Heroin-induced leukoencephalopathy: Chasing the imaging findings.

We present a case of a 29-year-old male who was brought into the hospital due to unresponsiveness and found to have heroin inhalational leukoencephalopathy (HLE). HLE is one component of a broad spectrum of opioid encephalopathies that is associated with heroin inhalation and other opioids. There is considerable overlap of HLE with other toxic and hypoxic-ischemic encephalopathies; however, the specific territories of brain involvement help distinguish it from other cerebral insults. The goal of this study is to help elucidate the findings of HLE and compare these findings to other toxic and hypoxic-ischemic encephalopathies.

Progressive multifocal leukoencephalopathy and spectrum of predisposing conditions: a 20-year retrospective cohort study in a tertiary center in São Paulo, Brazil.

BACKGROUND: Epidemiological studies on predisposing conditions and outcomes of progressive multifocal leukoencephalopathy (PML) cases have been carried out exclusively in high-income countries. We aim to report and compare the main characteristics and outcomes of patients with PML and several underlying diseases in a referral center in a middle-income country. METHODS: We performed a retrospective cohort study of PML cases admitted to a tertiary care hospital in São Paulo, Brazil during 2000-2022. Demographic and PML-specific variables were recorded. One-year case-fatality rate and factors associated with death were identified using a multivariate Cox proportional hazards regression model. RESULTS: Ninety-nine patients with PML were included. HIV infection (84.8%) and malignancy (14.1%) were the most prevalent underlying conditions. Other predisposing diseases were autoimmune/inflammatory diseases (5.1%) and solid organ transplantation (1.0%). One (1.0%) patient had liver cirrhosis and another (1.0%) patient was previously healthy. Focal motor deficits (64.2%) and gait instability (55.1%) were the most common signs. The one-year case-fatality rate was 52.5% (95% CI 42.2-62.7). The one-year case-fatality rate (95% CI) in patients with or without malignancy (85.7%, 95% CI 57.2-98.2% and 47.1%, 95% CI 36.1-58.2%, respectively) were statistically different (P = 0.009). Crude and adjusted Cox regression models identified malignancy as independently associated with death (adjusted HR = 3.92, 95% CI 1.76-8.73, P = 0.001). CONCLUSIONS: HIV/AIDS was the predisposing condition in 84.8% of PML cases. The one-year case-fatality rate was 52.5% and having a malignancy was independently associated with death. This study reports emerging data on the epidemiology and outcome of PML in a middle-income country.

Unraveling Labrune Syndrome: A Case Report on the Neurological Phenotype in SNORD118-Negative Patients.

Labrune syndrome is a rare neurogenetic disorder with varied presentations. Here, we report the case of a 53-year-old male who presented with seizures, gait imbalance, and upper limb tremors for two years. Imaging studies revealed extensive leukodystrophy, multiple cerebral calcifications, and cystic lesions characteristic of Labrune syndrome. However, whole exome sequencing did not detect the SNORD118 mutation, typically associated with Labrune syndrome. Although the SNORD118 mutation is commonly found in Labrune syndrome, a few cases of the syndrome without this mutation have also been reported. This suggests the possibility that other yet undiscovered mutations may cause the same phenotype.

Hypomyelinated vps16 Mutant Zebrafish Exhibit Systemic and Neurodevelopmental Pathologies.

Homotypic Fusion and Protein Sorting (HOPS) and Class C-core Vacuole/Endosome Tethering (CORVET) complexes regulate the correct fusion of endolysosomal bodies. Mutations in core proteins (VPS11, VPS16, VPS18, and VPS33) have been linked with multiple neurological disorders, including mucopolysaccharidosis (MPS), genetic leukoencephalopathy (gLE), and dystonia. Mutations in human Vacuolar Protein Sorting 16 (VPS16) have been associated with MPS and dystonia. In this study, we generated and characterized a zebrafish vps16(-/-) mutant line using immunohistochemical and behavioral approaches. The loss of Vps16 function caused multiple systemic defects, hypomyelination, and increased neuronal cell death. Behavioral analysis showed a progressive loss of visuomotor response and reduced motor response and habituation to acoustic/tap stimuli in mutants. Finally, using a novel multiple-round acoustic/tap stimuli test, mutants showed intermediate memory deficits. Together, these data demonstrate that zebrafish vps16(-/-) mutants show systemic defects, neurological and motor system pathologies, and cognitive impairment. This is the first study to report behavior abnormalities and memory deficiencies in a zebrafish vps16(-/-) mutant line. Finally, we conclude that the deficits observed in vps16(-/-) zebrafish mutants do not mimic pathologies associated with dystonia, but more align to abnormalities associated with MPS and gLE.

