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Labrune syndrome is an uncommon central nervous system disorder characterized by leukoencephalopathy, cerebral calcifications, and cysts on brain imaging. The basic pathology is microangiopathy resulting from a mutation in the SNORD118 gene. Radiological imaging is the hallmark of the disease., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present the case of a patient with leukoencephalopathy with calcifications and cysts (LCC), who experienced progressive severe hemiparesis despite multiple neurosurgical interventions of a large contralateral cyst. Bevacizumab was proposed as an ultimate treatment option based on prior case reports. While awaiting reimbursement approval for bevacizumab, major improvement occurred in both clinical and radiological disease manifestations. The disease course of LCC is variable and unpredictable; neurosurgical treatment should be reserved for severe and progressive neurological deficits. Bevacizumab has been reported as a promising alternative treatment option. Importantly, in our case the observed clinical improvement would have been attributed to the effects of bevacizumab, if started when requested. Our case underscores the need for a natural history study for LCC and the necessity of validating treatment efficacy by systematic evaluation through appropriate clinical trials rather than relying on anecdotal evidence from published case reports., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one kind of monogenic hereditary small-vessel disease in the brain caused by mutations in the NOTCH3 gene. However, it is rare for CADASIL to recur with different clinical manifestations in 1 patient, and some atypical clinical manifestations can easily lead to misdiagnosis by clinical physicians., Case Concern: A 34-year-old male presented with transient speech disorder accompanied by weakness in the left side of the body for 1 day in June 2020. Magnetic resonance imaging showed acute ischemic infarction in right centrum semiovale, along with multiple abnormal white matter hyperintensities in the brain. Genetic sequencing identified a heterozygous mutation in the NOTCH3 gene. The patient experienced recurrent episodes in 2021 and 2023, with varying clinical symptoms including visual blurring, abnormal limb sensation, and sudden cognitive dysfunction., Diagnosis: The diagnoses of CADASIL is based on clinical manifestations, imaging results, and genetic reports., Intervision and Outcomes: The patient was received symptomatic treatment including antiplatelet aggregation therapy, lipid regulation, and plaque stabilization, resulting in improved symptoms., Outcomes: During the course of the disease, after medication treatment and rehabilitation exercise, the patient clinical symptoms have significantly improved. Currently, the patient is closely following up and regularly undergoing relevant examinations., Lessons: In this rare case, we found that CADASIL can recur multiple times in a patient with different clinical symptoms, which can easily lead to clinical misdiagnosis. Clinicians should consider the possibility of CADASIL in young patients with sudden typical neurological dysfunction., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The increased risk of dementia after delirium and infection might be influenced by cerebral white matter disease (WMD). In patients with transient ischaemic attack (TIA) and minor stroke, we assessed associations between hospital admissions with delirium and 5-year dementia risk and between admissions with infection and dementia risk, stratified by WMD severity (moderate or severe vs absent or mild) on baseline brain imaging., Methods: We included patients with TIA and minor stroke (National Institutes of Health Stroke Score <3) from the Oxford Vascular Study (OXVASC), a longitudinal population-based study of the incidence and outcomes of acute vascular events in a population of 94 567 individuals, with no age restrictions, attending eight general practices in Oxfordshire, UK. Hospitalisation data were obtained through linkage to the Oxford Cognitive Comorbidity, Frailty, and Ageing Research Database-Electronic Patient Records (ORCHARD-EPR). Brain imaging was done using CT and MRI, and WMD was prospectively graded according to the age-related white matter changes (ARWMC) scale and categorised into absent, mild, moderate, or severe WMD. Delirium and infection were defined by ICD-10 coding supplemented by hand-searching of hospital records. Dementia was diagnosed using clinical or cognitive assessment, medical records, and death certificates. Associations between hospitalisation with delirium and hospitalisation with infection, and post-event dementia were assessed using time-varying Cox analysis with multivariable adjustment, and all models were stratified by WMD severity., Findings: From April 1, 2002, to March 31, 2012, 1369 individuals were prospectively recruited into the study. Of 1369 patients (655 with TIA and 714 with minor stroke, mean age 72 [SD 13] years, 674 female and 695 male, and 364 with moderate or severe WMD), 209 (15%) developed dementia. Hospitalisation during follow-up occurred in 891 (65%) patients of whom 103 (12%) had at least one delirium episode and 236 (26%) had at least one infection episode. Hospitalisation without delirium or infection did not predict subsequent dementia (HR 1·01, 95% CI 0·86-1·20). In contrast, hospitalisation with delirium predicted subsequent dementia independently of infection in patients with and without WMD (2·64, 1·47-4·74; p=0·0013 vs 3·41, 1·91-6·09; p<0·0001) especially in those with unimpaired baseline cognition (cognitive test score above cutoff; 4·01, 2·23-7·19 vs 3·94, 1·95-7·93; both p≤0·0001). However, hospitalisation with infection only predicted dementia in those with moderate or severe WMD (1·75, 1·04-2·94 vs 0·68, 0·39-1·20; p diff =0·023)., Interpretation: The increased risk of dementia after delirium is unrelated to the presence of WMD, whereas infection increases risk only in patients with WMD, suggesting differences in underlying mechanisms and in potential preventive strategies., Funding: National Institute for Health and Care Research and Wellcome Trust., Competing Interests: Declaration of interests STP has received honoraria from the Neurotorium Foundation, Universities of Trondheim, Sydney, LaTrobe and Michigan, and Ann Arbor and has received royalties from Oxford University Press and Cambridge University Press. STP is supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre and NIHR i4i programme grant NIHR204290. PMR has received royalties from Oxford University Press and Cambridge University Press and is supported by the NIHR Oxford Biomedical Research Centre and the Wellcome Trust. R L-F is funded by PMR's Wellcome Trust Investigator award. STP, RL-F, and PMR have accessed and verified the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. STP and PMR had final responsibility to submit for publication., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We report on a patient with delayed post-hypoxic leukoencephalopathy (DPHL) who showed akinetic mutism and gait disturbance, neural injuries that were demonstrated on diffusion tensor tractography (DTT). A patient was exposed to carbon monoxide (CO) and rapidly recovered; however, two weeks after onset, he began to show cognitive impairment and gait disturbance. At six weeks after CO exposure, he showed akinetic mutism and gait inability. DTT at 6-weeks post-exposure showed discontinuations in neural connectivities of the caudate nucleus to the medial prefrontal and orbitofrontal cortex in both hemispheres. In addition, the corticoreticulospinal tract revealed severe thinning in both hemispheres.

Competing Interests: Declaration of competing interest The authors have no relevant financial or nonfinancial interests to disclose. The authors have no competing interests to declare relevant to this article's content.

A patient in her 50s presented with altered mental status and shortness of breath at 4600 m elevation. After descent to the base of the mountain, the patient became comatose. She was found to have bilateral pulmonary infiltrates and a serum sodium of 102 mEq/L. She was rapidly corrected to 131 mEq/L in 1 day. Initial MRI showed intensities in bilateral hippocampi, temporal cortex and insula. A repeat MRI 17 days post injury showed worsened intensities in the bilateral occipital lobes. On admission to acute rehabilitation, the patient presented with blindness, agitation, hallucinations and an inability to follow commands. Midway through her rehabilitation course, antioxidant supplementations were started with significant improvement in function. Rapid correction of hyponatraemia may cause central pontine myelinolysis or extrapontine myelinolysis (EPM). In some cases of hypoxic brain injury, delayed post-hypoxic leucoencephalopathy (DPHL) may occur. Treatment options for both disorders are generally supportive. This report represents the only documented interdisciplinary approach to treatment of a patient with DPHL and EPM. Antioxidant supplementation may be beneficial as a treatment option for both EPM and DPHL., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Mutations in type IV collagen gene COL4A1 are identified as a cause of autosomal dominant cerebrovascular disease. We report an unusual late-onset presentation., Case Report: A 64-year-old male was found to have an ischemic stroke and diffuse white matter changes. Genetic testing revealed COL4A1 gene mutation of heterozygous Alu insertion at intron 16. Alu elements are known as "jumping genes," and Alu insertion is not previously reported in COL4A1 genetic syndromes. Our case has attributes consistent with a heritable leukoencephalopathy: (1) late-onset presentation, (2) intracerebral hemorrhages and microbleeds, (3) bilateral symmetrical leukoencephalopathy, (4) recurrence over a short period of time, (5) bilateral retinopathy, and (6) family history notable for brain aneurysm, kidney diseases, and early-onset stroke., Conclusions: Although the majority of COL4A1 genetic syndromes featuring cerebral small vessel disease are in children, this case highlights a late-onset patient with key features of COL4A1 syndromes associated with a heterozygous Alu intronic insertion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.

