Clinical and neuroradiographic features of fentanyl inhalation-induced leukoencephalopathy.

A man in his late 40s with no known past medical history was unresponsive for an unknown period of time. Crushed pills and white residue were found on a nearby table. On presentation he was obtunded and unresponsive to verbal commands but withdrawing to painful stimuli. The initial urine drug screen was negative, but a urine fentanyl screen was subsequently positive with a level of 137.3 ng/mL. MRI of the brain showed reduced diffusivity and fluid attenuated inversion recovery (FLAIR) hyperintensity symmetrically in the bilateral supratentorial white matter, cerebellum and globus pallidus. Alternative diagnoses such as infection were considered, but ultimately the history and workup led to a diagnosis of fentanyl-induced leukoencephalopathy. Three days after admission the patient became able to track, respond to voice and follow basic one-step commands. The patient does not recall the mechanism of inhalation. While there are case reports of heroin-induced leukoencephalopathy following inhaled heroin use and many routes of fentanyl, this is the first reported case of a similar phenomenon due to fentanyl inhalation.

Differential associations between abnormal cardiac left ventricular geometry types and cerebral white matter disease.

OBJECTIVES: Reduced cardiac outflow due to left ventricular hypertrophy has been suggested as a potential risk factor for development of cerebral white matter disease. Our study aimed to examine the correlation between left ventricular geometry and white matter disease volume to establish a clearer understanding of their relationship, as it is currently not well-established. METHODS: Consecutive patients from 2016 to 2021 who were ≥18 years and underwent echocardiography, cardiac MRI, and brain MRI within one year were included. Four categories of left ventricular geometry were defined based on left ventricular mass index and relative wall thickness on echocardiography. White matter disease volume was quantified using an automated algorithm applied to axial T2 FLAIR images and compared across left ventricular geometry categories. RESULTS: We identified 112 patients of which 34.8 % had normal left ventricular geometry, 20.5 % had eccentric hypertrophy, 21.4 % had concentric remodeling, and 23.2 % had concentric hypertrophy. White matter disease volume was highest in patients with concentric hypertrophy and concentric remodeling, compared to eccentric hypertrophy and normal morphology with a trend-P value of 0.028. Patients with higher relative wall thickness had higher white matter disease volume (10.73 ± 10.29 cc vs 5.89 ± 6.46 cc, P = 0.003), compared to those with normal relative wall thickness. CONCLUSION: Our results showed that abnormal left ventricular geometry is associated with higher white matter disease burden, particularly among those with abnormal relative wall thickness. Future studies are needed to explore causative relationships and potential therapeutic options that may mediate the adverse left ventricular remodeling and its effect in slowing white matter disease progression.

Pearls & Oy-sters: AARS2 Leukodystrophy-Tremor and Tribulations.

A 35-year-old woman with a progressive, bilateral upper limb tremor, personality change, behavioral disturbance, and primary ovarian insufficiency was found to have AARS2-related leukodystrophy. She had congenital nystagmus which evolved to head titubation by age 8 years and then developed an upper limb tremor in her mid-teens. These symptoms stabilized during her 20s, but soon after this presentation at age 35 years, neurologic and behavioral disturbances progressed rapidly over a 12-month period requiring transition to an assisted living facility with care support (4 visits/day) and assistance for all activities of daily living. MRI of the brain demonstrated confluent white matter changes predominantly involving the frontal lobes consistent with a leukodystrophy. All other investigations were unremarkable. Nongenetic causes of a leukodystrophy including sexually transmitted diseases and recreational drug use were excluded. Family history was negative for similar symptoms. Gene panel testing identified compound heterozygous pathogenic AARS2 mutations. This case highlights the importance of MRI brain imaging in progressive tremor syndromes, the utility of gene panels in simultaneous testing of multiple disorders with overlapping phenotypes, and the need for awareness of comorbid endocrinological disorders in many of the genetic leukodystrophies, whose identification may aid in clinical diagnosis.

Toxic and Drug-Related White Matter Diseases of the Brain and Spine.

