Young Adult , Child, Preschool , Medulloblastoma/radiotherapy , Radiation Injuries/pathology
8.
Radiologia (Engl Ed) ; 66(1): 32-46, 2024.
Article En | MEDLINE | ID: mdl-38365353

OBJECTIVE: To describe the magnetic resonance imaging (MRI) findings for the most common inflammatory and immune-mediated diseases that involve the brainstem. CONCLUSION: Inflammatory lesions involving the brainstem are associated with a wide range of autoimmune, infectious, and paraneoplastic syndromes, making the differential diagnosis complex. Being familiar with these entities, their clinical characteristics, and their manifestations on MRI, especially the number of lesions, their shape and extension, and their appearance in different sequences, is useful for orienting the radiological diagnosis.


Brain Stem , Magnetic Resonance Imaging , Brain Stem/diagnostic imaging , Brain Stem/pathology , Magnetic Resonance Imaging/methods , Diagnosis, Differential
9.
JAMA Neurol ; 81(3): 240-247, 2024 Mar 01.
Article En | MEDLINE | ID: mdl-38285456

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.


Encephalitis , Sudden Infant Death , Infant , Humans , Male , Middle Aged , Sudden Infant Death/genetics , Sudden Infant Death/pathology , Neuroinflammatory Diseases , Case-Control Studies , Multiomics , Neopterin , Brain Stem/pathology , Encephalitis/complications , Cytokines
10.
Neuroradiology ; 66(3): 325-332, 2024 Mar.
Article En | MEDLINE | ID: mdl-38200284

PURPOSE: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. METHODS: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. CONCLUSIONS: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.


Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/diagnostic imaging , Glioblastoma/surgery , Glioblastoma/pathology , Retrospective Studies , Magnetic Resonance Imaging/methods , Chemoradiotherapy , Brain Stem/diagnostic imaging , Brain Stem/surgery , Brain Stem/pathology , Brain Neoplasms/pathology
11.
Nature ; 625(7994): 345-351, 2024 Jan.
Article En | MEDLINE | ID: mdl-38057661

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.


Frontotemporal Lobar Degeneration , TATA-Binding Protein Associated Factors , Humans , Amyloid/chemistry , Amyloid/metabolism , Amyloid/ultrastructure , Brain Stem/metabolism , Brain Stem/pathology , Cryoelectron Microscopy , Frontotemporal Dementia/etiology , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Frontotemporal Lobar Degeneration/complications , Frontotemporal Lobar Degeneration/metabolism , Frontotemporal Lobar Degeneration/pathology , Motor Cortex/metabolism , Motor Cortex/pathology , Motor Neurons/metabolism , Motor Neurons/pathology , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , TATA-Binding Protein Associated Factors/chemistry , TATA-Binding Protein Associated Factors/metabolism , TATA-Binding Protein Associated Factors/ultrastructure , Temporal Lobe/metabolism , Temporal Lobe/pathology
12.
Childs Nerv Syst ; 40(1): 227-232, 2024 Jan.
Article En | MEDLINE | ID: mdl-37737897

We present the case of a previously healthy 13-year-old boy who was admitted to the emergency department with acute flaccid paralysis. Magnetic resonance imaging revealed radiological evidence of longitudinally extensive transverse myelitis. Additionally, homogeneous T2 signal increase was observed in the pons and medulla oblongata, initially indicating brainstem encephalitis. Subsequent evaluations confirmed a coexistence of diffuse midline glioma (DMG) in the brain stem alongside acute transverse myelitis (ATM). Children with ATM generally have a more favorable prognosis than adults. However, despite the implementation of advanced treatment methods, the patient's quadriplegia did not improve and resulted in spinal cord sequela atrophy. DMG exhibits an aggressive growth pattern and lacks a known curative treatment. This case represents an exceedingly rare synchronous occurrence of aggressive conditions, underscoring the importance of raising awareness among physicians. Furthermore, we aim to discuss the radiologic differential diagnosis, as this is the first documented instance in the literature.