Rationale: Toxic leukoencephalopathy, a condition resulting from exposure to toxic substances, can lead to malignant catatonia, a severe motor dysfunction with symptoms such as muscle rigidity and high-spiking fever, hypertensive urgency, and tachycardia. This case study investigates the relationship between toxic leukoencephalopathy-induced malignant catatonia and heart rate variability (HRV), a marker of autonomic nervous system function., Patient Concerns: A 51-year-old male presented to the emergency department with acute onset of progressively worsening mental status., Diagnoses: The patient was diagnosed with cocaine-induced toxic leukoencephalopathy causing malignant catatonia., Interventions: A 5-day escalating treatment regimen was instituted for the management of malignant catatonia until resolution. Daily HRV parameters in the temporal and frequency domain, geometric data, and cardiac entropy were recorded using HRVAnalysis v.1.2 (ANS Lab Tools). The HRV analysis was correlated with pharmacologic management, the Bush-Francis catatonia rating scale, and hemodynamic parameters, including blood pressure, heart rate, and temperature., Outcomes: The results showed a correlation between the severity and frequency of malignant catatonic episodes and the patient autonomic dysfunction. Improvement in malignant catatonia with pharmacological management was associated with an improved HRV, including elevated rMSSD, SDNN, cardiac entropy, and pNN50%., Lessons: Malignant catatonia is associated with decreased HRV, and its management is associated with an increase. This suggests a link between malignant catatonia and autonomic dysfunction, highlighting the potential benefits of treating malignant catatonia to improve autonomic function and reduce cardiovascular risk., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

A 30-year-old woman developed symptoms, signs and neurophysiology consistent with Guillain-Barré syndrome and was admitted to the neurosciences intensive care unit owing to respiratory compromise. Here, she received a clonidine infusion for agitation, complicated by a minor hypotensive episode, following which she became unconscious. MR scan of the brain showed changes compatible with hypoxic brain injury. Urinary amino acids showed increased urinary α-ketoglutarate. Genetic testing using whole-exome sequencing identified pathogenic variants in the SLC13A3 gene known to be associated with an acute reversible leukoencephalopathy with increased urinary α-ketoglutarate. The case highlights the importance of considering inborn errors of metabolism in cases of unexplained encephalopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Phenylketonuria (PKU) is the most prevalent congenital disease of amino acid metabolism. Neurological manifestations usually complicate PKU in untreated adult patients. This study describes neurological and imaging phenotypes of adult patients with untreated PKU., Methods: We investigated a cohort of 320 unrelated adult patients with suspected genetic leukoencephalopathies using whole-exome sequencing (WES). We analyzed the phenotypic features of adult PKU patients in our cohort and summarized cases reported in the literature., Results: We identified 10 patients in our cohort and 12 patients in the literature, who presented with neurological manifestations and were diagnosed with PKU in adulthood. Approximately 60% of these patients had onset of clinical features in adulthood. The most common neurological symptoms of patients presenting in adulthood were cognitive disturbance and spastic paralysis, followed by vision loss, cerebellar ataxia, weakness of limbs, and seizure. This differed from that of patients presenting with PKU features in childhood, who consistently had mental retardation with various neurological complications emerging during a broad age range. Imaging findings were similar between patients presenting with clinical features in childhood compared with adulthood, comprising symmetric periventricular white matter hyperintense on T2-weighted imaging and diffusion-weighted imaging predominantly in the parietal and occipital lobes. Also, normal brain imaging and diffuse leukoencephalopathies were observed in both patient groups., Conclusion: PKU with clinical features presenting in adulthood is an atypical subtype and should be considered during diagnosis of adults with neurological symptoms and leukoencephalopathy. DWI seems to be most helpful to distinguish patients with PKU. Additionally, we demonstrate that PKU constitutes a part (3.1%) of adult genetic leukoencephalopathies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: There is an unmet need for the treatment of colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy., Objectives: To evaluate the association of glucocorticoids (GCs) with disease onset and progression in CSF1R variant carriers., Methods: Retrospective cohort study on CSF1R variants carriers (n = 41) whose medical records were collected at Mayo Clinic Florida from 2003 to 2023. We retrieved information on sex, ethnicity, family history, medications, disease onset, course and duration, neuroimaging features, and activities of daily living (ADL)., Results: Risk of developing symptoms was significantly lower for individuals who used GCs (n = 8) compared to individuals who did not (n = 33) (12.5% vs. 81.8%, hazard ratio [HR] = 0.10, P = 0.036). The risk of becoming dependent in ADL was markedly lower for the GCs group (0.0% vs. 43.8%, P = 0.006). White matter lesions and corpus callosum involvement were less common in the GCs group (62.5% vs. 96.6%, P = 0.026; 37.5% vs. 84.6%, P = 0.017; respectively)., Conclusions: We found a protective association of GCs in CSF1R variant carriers against developing CSF1R-related leukoencephalopathy. We call for further studies to validate our findings and investigate the potential application of GCs in CSF1R-related leukoencephalopathy. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Competing Interests: Competing interests: None declared.

