Search Results (144)

Background/Objectives: Posterior fossa brain metastases (PFBMs) pose particular risks owing to their proximity to the brainstem and fourth ventricle. We evaluated the safety (treatment-related complications), local effectiveness, and procedural efficiency of volumetric modulated arc therapy (VMAT)-based stereotactic radiosurgery (VMAT-SRS) for PFBMs. Methods: This single-centre, retrospective study derived a PFBM subgroup from an overall institutional cohort of 123 patients treated with VMAT-RapidArc SRS/fSRS. The doses were 12–20 Gy (single fraction) or 5 × 6 Gy (selected cases). Local response (mRECIST) and predefined safety endpoints (symptomatic oedema with brainstem/IV-ventricle compromise, obstructive hydrocephalus, haemorrhagic transformation, CSF diversion, and urgent neurosurgery) were assessed. Overall survival and procedural time were analysed. Results: Thirty-one patients (39 lesions) were included; 76.9% of them received single-fraction SRS. In addition, 74.2% of patients had supratentorial metastases with posterior fossa involvement. Kaplan–Meier overall survival at 6, 12, 24, and 48 months was 74%, 58%, 26%, and 9.7%, respectively; the median survival time was 12.6 months. Among evaluable lesions, local control was 84.5% (per-lesion response: 15.5% PD, 28.1% SD, 34.4% PR, and 22.0% CR). No clinically significant posterior fossa local complications were observed. Three patients developed radiation-induced leukoencephalopathy after whole-brain radiotherapy (WBRT) and radiosurgery for synchronous supratentorial metastases. The median procedural time was 25.0 min (IQR 9.0) with one isocentre versus 52.5 min (IQR 9.75) with two. Conclusions: VMAT-SRS/fSRS for PFBMs achieved high local control, very low posterior fossa toxicity, and favourable procedural efficiency, supporting its use as a safe, rapid, frameless alternative to WBRT and other radiosurgical platforms such as Gamma Knife in appropriately selected patients. Full article

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant neurological disorder caused by mutations in the NOTCH3 gene. Disease-causing variants in NOTCH3 are primarily missense variants altering the number of cysteine residues in the translated NOTCH3 protein. The genetic screening of the NOTCH3 gene is currently considered the gold standard for CADASIL diagnosis. Methods The Genomics Research Centre has been performing diagnostic genetic testing for CADASIL since 1997. A total of 1281 patient samples suspected of having CADASIL were screened for NOTCH3 mutations from January 1, 1997, to October 1, 2025. Genomic sequencing was performed using Sanger sequencing of selected NOTCH3 exons or using next-generation sequencing to screen the entire NOTCH3 gene. Results In total, 12.1% of patients had a cysteine-altering NOTCH3 variant, including 49 variants in exons 2-24, and two variants in non-EGFr encoding exons. We also report the first CADASIL patient who is a compound heterozygote for two known pathogenic cysteine-altering NOTCH3 variants, who presented with a severe early onset of stroke, migraine, and white matter changes. Conclusions The compound heterozygosity identified in this patient appears to be associated with an early onset of CADASIL symptoms. Our study contributes to the elucidation of the spectrum of NOTCH3 variants associated with CADASIL. The majority of patients tested for CADASIL in this study did not contain a variant in NOTCH3, indicating that there are other genes or genetic variants contributing to disease in these patients. Full article

JC virus (JCV) replicates within the nuclei of glial cells in the human brain and causes progressive multifocal leukoencephalopathy. JCV possesses a small, circular, double-stranded DNA genome, divided into early and late protein-coding regions. The non-coding control region (NCCR) functions bidirectionally for both early and late genes, and the agnogene is located downstream of TCR and upstream of three capsid proteins in the late region. Previously, in cell culture systems, we demonstrated that these capsid proteins accumulate in intranuclear domains known as promyelocytic leukemia nuclear bodies (PML-NBs), where they assemble into virus-like particles (VLPs). To investigate the agnogene’s function, VLPs were formed in its presence or absence, and differential gene expression was analyzed using microarray technology. The results revealed altered expression of histone-modifying enzymes, including methyltransferases (EHMT1, PRMT7) and demethylases (KDM2B, KDM5C, KDM6B), as well as various kinases and phosphatases. Notably, CTDP1, which dephosphorylates the C-terminal domain of an RNA polymerase II subunit, was also differentially expressed. The changes were predominant in the presence of the agnogene. These findings indicate that the agnogene and/or its protein product likely influence epigenetic regulation associated with PML-NBs, which may influence cell cycle control. Consistently, in human brain tissue, JCV-infected glial cells displayed maintenance of a diploid chromosomal complement, likely through G2 arrest. The precise mechanism of this, however, remains to be elucidated. Full article