Encephalitis , Glioma , Myelitis, Transverse , Male , Adult , Child , Humans , Adolescent , Myelitis, Transverse/complications , Myelitis, Transverse/diagnostic imaging , Brain Stem/diagnostic imaging , Brain Stem/pathology , Glioma/complications , Glioma/diagnostic imaging , Glioma/pathology , Magnetic Resonance Imaging
13.
J Neurosurg ; 140(2): 469-477, 2024 Feb 01.
Article En | MEDLINE | ID: mdl-37542441

OBJECTIVE: Surgical treatment of brainstem cavernous malformations (CMs) is challenging. Surgery using the endoscopic transsphenoidal transclival approach (eTSTCA) is reported as a useful alternative for ventral brainstem CMs. However, CMs located in the ventral midline of the brainstem are rare, and only a small number of case reports on these CMs treated with the eTSTCA exist. The efficacy and safety of the eTSTCA have not yet been fully examined. METHODS: A retrospective analysis was performed for 5 consecutive patients who underwent surgery via the eTSTCA for treating ventral pontine CMs. RESULTS: The average maximum CM diameter was 26.0 mm (18-38 mm). All patients underwent MR-diffusion tensor imaging, which confirmed that the corticospinal tract (CST) deviated posteriorly or laterally to the CM. Direct brainstem cortical stimulation was performed to localize the CST before making the cortical incision. After the excision of the CM, the cavity was filled with artificial CSF to make an aqueous surgical field (wet-field technique) for observing the tumor cavity and confirming complete hemostasis and resection. Total removal was achieved in all patients. The preoperative modified Rankin Scale score was 3 in 3 patients and 4 in 2 patients, whereas it was 1 in 2 patients and 0 in 3 patients 3 months after surgery. Postoperative CSF leakage was observed in 1 patient, and transient abducens nerve palsy was observed in 1 patient. No other intra- or postoperative complications were observed. CONCLUSIONS: MR-diffusion tensor imaging and direct brainstem cortical stimulation were useful to ascertain the proximity of the CST to the CM. The endoscope provides a clear view even underwater, and it was safe and effective to observe the entire CM cavity and confirm complete hemostasis without additional retraction of the brainstem parenchyma, including the CST. The eTSTCA provides a direct access point to the lesion and may be a safer alternative treatment for patients whose CST deviates laterally or posteriorly to the CM.


Diffusion Tensor Imaging , Pons , Humans , Diffusion Tensor Imaging/methods , Retrospective Studies , Pons/surgery , Endoscopy , Brain Stem/diagnostic imaging , Brain Stem/surgery , Brain Stem/pathology , Postoperative Complications/pathology
14.
Neuroradiology ; 66(1): 101-108, 2024 Jan.
Article En | MEDLINE | ID: mdl-38040824

PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder characterized by cerebellar atrophy. However, studies to elucidate the longitudinal progression of the neuropathology are limited. We sought to identify brain macrostructural and microstructural alterations in patients with SCA2 using fixel-based analysis (FBA) to better understand its distribution patterns and progression. METHODS: We enrolled 9 patients with SCA2 and 16 age- and gender-matched controls. Longitudinal clinical and imaging data were collected at baseline, and 3.5 years later. Fiber density (FD), fiber-bundle cross-section (FC), and a combination of FD and FC (FDC) were calculated. The paired t-test was used to examine longitudinal differences. The associations between fixel-based metrics and clinical variables were explored in SCA2 patients. RESULTS: At baseline, patients with SCA2 displayed multiple white matter tracts with significantly decreased FD, FC, and FDC in the corticospinal tract, cerebellar peduncles, brainstem, corpus callosum, thalamus, striatum, and prefrontal cortex, compared to controls. Over time, many of these macrostructural and microstructural alterations progressed, manifesting lower FD, FC, and FDC in corticospinal tract, middle cerebellar peduncle, brainstem, striatum, fornix, and cingulum. No significant brain white matter alterations were found in the healthy controls over time. There was no association between the FBA-derived metrics and clinical variables in SCA2. CONCLUSION: This study provides evidence of brain macrostructural and microstructural alterations and of progression over time in SCA2. The FBA-derived metrics may serve as potential biomarkers of SCA2 progression.