Rationale: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is the most common subtype of mitochondrial encephalopathy. In the past, it was believed that most hereditary white matter lesions were lysosome storage disorders or peroxisome diseases. However, in recent years, white matter lesions have been increasingly regarded as a common feature of patients with mitochondrial diseases. In addition to stroke-like lesions, about half of the patients with MELAS reported white matter lesions in the brain., Patient Concerns: Herein, we provide a case of A 48-year-old female who presented with episodic loss of consciousness with twitching of extremities. Previous medical history revealed 10 years of history of epilepsy, 10 years of history of diabetes, a history of hearing loss, and unknown etiology. Ancillary findings included brain magnetic fluid-attenuated inversion recovery showed symmetrical lesions in the bilateral parietal lobe with high signal intensity at the edge, and high signal intensity in the bilateral occipital lobe, paraventricular white matter, corona radiata, and the center of semiovale., Diagnoses: Mitochondrial deoxyribonucleic acid gene sequencing returned A3243G point mutation and it supports the diagnosis of intracranial hypertension., Interventions: Considered the diagnosis of symptomatic epilepsy, the patient was treated with mechanical ventilation, midazolam, and levetiracetam, and the limb twitching symptoms were controlled. The patient was comatose, chronically bedridden, with gastrointestinal dysfunction, and was treated prophylactically with antibiotics against infection, parenteral nutrition, and other supportive measures. B vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone were given, and mechanical ventilation and midazolam were stopped after 8 days. He was discharged from the hospital on 30 days and continued symptomatic treatment with B-vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone, and antiepileptic treatment with levetiracetam, with outpatient follow-up., Outcomes: No further seizures were recorded and the patient recovered well., Lessons: MELAS syndrome without stroke-like episodes of diffuse posterior cerebral white matter lesions is rare in clinical practice, and the possibility of MELAS syndrome should be considered in symmetric posterior cerebral white matter lesions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

An 81-year-old woman was hospitalized with progressive consciousness disturbance. Blood tests showed acidemia with severe renal dysfunction, and a cerebral spinal fluid (CSF) test showed pleocytosis with myelin basic protein (MBP) elevation. Brain magnetic resonance imaging showed unilaterally dominant subcortical white matter lesions with lentiform fork sign on T2-weighted imaging. After initiating hemodialysis, her consciousness disturbance and white matter lesions improved, suggesting uremic encephalopathy (UE). Unilaterally dominant leukoencephalopathy and high pleocytosis with MBP elevation in CSF are less common than previously identified characteristics of UE. When unilateral leukoencephalopathy occurs in patients with renal failure, UE should be considered.

Background: Delayed post-hypoxic leukoencephalopathy is a rare entity following hypoxia. Clinical and radiological signs of delayed post-hypoxic leukoencephalopathy have not previously been reported following acute ischemic stroke., Case Presentation: We report a case of an 81-year-old Central European man who presented with a dissection-related occlusion of the left carotid artery. He showed clinical improvement immediately after endovascular stroke therapy, followed by a significant clinical and especially cognitive deterioration thereafter and a clinical recovery after several weeks. The clinical course of the patient was accompanied by morphological changes on magnetic resonance imaging characteristic of delayed post-hypoxic leukoencephalopathy; that is, strictly limited and localized unilaterally to the left anterior circulation., Conclusion: This case demonstrates that clinical symptoms and morphological changes on magnetic resonance imaging compatible with delayed post-hypoxic leukoencephalopathy do not necessarily only occur with global hypoxia, but can also occur in patients with a large vessel occlusion in the corresponding vascular territories., (© 2022. The Author(s).)

