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.

Progressive leukoencephalopathy as a manifestation of primary angiitis of the central nervous system: case report and review of the literature.

BACKGROUND AND OBJECTIVE: Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis solely affecting the vessels of the brain, spinal cord, and leptomeninges. A range of magnetic resonance imaging (MRI) features have been associated with PACNS, including cerebral infarction, hemorrhage, and parenchymal or leptomeningeal contrast enhancement. METHODS AND RESULTS: We describe a 51-year-old man with a case of PACNS manifesting as akinetic mutism with progressive leukoencephalopathy. DISCUSSION: Progressive leukoencephalopathy has not been well defined as a manifestation of PACNS. We review a small number of cases with comparable features, providing additional context on this PACNS manifestation with consideration of clinical subtypes.

Disseminating Necrotizing Leukoencephalopathy Associated With Intra-CSF Methotrexate Chemotherapy: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: Leptomeningeal metastases (LMs) are neoplasms that proliferate to membranes lining the brain and spinal cord. Intra-CSF methotrexate (MTX) chemotherapy is a prevalent treatment option. However, resultant long-term neurotoxicity can lead to irreversible disseminated necrotizing leukoencephalopathy (DNL). This study aims to determine the incidence, characteristics, risk factors, and outcomes of DNL following intra-CSF MTX chemotherapy for LM. METHODS: We retrospectively reviewed patients with LM who received intra-CSF MTX between 2001 and 2021 at the National Cancer Center of Korea. Patients with a follow-up duration of <3 months and those without follow-up MRI after MTX administration were excluded. The primary outcome was the development of DNL, evaluated based on the clinical and radiologic definitions of DNL. Logistic and Cox proportional regression models were used to assess the risk of DNL in patients with LM receiving intra-CSF MTX chemotherapy. RESULTS: Of the 577 patients included in the DNL investigation, 13 (2.3%) were identified to have irreversible DNL. The MRI features of DNL typically include necrotic changes in the bilateral anterior temporal region, extensive white matter, and/or brainstem lesions. All patients with DNL experienced fatal clinical course despite MTX cessation. Logistic regression analysis revealed that a cumulative dose of MTX significantly affected DNL occurrence. Multivariable analysis showed that the factor of ≥10 MTX rounds was significant for DNL development after adjusting for route of MTX administration and prior brain radiotherapy (odds ratio 7.32, 95% CI 1.42-37.77 at MTX rounds ≥10 vs < 10). In the Cox proportional hazards model considering time to occurrence of DNL, ≥10 rounds of MTX were identified as an independent predictor of DNL (hazard ratio 12.57, 95% CI 1.62-97.28, p = 0.015), even after adjusting for the synergistic effect of brain radiotherapy. DISCUSSION: DNL is a rare but fatal complication of intra-CSF MTX chemotherapy, and its progression cannot be prevented despite early recognition. The cumulative dose of intra-CSF MTX was an independent risk factor for DNL occurrence. Thus, intra-CSF MTX treatment for patients with LM should be administered with caution considering the possibility of the cumulative irreversible neurotoxicity.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders.

BACKGROUND: The pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders. METHODS: The participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2-3. RESULTS: Among the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration. CONCLUSION: There is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Increased risk for ex-vacuo ventriculomegaly with leukoencephalopathy (EVL) in whole brain radiation therapy and repeat radiosurgery treated brain metastasis patients.

INTRODUCTION: Cerebral atrophy with leukoencephalopathy is a known morbidity after whole brain radiation therapy (WBRT), resulting in ex-vacuo ventriculomegaly with leukoencephalopathy (EVL). Here we studied the correlation between WBRT, stereotactic radiosurgery (SRS), and risk for EVL in brain metastases patients. METHODS: In a retrospective study, we identified 195 patients (with 1,018 BM) who underwent SRS for BM (2007-2017) and had > 3 months of MRI follow-up. All patients who underwent ventriculoperitoneal shunting were excluded. Cerebral atrophy was measured by ex-vacuo-ventriculomegaly, defined based on Evans' criteria. Demographic and clinical variables were analyzed using logistic regression models. RESULTS: Ex-vacuo ventriculomegaly was observed on pre-radiosurgery imaging in 29.7% (58/195) of the study cohort. On multivariate analysis, older age was the only variable associated with pre-radiosurgery ventriculomegaly. Of the 137 patients with normal ventricular size before radiosurgery, 27 (19.7 %) developed ex-vacuo ventriculomegaly and leukoencephalopathy (EVL) post-SRS. In univariate analysis, previous whole brain radiation therapy was the main factor associated with increased risk for developing EVL (OR = 5.08, p < 0.001). In bivariate models that included prior receipt of WBRT, both the number of SRS treatments (OR = 1.499, p = 0.025) and WBRT (OR = 11.321, p = 0.003 were independently associated with increased EVL risk. CONCLUSIONS: While repeat radiosurgery contributes to the risk of EVL in BM patients, this risk is ∼20-fold lower than that associated with WBRT.

