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Neurotoxicity associated with high-dose chemotherapy and whole brain radiotherapy (WBRT) is one of major complications for patients with central nervous system lymphoma (CNSL). Here we determined the incidence and risk factors of treatment-related leukoencephalopathy (tLE) in a clinical setting. We retrospectively reviewed clinical and radiological findings of 126 patients with  (CNSL) treated with high-dose methotrexate with or without intrathecal methotrexate administration (IT MTX) and response-adapted WBRT. During the whole observation period with a median of 38.7 months, tLE was found in 33 patients, most of them asymptomatic, with the median time to development 3.0 months, and the cumulative incidence reaching 29.2% (95% confidence interval, 20.6-38.2%) two years post chemotherapy. By multivariable analysis, IT MTX was identified as the only one significant risk factor (hazard ratio, 4.50; P < 0.001), and the number of IT MTX was associated with the increased incidence and severity of tLE. These findings highlight the frequent neurological complications associated with CNS-directed therapy and confirm the neurotoxicity of IT MTX.

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Neurological manifestations are frequent in patients with SARS-CoV-2 infection and can be correlated with different pathogenic mechanisms which can be divided into two categories: direct invasion of the central nervous system by the virus and indirect effects deriving from the severity of the systemic infection and by the inflammatory response correlated with cytokine storm. Among the neurological manifestations, acute encephalopathy is very frequent and its nomenclature has recently been updated. The occurrence of a condition of altered mental status, reduced consciousness, delirium up to coma represents an element associated with a greater severity of the infection and mortality both in an Intensive Care Unit setting and in an Emergency Department setting. The tissue damage mechanisms found in COVID-19 patients' encephalopathy and neuroimaging patterns, as well as histopathology, are similar to those described in sepsis-associated encephalopathy, further confirming the role of indirect mechanisms, with no CNS invasion by the virus. The available data have some limitations, notably the underuse of diagnostic neuroimaging techniques in severely affected patients, particularly in the first wave of the pandemic.

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The article discusses the historical aspect and modern ideas about the etiology and pathogenesis of progressive multifocal leukoencephalopathy in patients with HIV infection. An analysis and synthesis of literature data on the clinical presentation of this pathology was carried out. The possibilities and limitations of laboratory and instrumental diagnostic methods, including neuroimaging methods, are discussed in detail. The pathomorphological signs of the disease in HIV-positive individuals are covered.

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Progressive Multifocal Leukoencephalopathy (PML), primarily affecting immunocompromised individuals due to the John Cunningham virus (JC), is common in HIV-positive adults but rare in paediatrics. We present a unique case of a 14-year-old female with PML as the initial manifestation of HIV, with MRI lesions isolated to the posterior fossa. Initial symptoms included fever and rash, progressing to neurological deficits and ataxia. Severe immune suppression due to HIV and JC virus in the cerebrospinal fluid were confirmed. Management included immune reconstitution therapy (antiretroviral treatment) and supportive care. Despite interventions, the patient had a slow recovery with significant residual neurological sequelae. Timely recognition of Immune Reconstitution Inflammatory Syndrome (IRIS) and steroid initiation proved helpful. Antiretroviral therapy improved the survival rate of HIV-related PML, but long-term neurological sequelae, especially in posterior fossa cases, significantly impact the patient's quality of life. This case highlights diagnostic and treatment challenges in paediatric PML, particularly with atypical lesions location.

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During the current opioid epidemic, the number of children with illicit toxic ingestions is increasing. Children presenting with altered mental status and neurologic, particularly cerebellar symptoms of unclear etiology, should be considered to undergo brain imaging as well as toxicology screening to not miss the possible complication of acute toxic leukoencephalopathy. We report the case of an eight-year-old child who presented with somnolence and respiratory depression of unclear etiology, responding profoundly to naloxone, quickly raising concern for drug ingestion. The toxicology screen was positive for fentanyl, cocaine metabolites, caffeine, and diphenhydramine, but not available until day 3 of the hospital stay. In the interim, head CT and brain MRI findings revealed concerning bilateral cerebellar hypodensities, suggestive of opioid-induced leukoencephalopathy. This condition has been described as potentially malignant and fatal, but very few cases of this pathology have been described in children so far. Fortunately, all neurological symptoms in our patient, including altered mental status, respiratory depression, atactic gait, blurry vision, and lower extremity pain, completely resolved within five days of presentation and the patient seemingly underwent a full clinical recovery without residual symptoms. Awareness and prompt recognition of acute toxic leukoencephalopathy in children presenting with altered mental status or neurological symptoms of unclear etiology is of utmost importance to prevent deterioration and optimize treatment, especially during times of a worsening opioid epidemic in our country.