Transient response to high-dose niacin therapy in a patient with NAXE deficiency.

Background: NAXE-encephalopathy or early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL-1) and NAXD-encephalopathy (PEBEL-2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation. Methods: We describe a patient with a confirmed PEBEL-1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL-1 and PEBEL-2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off-label use of a COX2 inhibitor to treat niacin-related urticaria in NAXE-encephalopathy. Results: So far, seven patients with PEBEL-1 and PEBEL-2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL-1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient. Conclusion: Despite previous positive results for niacin supplementation in patients with PEBEL-1 and PEBEL-2, this is the first report of a patient with PEBEL-1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date.

Chloride Voltage-Gated Channel 2 (CLCN2)-Related Leukoencephalopathy Exhibiting Reduced Choline Levels on Magnetic Resonance Spectroscopy.

In this article, we report the third case of chloride voltage-gated channel 2 (CLCN2)-related leukoencephalopathy (CC2L) in Japan. The patient presented with headache, vertigo, and mild visual impairment. The CLCN2 variant of the patient, NM_004366.6:c.61dup, p.(Leu21Profs*27), was also found in two other Japanese patients as this variant is relatively common in the Japanese population. Magnetic resonance imaging (MRI) revealed T2 prolongation with reduced diffusion in the bilateral posterior limbs of the internal capsule, cerebral peduncles, and superior and middle cerebellar peduncles. Magnetic resonance spectroscopy (MRS) of normal-appearing white matter revealed decreased choline content. This represents the first evidence of decreased choline levels in CC2L, highlighting the superior sensitivity of MRS over MRI.

A 12-year Life History of a Girl with Profound Intellectual Disability and Leukoencephalopathy: A Rare Clinical Presentation of X Chromosome Pentasomy.

This paper presents a unique 12-year case analysis of a girl with Penta-X syndrome, a chromosomal abnormality characterized by five X chromosomes instead of the normal two in healthy women. Pentasomy of X is a genetic, but not a hereditary disease affecting only women. Our patient demonstrated delayed mental, speech, and motor development along with physical anomalies such as craniofacial deformities, and eye pathology and was diagnosed with pentasomy of the X chromosome at the age of 3 after a cytogenetic examination. She developed epileptic seizures at the age of nine. Magnetic resonance imaging(MRI) revealed leukoencephalopathy with ventriculomegaly. The peculiarity of this observation is that the polysomy 49, XXXXX detected in the patient is characterized by a typical phenotypic presentation combined with demyelinating leukoencephalopathy, which has not been a typical feature of the disorder.

Leukoencephalopathy with cerebral calcifications and cysts: the neurosurgical perspective. Literature review.

PURPOSE: Labrune syndrome is a rare white matter disease characterised by angiomatous leukoencephalopathy, diffuse intracranial calcifications and supra- and infra-tentorial parenchymal cysts. The clinical worsening is often related to cyst expansion, and surgery may be advocated for symptomatic management in about one-third of cases. However, no consensus exists on surgical timing, the most effective procedure, and long-term results. MATERIAL AND METHODS: Electronic databases, such as PubMed/ MEDLINE and Google Scholar, were analysed for studies published to April 2022 using the search term "Labrune syndrome OR leukoencephalopathy with calcifications and cysts OR brain calcifications OR brain cysts AND therapy OR surgery RESULTS: We found 28 studies reported in the literature, and we added a new case we treated at our Institution, reaching a series of 37 patients. All the patients in this series underwent surgical intervention. We aimed to review all the pertinent literature to discuss clinical-radiological features and etiopathogenetic insights, addressing the specific issue of the surgical options, clinical results and prognosis. CONCLUSION: LCC is a rare neurodegenerative disorder without effective medical treatment. Surgery remains the only therapeutic option to control the disease to reduce the mass effect of growing cystic lesions. Almost half of the patients who underwent surgery required further approaches, with great concern for the associated disabilities. Several procedures have been described, with no evidence of the most effective. Individual-based surgical planning must be advocated, tailoring the approach to limit side effects. Mini-invasive neuroendoscopic approaches may be considered to achieve those satisfactory results.

Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S).

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S. METHODS: vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls. RESULTS: While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056). CONCLUSIONS: These findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.