FOLFIRI-bevacizumab-induced acute toxic leukoencephalopathy.

INTRODUCTION: Acute toxic leukoencephalopathy (ATL) is a rare complication of cancer treatment, with symptoms varying from mild cognitive impairment to coma. Recognition and management of ATL are important because in most cases, the cessation of the responsible agent is essential. CASE REPORT: We report a case of a 57-year-old male with relapsed right colon cancer who had multiple steps of chemotherapy, admitted to the emergency department (ED) with confusion and inability to talk, 4 days after FOLFIRI and bevacizumab treatment. To exclude cerebrovascular events cranial computed tomography and diffusion-weighted magnetic resonance imaging were evaluated. There was bilateral and symmetric diffusion restriction on white matter, which was consistent with ATL. MANAGEMENT AND OUTCOME: Supportive treatment such as optimization of blood pressure and metabolic control was applied since there is no specific treatment for ATL other than cessation of the responsible agents. 12 days after the admission to the ED his neurologic symptoms were normalized and there was no diffusion restriction on control imaging. DISCUSSION: ATL is a rare complication of cancer treatment and responsible agents are increasing in number due to the development of cancer treatment. ATL is associated with drugs that are used frequently such as 5-fluorouracil. ATL is mostly reversible, but the progression of neurologic symptoms was also reported. The diagnosis and cessation of the responsible agent are important in management.

Leukoencephalopathy with calcifications and cysts: A case report with literature review.

Leukoencephalopathy with calcifications and cysts (LCC; OMIM #614561) is a rare disease and at present there are less than 100 cases reported worldwide. Mutations in the SNORD118 gene is now known to be the cause of LCC. We present a case who was heterozygous for the n.70G>A and n.6C>T sequence variants of the SNORD118 gene, variants which to date have not been described. Compared with the cases that we reviewed, our patient had the second longest time to diagnosis (age 56) from onset of symptoms 40 years prior. Moreover, his cousin's family has a high prevalence of epilepsy. This paper reviewed all published reports to date that had descriptive cases involving LCC as well as testing for the SNORD118 gene. Since 1996 only 85 patients have been described in 59 case reports. In this review, we summarize their clinical features, especially central nervous system symptoms, treatment, pathology, and gene testing results.

Fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome: a case report.

BACKGROUND: Fluorouracil-induced leukoencephalopathy is a rare complication and has been reported to present as confusion, oculomotor abnormality, ataxia, and parkinsonism; however, there is no previous report of a presentation mimicking neuroleptic malignant syndrome. Acute cerebellar syndrome may occur, which can be explained by the extremely high accumulation of the drug in the cerebellum. However, presentation mimicking neuroleptic malignant syndrome similar to our case has never been reported. CASE PRESENTATION: Here, we describe a 68-year-old Thai male presenting with advanced-stage cecal adenocarcinoma, as well as symptoms and signs indicative of neuroleptic malignant syndrome. He received two doses of intravenous metoclopramide 10 mg 6 hours before his symptoms occurred. Magnetic resonance imaging scan revealed signal hyperintensity within the bilateral white matter. Further evaluation showed that his thiamine level was extremely low. Thus, he was diagnosed with fluorouracil-induced leukoencephalopathy mimicking neuroleptic malignant syndrome. The concomitant fluorouracil-induced thiamine deficiency eventually leads to rapid depletion of thiamine and was considered a risk factor for fluorouracil-induced leukoencephalopathy. CONCLUSION: Fluorouracil-induced leukoencephalopathy is believed to be caused by insult causing mitochondrial dysfunction. However, the exact mechanism remains unknown, but our finding suggests that thiamine deficiency plays a crucial role in fluorouracil-induced leukoencephalopathy. Diagnosis is usually delayed due to a lack of clinical suspicion and results in significant morbidity requiring unnecessary investigations.

Novel partial deletions, frameshift and missense mutations of CSF1R in patents with CSF1R-related leukoencephalopathy.

BACKGROUND AND PURPOSE: Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: CSF1R mutations were identified in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C-terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. CONCLUSIONS: Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

The Coexistence of Two Genetic Astrocytopathies-Megalencephalic Leukoencephalopathy and Vanishing White Matter Disease-in an Indian Child.