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BACKGROUND AND OBJECTIVES: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has recently been known as HTRA1-related cerebral small-vessel disease (CSVD), it is caused by variants in HTRA1. Recently, it has been reported to develop in heterozygotes with some variants of the gene. Multiple prospective studies have reported that the frequency of heterozygous HTRA1 variants developing CSVD is 2 - 6.5 % in CARASIL. Heterozygous variant cases lack unique clinical features, have an older age of onset, and are difficult to detect. Characteristic findings are required to identify such cases. METHOD: Magnetic resonance imaging (MRI) images of cases that experienced cerebral infarction and carried heterozygous variants in HTRA1 were reviewed. RESULTS: Four cases of heterozygous HTRA1-related CSVD in two families (Family 1: c.754G > A, p.A252T; three males. Family 2: c.497G > T, p.R166L, one female). In all cases, white matter lesions with lacunar infarcts were observed in the periventricular and basal ganglia, external capsule, and brainstem. Moreover, T2 star weighted image (T2*WI) low presented dot-like lesions were present along the surface of the brainstem, which have only been reported in one homozygous case. Susceptibility-weighted imaging (SWI) was performed in two cases, and the dot-like lesions on T2*WI resembled a pearly tiara along the surface of the brainstem. CONCLUSION: Brainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant. The pathology requires further investigation for diagnosis.

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BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. CASE PRESENTATION: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

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Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system (CNS) due to John Cunningham (JC) virus reactivation most often in immunocompromised patients. The brainstem and the anterior corpus callosum are uncommon locations for white matter lesions. We present a case of PML in a 40-year-old female presenting to the emergency department for a tonic seizure with transient postictal confusion. The inpatient workup revealed low cluster of differentiation cell counts (CD3 and CD4), transaminitis, positive drug screen, and abnormal electroencephalogram (EEG). The computed tomogram (CT) of the head and magnetic resonance image (MRI or MR) of the brain showed evidence of subcortical and periventricular white matter lesions in the right hemisphere extending into the brainstem and the left frontal lobe. The hospital course consisted of supportive measures, seizure treatment along with prophylaxis, and human immunodeficiency virus (HIV) management along with prophylactic antibiotics. The patient was discharged with appropriate medications and outpatient referrals. Overall, this case describes some key points. It highlights particular imaging characteristics of PML in the setting of inadequately treated HIV. For example, white matter lesions cross the anterior corpus callosum rather than the splenium, as in the "barbell" sign. In addition, the lesions extend inferiorly along the ipsilateral corticospinal tract into the midbrain and pons. This could be one of the first cases to capture both of these features given the rarity of their concomitant occurrence.