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder. The condition progresses relentlessly, with severe disability typically established within 6-14 years of symptom onset. There is no cure, and limited treatment options are available to slow disease progression. We describe the case of a 23-year-old woman with forgetfulness, unsteady gait, and falls. Neurologic examination revealed intermittent dystonic posturing of the right upper and lower limb when walking. The Addenbrooke's Cognitive Examination (ACE) score was 70/100. MRI sequences demonstrated frontal-predominant atrophy and extensive white matter hyperintensity. Differential diagnoses such as autoimmune, inflammatory, and neoplastic diseases were excluded, and a genetic diagnosis was considered. Lysosomal enzyme testing showed low arylsulfatase with elevated urinary sulfatides, and genetic testing revealed a homozygous pathogenic mutation in the ARSA gene securing a diagnosis of adult-onset MLD. A male sibling also had early cognitive impairment and was found to have the same mutation. Hematopoietic stem cell transplantation (HSCT) was offered after discussion with experts. The male sibling died of multiple complications after HSCT. The index patient is now 24 months after HSCT, and disease progression has halted. This case highlights the challenges in the accurate diagnosis of adult-onset leukoencephalopathies and explores potential treatment strategies. A stepwise approach to the differential diagnosis of white matter diseases is demonstrated. HSCT may be an effective treatment, but the significant complication rate needs to be carefully considered., (© 2022 American Academy of Neurology.)

Aim: To study the clinical and radiologic features of patients with capecitabine neurotoxicity., Methods: We performed a retrospective analysis and systematic review on the clinical and radiologic characteristics of all patients with capecitabine neurotoxicity reported in literature between 2003 and 2020., Results: 24 cases including our patient were retrospectively analysed, with their clinical and radiologic features summarized. Their median age was 59 years old (ranges from 31 to 82 years old). Encephalopathy was the predominant clinical symptom affecting more than half (15/24, 63%) of the patients. This was followed by cerebellar ataxia (10/24, 42%). Amongst the patients who had magnetic resonance imaging(MRI) brain imaging performed, majority of them (18/23, 78%) had acute radiologic abnormalities. Leukoencephalopathy was the commonest radiologic abnormality seen in more than half of the patients (15/23,65%). Despite the preponderance of female patients in our study, there were no significant statistical differences in the clinical and radiologic features. Short term prognosis was excellent with complete resolution of neurologic symptoms observed in nearly all of the patients (22/23, 96%)., Conclusion: Capecitabine-related neurotoxicity is an uncommon cause of toxic encephalopathy, with a predilection for females. Clinical features are non-specific, with encephalopathy being the commonest. Prognosis remains good with timely recognition, and cessation of capecitabine. Future research looking into other pathogenic pharmacogenetic processes should be conducted for further elucidation of these associations., Competing Interests: Declaration of Competing Interest None. All authors were involved in the writing and the review of this manuscript. We did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors report no conflicts of interest. This article has not been previously presented at scientific meetings in its present form, as an abstract, or in other relevant formats., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The complications of coronavirus disease 2019 (COVID-19), the clinical entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are not limited to the respiratory system. Leukoencephalopathy with microbleeds is increasingly seen in patients with COVID-19. New information is needed to delineate better the clinical implications of this infectious disease., Case Report: A 46-year-old man with confirmed SARS-CoV-2 infection was admitted to the intensive care unit (ICU) with severe COVID-19. After transfer to the general wards, the patient was noted drowsy, disorientated, with slow thinking and speech. A brain MRI showed bilateral symmetrical hyperintense lesions in the deep and subcortical whiter matter, involving the splenium of the corpus callosum, as well as multiple microhemorrhages implicating the splenium and subcortical white matter. No contrast-enhanced lesions were observed in brain CT or MRI. CSF analysis showed no abnormalities, including a negative rtRT-PCR for SARS-CoV-2. An outpatient follow-up visit showed near-complete clinical recovery and resolution of the hyperintense lesions on MRI, without microbleeds change., Conclusion: We present the case of a survivor of severe COVID-19 who presented diffuse posthypoxic leukoencephalopathy, and microbleeds masquerading as acute necrotizing encephalopathy. We postulate that this kind of cerebral vasogenic edema with microbleeds could be the consequence of hypoxia, inflammation, the prothrombotic state and medical interventions such as mechanical ventilation and anticoagulation.