Spinocerebellar Ataxias , White Matter , Humans , White Matter/diagnostic imaging , White Matter/pathology , Spinocerebellar Ataxias/diagnostic imaging , Brain/diagnostic imaging , Brain/pathology , Cerebellum/pathology , Brain Stem/pathology , Diffusion Magnetic Resonance Imaging/methods
15.
Am J Clin Oncol ; 47(3): 110-114, 2024 Mar 01.
Article En | MEDLINE | ID: mdl-37981700

OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.


Neuroma, Acoustic , Radiosurgery , Humans , Neuroma, Acoustic/diagnostic imaging , Neuroma, Acoustic/radiotherapy , Neuroma, Acoustic/etiology , Treatment Outcome , Radiosurgery/adverse effects , Radiosurgery/methods , Brain Stem/diagnostic imaging , Brain Stem/pathology , Follow-Up Studies , Retrospective Studies
16.
Clin Neurol Neurosurg ; 236: 108089, 2024 Jan.
Article En | MEDLINE | ID: mdl-38141551

BACKGROUND AND AIM: Brainstem descending modulatory circuits have been postulated to be involved in migraine. Differences in brainstem volume between migraineurs and healthy controls have been demonstrated in previous research, nevertheless, the effect of migraine aura on brainstem volume is still uncertain. The aim of this study was to investigate the brainstem volume in migraineurs and examine the effect of migraine aura on brainstem volume. METHODS: Our study included 90 female migraine patients without white matter lesions. (29 migraine patients with aura (MwA) and 61 migraine patients without aura (MwoA) and 32 age-matched female healthy controls (HC). Using the FreeSurfer image analysis suite, the volumes of the entire brainstem and its subfields (medulla, pons, and midbrain) were measured and compared between migraine subgroups (MwA vs. MwoA) and the healthy control group. The possible effects of migraine characteristics (i.e., disease duration and migraine attack frequency) on brainstem volume were also investigated. RESULTS: Migraineurs had greater medulla volume (MwoA 3552 ± 459 mm3, MwA 3424 ± 448 mm3) than healthy controls (3236 ± 411 mm3). Statistically, MwA vs. HC p = 0.040, MwoA vs. HC p = 0.002, MwA vs. MwoA p = 0.555. A significant positive correlation was found between disease duration and the volume of medulla in the whole migraine group (r = 0.334, p = 0.001). Neither the whole brainstem nor its subfields were significantly different in volume between migraine subgroups. CONCLUSION: Brainstem volume changes in migraine are mainly localized to the medulla and not specific to the presence of aura.


Epilepsy , Migraine with Aura , Migraine without Aura , Humans , Female , Brain Stem/diagnostic imaging , Brain Stem/pathology , Migraine with Aura/diagnostic imaging , Migraine without Aura/diagnostic imaging , Mesencephalon/pathology , Magnetic Resonance Imaging/methods
17.
Curr Oncol ; 30(11): 9772-9785, 2023 Nov 07.
Article En | MEDLINE | ID: mdl-37999129

The present review aims to investigate the survival and functional outcomes in adult high-grade brainstem gliomas (BGSs) by comparing data from resective surgery and biopsy. MEDLINE, EMBASE and Cochrane Library were screened to conduct a systematic review of the literature, according to the PRISMA statement. Analysis was limited to articles including patients older than 18 years of age and those published from 1990 to September 2022. Case reports, review articles, meta-analyses, abstracts, reports of aggregated data, and reports on multimodal therapy where surgery was not the primary treatment were excluded. The ROBINS-I tool was applied to evaluate the risk of bias. Six studies were ultimately considered for the meta-analysis. The resective group was composed of 213 subjects and the bioptic group comprised 125. The analysis demonstrated a survival benefit in those patients in which an extensive resection was possible (STR HR 0.59 (95% CI 0.42, 0.82)) (GTR HR 0.63 (95% CI 0.43, 0.92)). Although surgical resection is associated with increased survival, the significantly higher complication rate makes it difficult to recommend surgery instead of biopsy for BSGs. Future investigations combining volumetric data and molecular profiles could add important data to better define the proper indication between resection and biopsy.