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BACKGROUND: Few studies have quantitatively analyzed the imaging disparities between multiple sclerosis (MS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to compare the imaging characteristics of MS and CADASIL in middle-aged patients. MATERIALS AND METHODS: This retrospective study used a single-center database and included patients aged 40-60 years with MS and CADASIL who underwent the designated imaging protocol including 3D T1-weighted imaging and fluid attenuated inversion recovery (FLAIR), diffusion tensor imaging and susceptibility-weighted imaging between January 2018 and March 2023. Patients with MRI-detected macrobleeds were excluded. RESULTS: A total of 27 patients with MS (mean age, 46.7 years ± 4.4, 8 men) and 30 patients with CADASIL (mean age, 51.6 years ± 5.8, 14 men) were included. No significant differences were observed in the Fazekas grades of white matter lesions (WMLs). Patients with CADASIL exhibited greater external capsule involvement (56.7% vs.18.5 %; p = 0.006), whereas the MS group had more lesions in the corpus callosum (81.5% vs. 53.3 %, p = 0.02) and brainstem (74.1% vs. 46.7 %, p = 0.04). The CADASIL group exhibited a higher incidence of microbleeds (12.07 vs. 0.11, p = 0.001). The WMLs in the MS group exhibited a lower T1 lesion/cerebrospinal fluid signal index (2.206 vs. 2.882, p < 0.001). A value of ≤2.57 demonstrated a sensitivity of 92.6 % and a specificity of 90.0 % in differentiating MS. Patients with MS had a thinner corpus callosum (7.18 mm vs 7.86 mm, p = 0.04), while patients with CADASIL showed significantly higher mean diffusivity (0.8776 × 10-3 vs. 0.7637 × 10-3 mm2/s, p = 0.03) and lower fractional anisotropy (0.7581 vs. 0.8389, p = 0.04) in the splenium of the corpus callosum. CONCLUSION: Middle-aged patients with MS and CADASIL showed comparable Fazekas grades for WMLs. However, lesion distribution, T1 signal characteristics, and splenic diffusivity changes can help differentiate between MS and CADASIL.

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Neurological disorders and pain are prevalent clinical issues that severely impact patients' quality of life and daily functioning. With the advancing exploration of these disease mechanisms, G protein-coupled receptor 37 (GPR37) has emerged as a critical protein, garnering widespread attention in the scientific community. As a member of the G protein-coupled receptor family, GPR37 features a seven-transmembrane helix structure and is widely expressed in various brain regions, including the substantia nigra and striatum. In addition to neurons, GPR37 is also detected in immune cells within the nervous system, indicating its potential role in neuron-immune cell interactions. Research has shown that the expression level of GPR37 in neurological disorders can affect neuron survival, cellular signaling, and overall neurological health. Abnormal expression of GPR37 is often associated with disease progression and symptom exacerbation in neurological disorders such as Parkinson's disease and stroke. In the context of pain, GPR37 alleviates pain and inflammatory responses by regulating the phagocytic activity and polarization state of macrophages. This article aims to delve into the mechanistic roles of GPR37 in neurological disorders and pain. Through a comprehensive literature review, we summarize the latest research on GPR37's involvement in neurological diseases and pain, highlighting its critical roles in neural signaling, inflammatory responses, and neuroprotection. This understanding expands the comprehension of GPR37's biological functions and provides new perspectives for improving the clinical outcomes of patients with neurological disorders and pain.

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Progressive multifocal leukoencephalopathy (PML) is considered an often fatal, demon-leading disease primarily associated with immunosuppression. Immunocompromised individuals predominantly exhibit this manifestation, while immunocompatible patients rarely encounter it. We present a unique case of PML in an immunocompetent individual who initially presented with stroke-like symptoms, received management, and was subsequently discharged. He returned to our hospital a few days later with similar complaints, prompting further investigations that revealed PML, a condition often overlooked, especially in individuals with an intact immune system. Although he received successful treatment with mefloquine and other anti-malarial medications and followed up on an outpatient basis, his subsequent outcome was unfavourable. As a result, this case emphasises the importance of having PML as a significant differential and therapeutic option.

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Neurosarcoidosis (NS) is a rare subtype of sarcoidosis with a poor prognosis and diverse clinical presentations that often poses a diagnostic and therapeutic challenge. We describe the case of a 53-year-old male with an initial diagnosis of lingual sarcoidosis, who subsequently developed ataxia and rapidly progressive cognitive impairment. A lumbar puncture revealed hypoglycorrhachia, hyperproteinorrachia, lymphocytic pleocytosis, and elevated IL-6 levels (600 pg/ml). Cerebrospinal fluid flow cytometry showed an elevated CD4 lymphocyte concentration and a CD4+/CD8+ ratio of 3.91, indicative of NS. Brain MRI showed hyperintense periventricular and subcortical lesions on FLAIR/T2 resembling progressive multifocal leukoencephalopathy (PML), although negative PCR for JC virus ruled out the differential diagnosis. Following a favorable evolutionary course with corticosteroid pulses, the patient relapsed with normotensive hydrocephalus, treated with immunosuppressants and ventriculoperitoneal shunting with a good response to date. This case underscores the importance of maintaining a high index of suspicion for NS in individuals with sarcoidosis and neurologic symptoms. In these cases, cerebrospinal fluid biomarkers such as IL-6 and CD4+/CD8+ ratio are essential to guide the diagnosis. Furthermore, it highlights that hydrocephalus is a rare complication and requires a multidisciplinary approach, including medical and neurosurgical treatment.