Introduction: In stroke survivors with aphasia (SWA), differences in behavioral language performance have been observed between Black and White Americans. These racial differences in aphasia outcomes may reflect biological stroke severity, disparities in access to care, potential assessment bias, or interactions between these factors and race. Understanding the origin of disparities in aphasia outcomes is critical to any efforts to promote health equity among SWA. In this study, we explore aphasia outcomes by examining the relationship between race, socioeconomic status, and neurological factors in SWA., Method: Eighty-five chronic left-hemisphere SWA (31 Black, 54 White) participated in the study. The primary aphasia outcome measure was the Western Aphasia Battery-Revised (WAB-R). Lesion size was measured based on manual lesion segmentations. FLAIR and T2 images were scored for severity of white matter disease. Independent sample t-tests were used to determine differences by race in education, age, income, aphasia severity, white matter disease, and lesion size. A linear regression model was used to explore factors that predicted aphasia severity on the WAB-R., Result: Level of education and estimated income differed by race in our sample. For predictors of aphasia severity, the regression model revealed a significant effect of lesion size on WAB Aphasia Quotient and an interaction of race x lesion size, such that Black and White participants with small lesions had similar WAB scores, but in individuals with larger lesions, Black participants had lower WAB scores than White participants., Conclusion: We suggest two explanations for the difference between Black and White SWA in the relationship between lesion size and aphasia severity. First, the impact of disparities in access to rehabilitation after stroke may be more evident when a stroke is larger and causes significant aphasia. Additionally, an assessment bias in aphasia outcome measures may be more evident with increasing severity of aphasia. Future studies should further discern the drivers of observed disparities in aphasia outcomes in order to identify opportunities to improve equity in aphasia care., (Copyright © 2022. Published by Elsevier Inc.)

Objective: This study aimed to examine the relationship between covert cerebrovascular disease, comprised of covert brain infarction and white matter disease, discovered incidentally in routine care, and subsequent Parkinson disease., Methods: Patients were ≥50 years and received neuroimaging for non-stroke indications in the Kaiser Permanente Southern California system from 2009 to 2019. Natural language processing identified incidentally discovered covert brain infarction and white matter disease and classified white matter disease severity. The Parkinson disease outcome was defined as 2 ICD diagnosis codes., Results: 230,062 patients were included (median follow-up 3.72 years). A total of 1,941 Parkinson disease cases were identified (median time-to-event 2.35 years). Natural language processing identified covert cerebrovascular disease in 70,592 (30.7%) patients, 10,622 (4.6%) with covert brain infarction and 65,814 (28.6%) with white matter disease. After adjustment for known risk factors, white matter disease was associated with Parkinson disease (hazard ratio 1.67 [95%CI, 1.44, 1.93] for patients <70 years and 1.33 [1.18, 1.50] for those ≥70 years). Greater severity of white matter disease was associated with increased incidence of Parkinson disease(/1,000 person-years), from 1.52 (1.43, 1.61) in patients without white matter disease to 4.90 (3.86, 6.13) in those with severe disease. Findings were robust when more specific definitions of Parkinson disease were used. Covert brain infarction was not associated with Parkinson disease (adjusted hazard ratio = 1.05 [0.88, 1.24])., Interpretation: Incidentally discovered white matter disease was associated with subsequent Parkinson disease, an association strengthened with younger age and increased white matter disease severity. Incidentally discovered covert brain infarction did not appear to be associated with subsequent Parkinson disease. ANN NEUROL 2022;92:620-630., (© 2022 American Neurological Association.)