Background/Objectives: Frank’s sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank’s sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank’s sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank’s sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose–response relationships across WMH tertiles. Results: Frank’s sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128–15.733, p = 0.032). Within CADASIL, Frank’s sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose–response relationship emerged across WMH tertiles, with Frank’s sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134–11.253, p = 0.030). Conclusions: Frank’s sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose–response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank’s sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification. Full article

Background: Aminoacyl-tRNA synthetases (ARSs) are a group of enzymes responsible for the first step of protein translation. Among them, the KARS1 gene encodes lysyl-tRNA synthetase 1, an enzyme essential for charging tRNA-Lys with lysine in both the cytoplasm and mitochondria. Mutations in KARS1 are associated with a wide range of clinical phenotypes, including leukoencephalopathy, hereditary deafness, peripheral neuropathies, and multisystemic involvement. Methods: We hereby report a detailed case study of a 15-month-old boy presenting at age 5 months with developmental delay, microcephaly, hypotonia, sensorineural deafness, retinopathy, visual impairment, nystagmoid eye movements, and hepatic and immuno-hematological abnormalities. In addition, he exhibited a severe hyperkinetic movement disorder, not previously reported in the literature, and developed epilepsy at 13 months. Genetic testing identified two rare compound heterozygous variants in the KARS1 gene. Results: With this report, we aim to contribute to the expanding of both the clinical phenotype and the allelic spectrum of lysyl-tRNA synthetase-related disorders. Our study also includes a review of previously described KARS1 cases presenting with movement disorders. Conclusions: Our findings further highlight the importance of assessing systemic involvement and performing brain and spinal neuroimaging, as well as implementing genetic screening, in infants presenting with global developmental delay, sensory deficits, and movement disorders—features that may suggest a mitochondrial disorder such as those involving ARS mutations. Full article

Background/Objectives： Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a prevalent Mendelian disorder caused by mutations in the NOTCH3 gene, primarily impacting cerebral small blood vessels. This review aims to explore the involvement of large intracranial arteries in CADASIL, particularly focusing on the association with RNF213 polymorphisms, especially in Asian populations. Methods： A comprehensive literature review was conducted to gather data on the morphological features of both small and large intracranial arteries in CADASIL, examining clinical manifestations, imaging findings, and genetic associations. Results： The findings indicate that while CADASIL is predominantly characterized by small vessel disease, a significant number of patients also exhibit large artery involvement, particularly Asian populations where RNF213 polymorphisms may play a critical role. The review highlights the evidence of intracranial stenosis and the potential implications of traditional vascular risk factors, such as hypertension and diabetes mellitus, which are prevalent in these populations. Conclusions： The involvement of larger intracranial arteries in CADASIL underscores the complexity of the disease, suggesting that both genetic predispositions and environmental factors contribute to vascular abnormalities. Further research is needed to clarify these relationships and improve diagnostic and therapeutic strategies for CADASIL patients. Full article