Toxic leukoencephalopathy and myelopathy are common neurologic complications of a wide range of chemotherapeutic and substance abuse agents. During the last decade, there has been a significant change in the profile of white matter toxins, primarily driven by the development and usage of new chemotherapeutic and immunotherapeutic agents and by the continuous increase in illicit drug abuse with contaminants. Neuroimaging in the form of MR imaging forms the cornerstone in the diagnosis of these entities, many of which are reversible and amenable to rapid correction. Chronic white matter changes are also seen with these toxins with gradually progressive clinicoradiological findings.

On punctate white matter lesions in preterm infants: Is ultrasound diagnosis feasible?

OBJECTIVES: To observe hyperechoic nodular or punctate white matter lesions (HNPL) in a population of preterm infants using routine cranial ultrasound (cUS), to describe the characteristics of HNPL, and to compare them with punctate white matter lesions (PWML) detected in magnetic resonance imaging (MRI). DESIGN: Retrospective observational single-center cohort study. SETTING: Level 2B neonatal unit in France. PATIENTS: 307 infants born <33 weeks gestation undergoing routine cUS with a total of 961 cUS performed. MAIN OUTCOME MEASURES: Description of lesions (HNPL/PWML): presence or absence, number, size, location, and structural distribution. RESULTS: Among the 307 included infants, 63 (20.5%) had at least one cerebral lesion, with 453 HNPL for 63 infants. HNPL were numerous (more than three in 66.6% of cases), primarily grouped in clusters (76.2%), located near the lateral ventricles (96.8%), and measuring more than 2 mm (79%). HNPL were diagnosed on day 29 on average and persisted until term. Overall, 43 MRI were performed in 307 infants, on average 18.9 days after last cUS, in 21 of those the indication was presence of HPNL on cUS. Of these 21 MRI, 14/21 presented 118 PWML compared to 173 HNPL on cUS. In the remaining MRI (7/21), no PWML were detected compared to 47 HNPL on cUS. CONCLUSIONS: In our population of 307 preterm infants, cUS allowed the diagnosis of HNPL, with a large similarity to PWML in MRI and a better sensitivity. But in the absence of data on inter-observer variability, we cannot exclude overdiagnosis of HNPL.

Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based study.

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; pdiff=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.

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.

Significance of Persistent Systemic Support in the Clinical Course of Delayed Post-hypoxic Leukoencephalopathy Following Severe Coronavirus Disease 2019.

A 45-year-old woman was hospitalized with severe coronavirus disease 2019 pneumonia. Following cytokine storm-induced multiorgan failure and lethal arrhythmia, the patient developed a sustained coma with flaccid quadriplegia. A cerebrospinal fluid examination excluded infectious and immunogenic encephalopathies, and diffusion-weighted magnetic resonance imaging demonstrated high-intensity areas in the white matter with a cortex-sparing distribution, suggesting delayed post-hypoxic leukoencephalopathy. As a result of intensive cardiopulmonary support for a month, the neurological function gradually recovered. Based on the reversible clinical course noted in this patient, accurate diagnosis and persistent medical approaches are important for the management of coronavirus disease 2019-related delayed post-hypoxic leukoencephalopathy.

Etiologic Spectrum of Pediatric-Onset Leukodystrophies and Genetic Leukoencephalopathies: The Five-Year Experience of a Tertiary Care Center in Southern India.