Brain Neoplasms , Glioma , Humans , Adult , Glioma/surgery , Glioma/pathology , Biopsy , Combined Modality Therapy , Brain Stem/pathology
18.
World Neurosurg ; 180: 149-154.e2, 2023 Dec.
Article En | MEDLINE | ID: mdl-37783305

OBJECTIVE: Posterior fossa decompression (PFD) surgery creates more space at the skull base, reduces the resistance to the cerebrospinal fluid motion, and alters craniocervical biomechanics. In this paper, we retrospectively examined the changes in neural tissue dimensions following PFD surgery on Chiari malformation type 1 adults. METHODS: Measurements were performed on T2-weighted brain magnetic resonance images acquired before and 4 months after surgery. Measurements were conducted for neural tissue volume and spinal cord/brainstem width at 4 different locations; 2 width measurements were made on the brainstem and 2 on the spinal cord in the midsagittal plane. Cerebellar tonsillar position (CTP) was also measured before and after surgery. RESULTS: Twenty-five adult patients, with a mean age of 38.9 ± 8.8 years, were included in the study. The cervical cord volume increased by an average of 2.3 ± 3.3% (P = 0.002). The width at the pontomedullary junction increased by 2.2 ± 3.5% (P < 0.01), while the width 10 mm caudal to this junction increased by 4.2 ± 3.9% (P < 0.0001). The spinal cord width at the base of second cervical vertebra and third cervical vertebra did not significantly change after surgery. The CTP decreased by 60 ± 37% (P < 0.0001) after surgery, but no correlation was found between CTP change and dimension change. CONCLUSIONS: The brainstem width and cervical cord volume showed a modest increase after PFD surgery, although standard deviations were large. A reduction in compression after PFD surgery may allow for an increase in neural tissue dimension. However, clinical relevance is unclear and should be assessed in future studies with high-resolution imaging.


Arnold-Chiari Malformation , Cervical Cord , Adult , Humans , Middle Aged , Cervical Cord/diagnostic imaging , Cervical Cord/surgery , Cervical Cord/pathology , Retrospective Studies , Decompression, Surgical/methods , Arnold-Chiari Malformation/diagnostic imaging , Arnold-Chiari Malformation/surgery , Arnold-Chiari Malformation/pathology , Brain Stem/diagnostic imaging , Brain Stem/surgery , Brain Stem/pathology , Spinal Cord/surgery , Magnetic Resonance Imaging , Cranial Fossa, Posterior/diagnostic imaging , Cranial Fossa, Posterior/surgery , Cranial Fossa, Posterior/pathology , Treatment Outcome
19.
BMC Neurol ; 23(1): 386, 2023 Oct 26.
Article En | MEDLINE | ID: mdl-37884876

Bickerstaff's brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient's serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient's clinical course and history, he was diagnosed with Bickerstaff's brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.


Autoimmune Diseases of the Nervous System , Colitis, Ulcerative , Encephalitis , Ophthalmoplegia , Male , Humans , Middle Aged , Brain Stem/diagnostic imaging , Brain Stem/pathology , Colitis, Ulcerative/complications , Colitis, Ulcerative/pathology , Mesalamine , Encephalitis/complications , Encephalitis/diagnosis , Quadriplegia , Ataxia/complications , Gangliosides
20.
BMJ Case Rep ; 16(10)2023 Oct 31.
Article En | MEDLINE | ID: mdl-37907311

A man in his 30s presented with a 6-month history of progressive left face, arm and leg weakness. Medical history included epilepsy and vitamin B12 deficiency. Three maternal second degree relatives died before the age of 7 from various neurological disorders. Examination revealed a mild left facial droop and weakness of the left shoulder, hip and ankle. Reflexes were symmetrical and tone was normal. Differential diagnosis included glioma, subacute infarction, lymphoma and demyelination. MRI brain showed an extensive right sided subcortical white matter lesion, with extension into the brainstem. The patient's weakness progressed over 3 months. Brain biopsy showed evidence of demyelination and gliosis. A pathological diagnosis of tumefactive multiple sclerosis was made, but also rare metabolic disorders such as X-linked adrenoleukodystrophy (X-ALD) were proposed. Serum very long-chain fatty acids were significantly elevated. Genetic testing showed a mutation in the ABCD1 gene, confirming a diagnosis of X-ALD.


Adrenoleukodystrophy , Humans , Male , Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/genetics , Brain Stem/pathology , Magnetic Resonance Imaging , Mutation , Neuroimaging , Adult
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