Atypical Demyelinating Disorders: MR Imaging Features, Atypical Triggers, and Etiopathogenesis.

Atypical demyelinating lesions (ADLs) can be idiopathic, occurring as isolated and self-limited events, or can appear in different stages of relapsing demyelinating diseases. Not infrequently, ADLs occur in inflammatory syndromes associated with exogenous or endogenous toxic factors, metabolic imbalance, or infectious agents. It is important to recognize imaging patterns that indicate an inflammatory/demyelinating substrate in central nervous system lesions and to investigate potential triggers or complicating factors that might be associated. The prognostic and treatment strategies of ADLs are influenced by the underlying etiopathogenesis.

Routine MR Imaging Protocol and Standardization in Central Nervous System Demyelinating Diseases.

Standardized MR imaging protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS) and the appropriate use of MR imaging in routine clinical practice. Advances in using MR imaging to establish an earlier diagnosis of MS, safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MR imaging for diagnostic, prognostic, and monitoring purposes suggest a changing role of MR imaging for the management and care of MS patients. The MR imaging protocol emphasizes 3 dimensional acquisitions for optimal comparison over time.

Symmetric leukoencephalopathy associated with systemic lupus erythematosus: A systematic review of a distinctive neurorheumatologic syndrome.

BACKGROUND: A symmetric leukoencephalopathy can occur in the context of systemic lupus erythematosus (SLE), often as a first manifestation of underlying rheumatologic disease. Recognition of this distinctive syndrome can prompt investigation for SLE when undiagnosed, or prompt treatment initiation when the diagnosis is already known. Earlier recognition of this syndrome could lead to more effective treatment of the disease. METHODS: Clinical, laboratory, and radiographic features of three patients were described from an academic medical center in the United States with treatment dates between 2015 and 2022. A systematic review of literature from 1991 to 2023 yielded data for an additional 23 patients. RESULTS: Twenty-six total patients with symmetric leukoencephalopathy were included in this study. The median age of the patients was 37 years (range 10-69), 22 patients (85 %) were female, and 4 (15 %) were male. Fourteen of 26 patients (54 %) had this as the first clinical manifestation of SLE. Contrast enhancement was present on MRI brain in 3/26 (88 %) patients. Twenty patients (77 %) were treated with pulse-dose steroids, and all but one patient received some immunomodulatory therapy. Seven patients (27 %) progressed to death. No meaningful predictive differences were found between patients who survived and those who did not. CONCLUSIONS: In this case series and literature review patients developed symmetric leukoencephalopathy in systemic lupus erythematosus most often as the first clinical manifestation of SLE. Clinicians should consider this syndrome in any patient with acute onset of symmetric leukoencephalopathy on brain magnetic resonance imaging.

Adult-onset leukoencephalopathy with vanishing white matter with compound heterozygous EIF2B3 gene variants.

BACKGROUND: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive disorder affecting the white matter of the brain. It typically manifests during childhood, with clinical features including sudden and severe neurological deterioration triggered by stressors such as febrile illness, minor head trauma, or stressful events. Adult-onset cases of VWM are exceptionally uncommon. CASE PRESENTATION: In this case, we present an adult patient who exhibited late-onset progressive VWM characterized by ataxia, postural instability, cognitive impairment, and emotional disturbances. Comprehensive screening for endocrine, metabolic, tumor, and immunologic disorders yielded normal or negative results. Brain imaging revealed diffuse and confluent hyperintensity in the white matter on T2-weighted images, along with periventricular cavitations. Genetic testing confirmed the diagnosis of VWM, identifying two heterozygous variants in the eukaryotic translation initiation factor 2B subunit γ (EIF2B3) gene: a pathogenic variant, c.1037 T > C (p.I346T), and a variant of undetermined significance, c.22A > T (p.M8L). Upon a 2-year follow-up, the patient's symptoms deteriorated rapidly following a COVID-19 infection. CONCLUSIONS: In conclusion, we have presented a case of classical adult-onset VWM. Since there are no cures or definitive treatments for the disease, it's extremely important to focus on early diagnosis and the prevention of stressors to avoid acute deterioration.

Nailfold capillary measurements correlated to NOTCH3 R544C mutation in preclinical CADASIL patients.