BACKGROUND: White matter (WM) disorders with a genetic etiology are classified as leukodystrophies (LDs) and genetic leukoencephalopathies (GLEs). There are very few studies pertaining to the etiologic spectrum of these disorders in the Asian Indian population. METHODS: This study was conducted over a period of five years from January 2016 to December 2020, in the medical genetics department of a tertiary care hospital in southern India. A total of 107 patients up to age 18 years, with a diagnosis of a genetic WM disorder confirmed by molecular genetic testing and/or metabolic testing, were included in the study and categorized into LD or GLE group as per the classification suggested by the Global Leukodystrophy Initiative consortium in 2015. RESULTS: Forty-one patients were diagnosed to have LDs, and 66 patients had GLEs. The two most common LDs were metachromatic LD (16 patients) and X-linked adrenoleukodystrophy (seven patients). In the GLE group, lysosomal storage disorders were the most common (40 patients) followed by mitochondrial disorders (nine patients), with other metabolic disorders and miscellaneous conditions making up the rest. The clinical presentations, neuroimaging findings, and mutation spectrum of the patients in our cohort are discussed. CONCLUSIONS: This is one of the largest cohorts of genetic WM disorders reported till date from the Asian Indian population. The etiologies and clinical presentations identified in our study cohort are similar to those found in other Indian studies as well as in studies based on other populations from different parts of the world.

The Dark side of the White Matter. Diffuse subcortical White Matter Hypointensity on T2/FLAIR: A systematic review of a frequently underrecognized sign.

BACKGROUND AND OBJECTIVES: Many reversible brain MRI abnormalities have been described, among these the most frequently reported are cortical hyperintensities on FLAIR/T2 occurring during seizures. Much less attention has been given to those situations where White Matter goes Dark: subcortical white matter hypointensity on T2/FLAIR. Our aim is to identify the medical condition "Dark White Matter" (DWM) is more frequently associated with. This is the first systematic review on DWM. METHODS: PubMed was searched in August 2023. Included studies were those reporting Diffuse Subcortical White Matter Hypointensity on T2/FLAIR. Mainly case reports were included. Individual patient-level data was included whenever available. Frequency measures of the different diseases were calculated. RESULTS: 56 studies were included, 228 patients were eligible for analysis. DWM happened in isolation, with no cortical abnormalities, in 71 cases and was associated with seizures in >61.4% of cases. The most frequently DWM-associated disease was Non-Ketotic Hyperglycaemic hyperosmolar state (NKH), followed by Encephalitis, Moyamoya disease, Genetic Causes, and Subdural Hematoma. Frequency of NKH was 32%. NKH was associated with seizures in 100% of cases and the most frequently involved lobe was the occipital one. When considering only the subgroup of patients with seizures, DWM was indicative of NKH in 51.4% of cases and Encephalitis in 26.4% of cases. Key limitations are heterogeneity and missing data. DISCUSSION: DWM is frequently underdiagnosed. This sign can exist alone and it is not merely a consequence of cortical involvement. Moreover, it has important implications, both diagnostic and therapeutic, as it is more frequently associated with NKH, especially in the context of seizures, where anti-seizure medication is not the first line of treatment. We also discuss the pathogenesis of DWM by finding a common link between the most frequently associated diseases.

[Debut and evolution MRI images of a child with a new genetic variant of vanishing white matter leukodystrophy]. / Imágenes de resonancia magnética de inicio y evolución de un niño con nueva variante genética de leucodistrofia evanescente.

TITLE: Imágenes de resonancia magnética de inicio y evolución de un niño con nueva variante genética de leucodistrofia evanescente.

Cough elixir overdose causing toxic leuco-encephalopathy and serotonin syndrome.

Acute toxic leukoencephalopathy and serotonin syndrome are rare neurological complications associated with various drugs and toxins, some of which overlap. However, the co-occurrence of these conditions is poorly documented. We present the case of a 14-year-old boy who suddenly developed altered consciousness and autonomic dysfunction after consuming excessive quantities of cough remedies containing dextromethorphan, chlorphenamine, dichlorobenzyl alcohol, and amylmetacreson. Magnetic resonance imaging of the brain revealed distinct white matter lesions. With supportive care, the patient rapidly improved, and the magnetic resonance imaging abnormalities disappeared. The swift resolution, typical magnetic resonance imaging findings, and a history of exposure to drugs affecting the central nervous system's serotonergic system suggested concurrent acute toxic leukoencephalopathy and serotonin syndrome. The components of cough medications can be hazardous in overdose due to their potential to enhance serotonin toxicity and cause direct or indirect central nervous system white matter damage. Early recognition and appropriate treatment are essential for recovery.

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.