Background: The central variant of posterior reversible encephalopathy syndrome (cvPRES) is an atypical subtype of PRES. Although no unifying definitions exists, it is most often characterized by vasogenic edema involving “central” structures, such as the brainstem, subcortical nuclei, and spinal cord, with relative sparing of the parieto-occipital lobes. Methods: This systematic review and meta-analysis followed the PRISMA guidelines and was pre-registered on PROSPERO [CRD42023483806]. Both the Joanna Briggs Institute and New-Castle Ottawa scale were used for case reports and cohort studies, respectively. The meta-analysis was completed using R-Studio and its associated “metafor” package. Results: A comprehensive search in four databases yielded 70 case reports/series (n = 100) and 12 cohort studies. The meta-analysis revealed a pooled incidence rate of 13% (95% CI: 9–18%) for cvPRES amongst included cohort studies on PRES. Significant heterogeneity was observed (I² = 71% and a τ² = 0.2046). The average age of affected individuals was 40.9 years, with a slightly higher prevalence in males (54%). The most common etiological factor was hypertension (72%). Fifty percent had an SBP >200 mmHg at presentation and a mean arterial pressure (MAP) of 217.6 ± 40.82. Imaging revealed an increased T₂ signal involving the brain stem (88%), most often in the pons (62/88; 70.45%), and 18/100 (18%) cases of PRES with spinal cord involvement (PRES-SCI). Management primarily involved blood pressure reduction, with adjunctive therapies for underlying causes such as anti-seizure medications or hemodialysis. The MAP between isolated PRES-SCI and cvPRES without spinal cord involvement did not show significant differences (p = 0.5205). Favorable outcomes were observed in most cases, with a mortality rate of only 2%. Conclusions: cvPRES is most often associated with higher blood pressure compared to prior studies with typical PRES. The pons is most often involved. Despite the severity of blood pressure and critical brain stem involvement, those with cvPRES have favorable functional outcomes and a lower mortality rate than typical PRES, likely attributable to reversible vasogenic edema without significant neuronal dysfunction. Full article

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with PML. Methods: Nineteen patients meeting the 2013 consensus criteria for “definite PML” were included, and JCV-specific T lymphocytes expanded from autologous or allogeneic peripheral blood mononuclear cells (PBMCs) using JCV antigen-derived peptides were administered. Clinical outcomes were monitored through neuroimaging and biological markers. Results: The mean age at diagnosis was 56.5 years, with a mean time to treatment of three months. Patients received a median of two infusions. At 12 months, six patients (31.6%) survived, while 13 (68.4%) had died, primarily due to PML progression. Survivors had a higher median baseline Karnofsky performance scale (KPS) score (50% vs. 30%, p = 0.41) and a significantly shorter diagnosis delay. MRI assessment showed a reduced disease burden in survivors, and JCV-DNA copy numbers decreased overall. One case of immune reconstitution inflammatory syndrome (IRIS) was observed. Conclusions: Adoptive JCV-specific T lymphocytes may represent a safe therapeutic option for PML patients, and the MRI burden and JCV-DNA copy may serve as biomarkers for disease monitoring. Full article

Background: B-cell-depleting drugs targeting the CD20 antigen have been increasingly implemented as an “exit strategy” from natalizumab for relapsing–remitting multiple sclerosis (RRMS) patients due to the increased risk of progressive multifocal leukoencephalopathy. Data on recently approved anti-CD20 drugs, such as ofatumumab serving as a natalizumab “exit strategy”, are lacking. Furthermore, due to their immunosuppressive mechanism of action, prolonged use of these “highly effective” drugs is associated with the development of hypogammaglobulinemia and, consequently, a higher risk of infections. There are no guidelines for monitoring serum immunoglobulin levels in individuals undergoing “highly effective” multiple sclerosis treatment. Methods: We present a case of a 26-year-old male RRMS patient with selective IgM deficiency and multiple sclerosis initially treated with natalizumab and later ofatumumab. Results: The patient achieved “no evident disease activity “status while undergoing treatment with natalizumab and ofatumumab, but these therapies, especially ofatumumab, greatly impacted further drops in IgM levels. However, no significant decrease in IgG levels was observed, and no infectious events occurred. In addition, the patient did not show signs of disease activity while on ofatumumab, which also offered a more convenient mode of administration. Conclusions: Our experience points to the need to further explore benefit–risk ratios of highly effective treatments, even in cases with low immunoglobulin levels. However, closely monitoring immunoglobulin levels and conducting clinical follow-ups to ensure prompt recognition of potential infectious complications constitute approaches that have been thought of for such patients. Full article