Background: Posterior reversible encephalopathy syndrome (PRES) is classically a reversible clinical radiographic syndrome associated with predominantly posterior leukoencephalopathy on neuroimaging. Magnetic resonance imaging (MRI) in adults demonstrates almost universally reversible parietal-occipital disease. We aimed to demonstrate in a cohort of children that "atypical" distribution is expected, acutely and on follow-up., Methods: A retrospective review of children diagnosed with PRES from 2010 to 2018 at our children's hospital was performed. All had MRI at diagnoses, with over half having follow-up MRIs. Images were reviewed by a neuroradiology-trained pediatric radiologist for confirmation of findings consistent with PRES/identification of involved regions., Results: Nineteen patients (aged zero to 18 years, 53% female) were included. Notably, two were infants. Nearly all had seizures; all had altered mental status and hypertension. Fifteen (84%) had MRI described as "atypical." Distribution of MRI findings was anatomically widespread, including nine with frontal findings. Twelve (63%) had follow-up imaging, of which approximately half remained abnormal., Conclusions: Pediatric PRES MRI findings were more often atypical at time of diagnosis. Vasogenic edema related to the acute phases of PRES typically resolved; however, follow-up imaging identified new volume loss in the areas affected. Two of our subjects were younger than 13 months, younger than typically described. Our series demonstrates that imaging distribution in children with PRES does not mirror the classical posterior, reversible distribution described in adults and continues the recent trend of identifying PRES in infants., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Homozygous or compound heterozygous mutations in the NAD(P)HX epimerase (NAXE) gene, cause early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy 1. This disorder is characterized by psychomotor regression, hypotonia, ataxia, respiratory insufficiency, tetraparesis, and seizures, leading to coma and death in early childhood. In this study, whole-exome sequencing was used to identify the pathogenic variant, followed by confirmation of identified variant in the proband and segregation analysis in the family by Sanger sequencing. Several in-silico prediction tools were employed to provide additional evidences on the pathogenicity of the identified variant. The proband was an affected 3-year-old boy presented with encephalopathy and developmental regression from Ardebil province, northwest of Iran. Additional clinical features were cognitive regression and a high level of lactate in CSF. The clinical presentation was suggestive of a mitochondrial disorder. In addition, his brother died at the age of 20 months old due to encephalopathy, seizures, developmental regression, and loss of consciousness. We found a novel homozygous missense variant within the NAXE gene, [NM&#95;144772.3:c.565G > A; p.(Gly189Ser)]. Applying different in-silico prediction tools and bioinformatics databases analysis showed that this variant is damaging. So far, seven mutations have been reported in the NAXE gene. In this study, we report the first mutation in the Iranian population and the eighth one in total for this gene., (© 2021. Belgian Neurological Society.)

Objective: To describe cerebral abnormalities and their risk factors in a contemporary cohort of infants born extremely premature after the introduction of routine cerebral magnetic resonance imaging (cMRI) at term-equivalent age., Study Design: All cMRI examinations performed during November 2017 and November 2020, based on a standardized neonatal cMRI protocol, were included into analysis. Pathologies were retrospectively classified into 3 categories: intraventricular hemorrhage (IVH), white matter disease, and cerebellar injuries., Results: A total of 198 cMRI examinations were available for analyses; 93 (47%) showed abnormalities, most frequently IVH (n = 65, 33%), followed by cerebellar injuries (n = 41, 21%), and white matter disease (n = 28, 14%). Severe abnormalities were found in 18% of patients (n = 36). Significant clinical risk factors for abnormalities on cMRI were lower Apgar scores, lower umbilical artery and first neonatal pH, asphyxia, blood culture-proven sepsis (especially late-onset), and prolonged need of respiratory support and supplemental oxygen., Conclusions: After routine cMRI, without preconfirmed pathology by cranial ultrasonography, low-grade IVH, noncystic white matter disease, and cerebellar injuries were the most frequently found abnormalities. The clinical value and long-term benefit of the detection of these low-grade pathologies have yet to be confirmed., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rotavirus infection has been reported to be associated with neonatal seizures with a diffuse and symmetrical diffusion restriction of periventricular white matter, namely, neonatal rotavirus-associated leukoencephalopathy. The extensive white matter injury seen in this cohort raises concerns about the long-term neurodevelopmental outcomes. In the present study, we prospectively assessed the neurodevelopmental outcomes of 13 patients with neonatal rotavirus-associated leukoencephalopathy at a median age of 26 months (range, 23-68 months). Neurodevelopmental outcomes were evaluated using a neurological examination, developmental evaluations, and magnetic resonance imaging (MRI) of the brain. Overall, 