La neurosarcoidosis es un subtipo raro de sarcoidosis con mal pronóstico y diversas presentaciones clínicas que a menudo plantea un reto diagnóstico y terapéutico. Describimos el caso de un varón de 53 años con diagnóstico inicial de sarcoidosis lingual, que posteriormente desarrolló ataxia y deterioro cognitivo de rápida evolución. Una punción lumbar reveló hipoglucorraquia, hiperproteinorraquia, pleocitosis linfocítica y niveles elevados de IL-6 (600 pg/ml). La citometría de flujo del líquido cefalorraquídeo mostró una concentración elevada de linfocitos CD4 y un cociente CD4+/CD8+ de 3.91, indicativo de neurosarcoidosis. La RM cerebral evidenció lesiones hiperintensas periventriculares y subcorticales en FLAIR/T2 que se asemejaban a una leucoencefalopatía multifocal progresiva (LMP), aunque la PCR negativa para el virus JC descartó el diagnóstico diferencial. Tras un curso evolutivo favorable con pulsos de corticoides, el paciente recayó con hidrocefalia normotensiva, tratada con inmunosupresores y derivación ventriculoperitoneal con buena respuesta hasta la fecha. Este caso subraya la importancia de mantener un alto índice de sospecha de neurosarcoidosis en individuos con sarcoidosis y síntomas neurológicos. En estos casos, los biomarcadores del líquido cefalorraquídeo tales como la IL-6 y el cociente CD4+/CD8+ son esenciales para orientar el diagnóstico. Además, destaca que la hidrocefalia es una complicación poco frecuente y requiere un abordaje multidisciplinario, que incluya tratamiento médico y neuroquirúrgico.

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Progressive multifocal leukoencephalopathy (PML) is a severe, demyelinating disease of the central nervous system caused by JC virus infection. The disease can be seen in sarcoidosis patients without additional risk factors. Here, we present an individual with PML secondary to sarcoidosis treated with 8 doses of pembrolizumab, a Programmed Cell-Death-1 (PD-1) Immune Checkpoint Inhibitor who showed significant improvement. This report illustrates the objective clinical and radiological improvement in a patient with PML due to sarcoidosis, and suggests further study of immune checkpoint inhibitors as a potential treatment for sarcoidosis patients with PML.

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Demyelinating central nervous system (CNS) disorders are a diverse group of conditions characterised by damage to the myelin sheath. These include not only primary autoimmune disorders such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), but secondary demyelinating conditions caused by infection and neoplasm, where immunosuppressive therapy may worsen the condition or delay definitive treatment. We describe a young man with an unusual presentation of CNS demyelinating disease associated with HIV infection and positive syphilis serology. MRI brain and spine showed a demyelinating tumefactive lesion accompanied by longitudinal extensive transverse myelitis, and we initially suspected NMOSD. However anti-aquaporin 4 antibodies were negative, going against a diagnosis of NMOSD and he then tested positive for HIV which led us to consider TB myelitis, neurosyphilis and HIV vacuolar myelopathy. He was commenced on highly active retroviral therapy and treated with steroids and immunosuppression. He did not respond to treatment as expected so a brain biopsy was required to narrow the differential. Brain biopsy initially raised the possibility of progressive multifocal leukoencephalopathy which is associated with infection with the John Cunningham (JC) virus. Ultimately JC Virus PCR on the biopsy was negative, the final report suggesting nonspecific active chronic inflammation. We detail his clinical course and the diagnostic challenges along the way.