Background: An increased risk of cognitive decline has been reported in patients with older age bipolar disorder (OABD); however, the underlying factors contributing to this association remain unclear. This cross-sectional study aims to identify the clinical features associated with cognitive impairment in OABD. Methods: A total of 152 participants, aged at least 50 years and diagnosed with bipolar disorder (BD) and related disorders in agreement with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria, were included in the study and divided into two subgroups based on the presence/absence of cognitive impairment, defined as a diagnosis of Mild Neurocognitive Disorder or Major Neurocognitive Disorder. Univariate comparisons and multivariate logistic regression models were performed to investigate the associations between clinical variables and cognitive impairment. Results: Cognitively impaired patients had a higher prevalence of otherwise specified BD/cyclothymic disorder, while BD type 2 was more common in the cognitively unimpaired group. Additionally, the cognitively impaired group had a later onset of major mood episodes (p < 0.05), fewer lifetime depressive episodes (p = 0.006), a higher prevalence of vascular leukoencephalopathy (p = 0.022) and dyslipidemia (p = 0.043), a lower prevalence of agoraphobia (p = 0.040), worse global functioning (p < 0.001), and higher psychopathology severity (p < 0.001). Late onset, vascular leukoencephalopathy, and dyslipidemia were all independently associated with cognitive impairment. Conclusions: Atypical BD, late onset of mood episodes, and somatic comorbidities like vascular leukoencephalopathy and dyslipidemia are associated with a higher risk of developing cognitive impairment and neurodegenerative disorders in OABD patients. Full article

Polyomaviruses (PyVs) are non-enveloped double-stranded DNA viruses that can cause significant morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). BKPyV is primarily associated with hemorrhagic cystitis (HC), while JCPyV causes progressive multifocal leukoencephalopathy (PML). The pathogenesis of these diseases involves viral reactivation under immunosuppressive conditions, leading to replication in tissues such as the kidney, bladder, and central nervous system. BKPyV-HC presents as hematuria and urinary symptoms, graded by severity. PML, though rare after allo-HSCT, manifests as neurological deficits due to JCPyV replication in glial cells. Diagnosis relies on nucleic acid amplification testing for DNAuria or DNAemia as well as clinical criteria. Management primarily involves supportive care, as no antiviral treatments have proven consistently effective for either virus and need further research. This review highlights the virology, clinical presentations, and management challenges of PyV-associated diseases post-allo-HSCT, emphasizing the need for improved diagnostic tools and therapeutic approaches to mitigate morbidity and mortality in this vulnerable population. Full article

Background: Cocaine has been shown to cause cytotoxic neuronal damage, which has been implicated in cases of leukoencephalopathy. We present a case of cocaine-induced toxic encephalopathy resulting in predominant lesions to the gray matter on magnetic resonance imaging (MRI). Case Presentation: A 70-year-old female presented acutely with confusion, agitation, and disorientation. She was markedly hypertensive with other vital signs within normal range. On presentation to the emergency department, she was uncooperative and had an unsteady gait but showed no focal neurological deficits. Her lab work was positive for elevated cardiac troponins, elevated D-dimer, and a urine drug screen positive only for cocaine. Head computed tomography (CT) showed no hemorrhage and head CT angiogram showed no abnormalities and no significant vascular stenosis. Chest X-ray and CT showed diffuse ground glass opacities compatible with atypical pneumonia. Antibiotics were initiated to treat the pneumonia and antihypertensives were administered to manage her blood pressure. She was also given IV thiamine. Brain MRI showed restricted diffusion involving bilateral hippocampi, thalami, putamen, caudate, and right occipital lobe, findings suspicious for cytotoxic edema. After acute stabilization, the patient demonstrated profound anterograde and retrograde amnesia, which improved gradually over days to weeks. She was eventually discharged to a skilled nursing facility. Conclusion: To our knowledge, this is the first reported case of profound amnesia secondary to cocaine-induced toxic encephalopathy with bilateral hippocampal involvement. These symptoms correlate with the implicated neuroanatomical structures. This case demonstrates that cocaine may be implicated in toxic encephalopathy affecting the brain’s gray matter and highlights a unique presentation of these findings. Full article