6 of the 13 patients (46%) had abnormal neurodevelopmental outcomes: 1 patient had mental retardation, visual-motor integration (VMI) dysfunction, cerebral palsy, and epilepsy; 1 patient had cerebral palsy and VMI dysfunction; remaining 4 patients had VMI dysfunction. Follow-up MRI in 12 of 13 patients showed an increased signal intensity on periventricular white matter in all patients. These findings suggested that neonatal rotavirus-associated leukoencephalopathy could not be assumed to be benign in long-term neurodevelopment, particularly in VMI function. Early intervention and long-term follow-up are necessary for these patients. Our findings raise caution for rotavirus infection in this vulnerable population for infants., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To assess the frequency of silent brain infarcts (SBIs) and white matter disease (WMD) and associations with stroke risk factors (RFs) in a real-world population., Patients and Methods: This was an observational study of patients 50 years or older in the Kaiser Permanente Southern California health system from January 1, 2009, through June 30, 2019, with head computed tomography or magnetic resonance imaging for nonstroke indications and no history of stroke, transient ischemic attack, or dementia. A natural language processing (NLP) algorithm was applied to the electronic health record to identify individuals with reported SBIs or WMD. Multivariable Poisson regression estimated risk ratios of demographic characteristics, RFs, and scan modality on the presence of SBIs or WMD., Results: Among 262,875 individuals, the NLP identified 13,154 (5.0%) with SBIs and 78,330 (29.8%) with WMD. Stroke RFs were highly prevalent. Advanced age was strongly associated with increased risk of SBIs (adjusted relative risks [aRRs], 1.90, 3.23, and 4.72 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s) and increased risk of WMD (aRRs, 1.79, 3.02, and 4.53 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s). Magnetic resonance imaging was associated with a reduced risk of SBIs (aRR, 0.87; 95% CI, 0.83 to 0.91) and an increased risk of WMD (aRR, 2.86; 95% CI, 2.83 to 2.90). Stroke RFs had modest associations with increased risk of SBIs or WMD., Conclusion: An NLP algorithm can identify a large cohort of patients with incidentally discovered SBIs and WMD. Advanced age is strongly associated with incidentally discovered SBIs and WMD., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

White matter hyperintensities (WMH) are a key hallmark of subclinical cerebrovascular disease and are known to impair cognition. Here, we parcellated WMH using a novel system that segments WMH based on both lobar regions and distance from the ventricles, dividing the brain into a coordinate system composed of 36 distinct parcels ('bullseye' parcellation), and then investigated the effect of distribution on cognition using two different analytic approaches. Data from a well characterized sample of healthy older adults (58 to 84 years) who were free of dementia were included. Cognition was evaluated using 12 computerized tasks, factored onto 4 indices representing episodic memory, speed of processing, fluid reasoning and vocabulary. We first assessed the distribution of WMH according to the bullseye parcellation and tested the relationship between WMH parcellations and performance across the four cognitive domains. Then, we used a data-driven approach to derive latent variables within the WMH distribution, and tested the relation between these latent components and cognitive function. We observed that different, well-defined cognitive constructs mapped to specific WMH distributions. Speed of processing was correlated with WMH in the frontal lobe, while in the case of episodic memory, the relationship was more ubiquitous, involving most of the parcellations. A principal components analysis revealed that the 36 bullseye regions factored onto 3 latent components representing the natural aggrupation of WMH: fronto-parietal periventricular (WMH principally in the frontal and parietal lobes and basal ganglia, especially in the periventricular region); occipital; and temporal and juxtacortical WMH (involving WMH in the temporal lobe, and at the juxtacortical region from frontal and parietal lobes). We found that fronto-parietal periventricular and temporal & juxtacortical WMH were independently associated with speed of processing and episodic memory, respectively. These results indicate that different cognitive impairment phenotypes might present with specific WMH distributions. Additionally, our study encourages future research to consider WMH classifications using parcellations systems other than periventricular and deep localizations., (© 2022. The Author(s).)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's f  = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression. Impact statement Diffusion tensor imaging outperforms conventional imaging of subcortical small vessel disease as a potential marker of future disease progression. Here we identified the left superior longitudinal temporal fasciculus as a critical white matter fiber bundle, of which worse diffusivity can link presence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutations to greater severity of small vessel disease and worse executive functioning in asymptomatic stages of the disease. This tract may hold promise and deserves further examination as an early indicator of disease progression.