A 9-month-old male child, born of second-degree consanguinity, presented with a progressively enlarging head since early infancy. The child had normal early development, but further acquisition of milestones after 6 months was delayed. He had afebrile seizures at 9 months, followed by the appearance of appendicular spasticity. First magnetic resonance imaging (MRI) showed nonenhancing, diffuse, bilaterally symmetrical T1/fluid-attenuated inversion recovery (FLAIR) hypointensity and T2 hyperintensity of the cerebral white matter and anterior temporal cysts. Subsequently, the periventricular and deep white matter developed microcystic changes with a pattern of radial stripes. Next-generation sequencing revealed homozygous autosomal recessive variations in the MLC1 gene [c.188T > G, (p.Leu63Arg)] on exon 3 and also in the EIF2B3 gene [c.674G > A, (p.Arg225Gln)] on exon 7, the parents being heterozygous carriers for both variations. This article highlights the rare occurrence of two leukodystrophies of diverse pathogenesis in a child from a nonpredisposed community.

Juxtacortical White Matter Hypointensity on T2*Gradient Echo Image in Vanishing White Matter Disease: A Case Report.

BACKGROUND Vanishing white matter disease (VWMD) - also known as childhood ataxia with central nervous system hypomyelination - is one of the most commonly inherited white matter diseases in children. Notably, a course of chronic progressive disease with episodes of rapid and major stress-induced neurological deterioration, such as fever and minor head trauma, is a typical clinical feature of VWMD. The combination of clinical features with specific magnetic resonance imaging findings, including diffuse and extensive white matter lesions with rarefaction or cystic destruction, could recommend a genetic diagnosis. However, VWMD is phenotypically diverse and can affect individuals of all ages. CASE REPORT A 29-year-old female patient presented with recent aggravation in gait disturbance. She had progressive movement disorder, with symptoms ranging from hand tremors to upper- and lower-extremity weakness, for 5 years. Whole-exome sequencing was performed to confirm the diagnosis of VWMD, and it revealed a mutation in homozygous eIF2B2 gene. The temporal evolution of VWMD observed in the patient for 17 years (from the age of 12 to 29 years) indicated an increased extent of T2 white matter hyperintensity in the cerebrum into the cerebellum and an increased amount of dark signal intensities in the globus pallidus and dentate nucleus. Moreover, a T2*-weighted imaging (WI) scan revealed diffuse, linear, and symmetrical hypointensity along the juxtacortical white matter on the magnification view. CONCLUSIONS This is the case report about rare and unusual finding of diffuse linear juxtacortical white matter hypointensity on T2*-WI scan as a potential radiographic marker for adult-onset VWMD.

LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes.

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Magnetic resonance imaging of disorders with white matter changes in children and adolescents: a pictorial essay.

White matter changes are seen in a spectrum of disorders in children and adolescents. Understanding their distribution and appearance helps to reach diagnoses in daily radiologic practice. This pictorial essay will outline the magnetic resonance imaging (MRI) appearances of diseases with white matter changes including demyelinating diseases, dysmyelinating disorders/leukodystrophies, infections, autoimmune diseases, vascular causes, mitochondrial disorders and neurocutaneous syndromes, along with a brief overview of clinical aspects of the diseases such as typical age of presentation, etiology, symptoms and signs and treatment options. This article highlights important features in common white matter diseases in children and adolescents.

Cochlear implantation in a profoundly deaf child with cystic leukoencephalopathy without megalencephaly.

BACKGROUND: Cochlear implantation candidacy criteria have continued to evolve over the years, and cochlear implantation is possible with many inner-ear and brain anomalies with good hearing and linguistic outcomes. Cystic leukoencephalopathy without megalencephaly is a rare disease in children, with only 30 cases reported in the literature, but it is associated with hearing loss in only three cases. Radiological investigations can help in diagnosing this rare entity before proceeding with cochlear implantation. CASE REPORT: A four-year-old female child born out of consanguinity with normal psychomotor development, bilateral sensorineural hearing loss and an incidental magnetic resonance imaging finding of cystic leukoencephalopathy without megalencephaly underwent successful cochlear implantation. Her post-operative period was uneventful with successful mapping of the cochlear implant. CONCLUSION: This is the first reported case of cystic leukoencephalopathy without megalencephaly and with sensorineural hearing loss in which cochlear implantation was performed successfully. White matter and temporal lobe abnormalities should not deter paediatric cochlear implantation.

5-Fluorouracil-induced leukoencephalopathy.

ABSTRACT: The incidence of 5-Fluorouracil (5FU)- induced leukoencephalopathy is <5% among the patients treated with this agent. It may present with disorientation, confusion, agitation, seizure, and coma. It should be suspected when patients present with any of these symptoms during or immediately after 5FU chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the drug. Therefore, clinicians should be aware of the possibility of this adverse neurologic effect of 5FU. We describe the case of a 35-year-old female with carcinoma esophagus with 5FU-induced leukoencephalopathy.