Background/Objectives: Recent advances in stroke genetics have substantially enhanced our understanding of the complex genetic architecture underlying cerebral infarction and other stroke subtypes. As knowledge in this field expands, healthcare providers must remain informed about these latest developments. This review aims to provide a comprehensive overview of recent advances in stroke genetics, with a focus on cerebral infarction, and discuss their potential impact on patient care and future research directions. Methods: We reviewed recent literature about advances in stroke genetics, focusing on cerebral infarction, and discussed their potential impact on patient care and future research directions. Key developments include the identification of monogenic stroke syndromes, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by mutations in the NOTCH3 and HTRA1 genes, respectively. In addition, the role of RNF213 in moyamoya disease and other cerebrovascular disorders, particularly in East Asian populations, has been elucidated. The development of polygenic risk scores for assessing genetic predisposition to stroke has demonstrated the potential to improve risk prediction beyond traditional factors. Genetic studies have also elucidated the distinct genetic architecture of stroke subtypes, including large artery atherosclerosis, small vessel disease, and cardioembolic stroke. Furthermore, the investigation of epigenetic modifications influencing stroke risk and its outcomes has revealed new research avenues, while advancements in pharmacogenomics highlight the potential for personalized stroke treatment based on individual genetic profiles. Conclusions: These genetic discoveries have important clinical implications, including improved risk stratification, targeted prevention strategies, and the development of novel therapeutic approaches. Full article

Background: Recent advances in childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) management provide higher survival rates at the cost of increased toxicities. Acute neurotoxicity affects up to 10% of patients, requiring rapid recognition and treatment. Methods: A retrospective observational study was performed to determine the frequency, clinical manifestations, radiological characteristics, treatment options and outcome of acute neurological adverse events in pediatric patients with lymphoid malignancies at the Department of Oncology and Hematology, Children’s Hospital Zagreb, Croatia. Results: A total of 56 patients (48 ALL and 8 LL, male/female ratio 1:1, average age 5.4 years) were treated mainly according to the ALL-IC BFM 2009 protocol. The B-immunophenotype was the most frequent (85.7%). Most patients were stratified to the intermediate risk group (39.3%), and two were initially diagnosed with central nervous system infiltration. Acute neurotoxic events were registered in 11 patients (19.6%), most commonly in the 6–10-year age group (66.7%), predominately in females (72.7%) and high-risk group (54.5%). The most frequent clinical presentation was seizures (83.3%), with status epilepticus in four cases. We detected electroencephalogram (EEG) irregularities in almost all patients and various morphological changes in the brain magnetic resonance imaging (MRI), most often consistent with posterior reversible encephalopathy syndrome and leukoencephalopathy. Approximately half the patients received prolonged antiepileptic therapy. No apparent residual neurologic manifestations have been observed. Conclusions: Acute neurotoxicity is a rather frequent treatment-related adverse event, associated with high-risk disease. Early recognition and timely management are essential for rapid recovery and optimal outcomes. Full article

JC polyomavirus (JCPyV) establishes a persistent, asymptomatic kidney infection in most of the population. However, JCPyV can reactivate in immunocompromised individuals and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease with no approved treatment. Mutations in the hypervariable non-coding control region (NCCR) of the JCPyV genome have been linked to disease outcomes and neuropathogenesis, yet few metanalyses document these associations. Many online sequence entries, including those on NCBI databases, lack sufficient sample information, limiting large-scale analyses of NCCR sequences. Machine learning techniques, however, can augment available data for analysis. This study employs a previously compiled dataset of 989 JCPyV NCCR sequences from GenBank with associated patient PML status and viral tissue source to train multilayer perceptrons for predicting missing information within the dataset. The PML status and tissue source models were 100% and 87.8% accurate, respectively. Within the dataset, 348 samples had an unconfirmed PML status, where 259 were predicted as No PML and 89 as PML sequences. Of the 63 sequences with unconfirmed tissue sources, eight samples were predicted as urine, 13 as blood, and 42 as cerebrospinal fluid. These models can improve viral sequence identification and provide insights into viral mutations and pathogenesis. Full article