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Colony stimulating factor 1 receptor (CSF1R) is an essential receptor for both colony stimulating factor 1 (CSF1) and interleukin (IL) 34 signaling expressed on monocyte precursors and myeloid cells, including monocytes, dendritic cells (DC), and microglia. In humans, dominant heterozygous pathogenic variants in CSF1R cause a neurological condition known as CSF1R-related disorder (CSF1R-RD), typically with late onset, previously referred to as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). CSF1R-RD is characterized by microglia reduction and altered monocyte function; however, the impact of pathogenic CSF1R variants on the human DC lineage remains largely unknown. We previously reported that cord blood CD34+ stem cell-derived DCs generated in vitro originate specifically from CSF1R expressing precursors. In this study, we examined the DC lineage of four unrelated patients with late-onset CSF1R-RD who carried heterozygous missense CSF1R variants (c.2330G>A, c.2375C>A, c.2329C>T, and c.2381T>C) affecting different amino acids in the protein tyrosine kinase domain of CSF1R. CD34+ stem cells and CD14+ monocytes were isolated from peripheral blood and subjected to an in vitro culture protocol to differentiate towards conventional DCs and monocyte-derived DCs, respectively. Flow cytometric analysis revealed that monocytes from patients with late-onset CSF1R-RD were still able to differentiate into monocyte-derived DCs in vitro, whereas the ability of CD34+ stem cells to differentiate into conventional DCs was impaired. Strikingly, the peripheral blood of patients contained all naturally occurring DC subsets. We conclude that the in vitro abrogation of DC-development in patients with heterozygous pathogenic missense CSF1R variants does not translate to an impairment in DC development in vivo and speculate that CSF1R signalling in vivo is compensated, which needs further study.

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Neuroglial cells, also known as glia, are primarily characterized as auxiliary cells within the central nervous system (CNS). The recent findings have shed light on their significance in numerous physiological processes and their involvement in various neurological disorders. Leukodystrophies encompass an array of rare and hereditary neurodegenerative conditions that were initially characterized by the deficiency, aberration, or degradation of myelin sheath within CNS. The primary cellular populations that experience significant alterations are astrocytes, oligodendrocytes and microglia. These glial cells are either structurally or metabolically impaired due to inherent cellular dysfunction. Alternatively, they may fall victim to the accumulation of harmful by-products resulting from metabolic disturbances. In either situation, the possible replacement of glial cells through the utilization of implanted tissue or stem cell-derived human neural or glial progenitor cells hold great promise as a therapeutic strategy for both the restoration of structural integrity through remyelination and the amelioration of metabolic deficiencies. Various emerging treatment strategies like stem cell therapy, ex-vivo gene therapy, infusion of adeno-associated virus vectors, emerging RNA-based therapies as well as long-term therapies have demonstrated success in pre-clinical studies and show promise for rapid clinical translation. Here, we addressed various leukodystrophies in a comprehensive and detailed manner as well as provide prospective therapeutic interventions that are being considered for clinical trials. Further, we aim to emphasize the crucial role of different glial cells in the pathogenesis of leukodystrophies. By doing so, we hope to advance our understanding of the disease, elucidate underlying mechanisms, and facilitate the development of potential treatment interventions.

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BACKGROUND: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. METHODS: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. FINDINGS: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. INTERPRETATION: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. FUNDING: The Wellcome Trust, the MRC.

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Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. Using both in vitro analysis and a human glial chimeric mouse model of JCV infection, we found that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells. Accordingly, bulk and single cell RNA-sequence analysis revealed that JCV-infected glia differentially manifested cell cycle-linked disruption of both DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Importantly, in vivo infection triggered the death of uninfected as well as infected glia, reflecting significant bystander death. Together, these data suggest that JCV propagation in PML may be accelerated by glial cell division. As such, the accentuated glial proliferation attending disease-associated demyelination may provide an especially favorable environment for JCV propagation, thus potentiating oligodendrocytic bystander death and further accelerating demyelination in susceptible hosts.