BACKGROUND: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by NOTCH3 mutation. Nailfold capillaroscopy is a non-invasive technique typically used for rheumatic diseases. It has potential in other conditions linked to vascular pathology. However, capillaroscopy in CADASIL has not been explored. This study aims to investigate whether capillaroscopy measurements can correlate with brain vascular changes in preclinical CADASIL patients, specifically those with NOTCH3 mutation. METHODS: This study included 69 participants from the Taiwan Precision Medicine Initiative (TPMI) dataset who visited Taichung Veterans General Hospital from January to December 2022. All individuals underwent genetic studies, brain imaging and nailfold capillaroscopy. The Mann-Whitney U test was used to compare results of brain imaging between carriers and controls. It was also used to compare measurements in nailfold capillaroscopy within each group. Spearman Rank Correlation Analysis was used to explore the relationship between capillary measurements and brain MRI results. RESULTS: White matter hyperintensities (WMH) expression was positively correlated with capillary dimension and negatively correlated with density. Our results presented that R544C carriers exhibited a diffuse increase in WMH (p < 0.001) and a global reduction in gray matter volume but preserved in specific areas. The white matter lesion scores in all brain regions were higher in the mutation carriers than the controls. (p < 0.001). CONCLUSION: This research highlights the association of nailfold capillaroscopy findings with white matter lesions in preclinical CADASIL patients. Capillaroscopy guides an effective screening strategy in individuals with NOTCH3 mutations.

A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype.

Cytochrome c oxidase (COX) deficiency is a phenotypically diverse group of diseases caused by variants in over 30 genes. Biallelic pathogenic variants in COX6B1 have been described in four patients to date with varying disease manifestations. We describe the clinical features and follow-up of a patient with a novel homozygous pathogenic variant in COX6B1 who presented acutely with severe encephalomyopathy associated with an infection. New findings include ophthalmological evaluation and follow-up of neuroradiological investigations. The novel p.Trp31Arg variant was predicted to be pathogenic in silico, and further functional analyses with biochemical analysis of mitochondrial function showed isolated COX deficiency. Muscle biopsy showed a specific lack of COX6B1 protein together with complex IV deficiency on western blot, enzyme histochemistry, and immuno-histochemistry.

A case of a cerebellar form of progressive multifocal leukoencephalopathy in a patient undergoing peritoneal dialysis.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system, is caused by the reactivation of the polyomavirus JC virus (JCV). It favors the cerebrum and typically occurs in patients with immunodeficiencies, with a progressive course and fatal outcome in the majority of cases. However, the cerebellar form of PML, characterized by isolated posterior fossa lesions, such as those in the cerebellum or brainstem at disease onset, is rare, and reports of its occurrence in peritoneal dialysis (PD) patients are lacking. In this paper, we describe a rare case of a cerebellar form of PML in a PD patient. A 64-year-old man undergoing PD was referred to our hospital for anorexia, nausea, and vomiting in the past month. He had finger-to-nose test abnormalities, gaze-directed nystagmus, and scanning speech. He was diagnosed with the cerebellar form of PML based on his progressive cerebellar symptoms, the typical magnetic resonance imaging findings, and the presence of JCV-DNA in the cerebrospinal fluid polymerase chain reaction test. He developed nocturnal delirium, aggravated disquiet, and died of pneumonia on the 69th day. Clinicians should consider the cerebellar form of PML as a differential diagnosis if PD patients develop progressive cerebellar symptoms.

Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

Chemokine-mediated cell migration into the central nervous system in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.

Identification and characterization of a novel intronic splicing mutation in CSF1R-related leukoencephalopathy.

AIMS: Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressing neurodegenerative disease caused by CSF1R gene mutations. This study aimed to identify and investigate the effect of a novel intronic mutation (c.1754-3C>G) of CSF1R on splicing. METHODS: A novel intronic mutation was identified using whole-exome sequencing. To investigate the impact of this mutation, we employed various bioinformatics tools to analyze the transcription of the CSF1R gene and the three-dimensional structure of its encoded protein. Furthermore, reverse transcription polymerase chain reaction (RT-PCR) was performed to validate the findings. RESULTS: A novel mutation (c.1754-3C>G) in CSF1R was identified, which results in exon 13 skipping due to the disruption of the 3' splice site consensus sequence NYAG/G. This exon skipping event was further validated in the peripheral blood of the mutation carrier through RT-PCR and Sanger sequencing. Protein structure prediction indicated a disruption in the tyrosine kinase domain, with the truncated protein showing significant structural alterations. CONCLUSIONS: Our findings underscore the importance of intronic mis-splicing mutations in the diagnosis and management of CSF1R-related leukoencephalopathy.