Acute Toxic Leukoencephalopathy Research Articles

Accidental transdermal fentanyl overdose in a child

Fentanyl is a synthetic opioid that provides analgesia for procedures with moderate to severe pain and also can be used to manage acute or chronic pain. Fentanyl is available in several dosing forms and is more widely used as a transdermal patch for the management of chronic pain at home. Accidental exposure to even one dose of fentanyl, especially by children can result in a fatal overdose leading to disturbances of consciousness and/or respiratory depression. A nine-year-old boy was referred to the pediatric emergency department because of disturbed consciousness and respiratory depression. A patch of fentanyl 100 mcg/h was found on the bruised knee during the examination. For treatment, he got naloxone 0.1 mg, infusion therapy and artificial lung ventilation due to respiratory depression. Signs characteristic of acute toxic leukoencephalopathy and hypoxic-ischemic encephalopathy were found on brain magnetic resonance imaging (MRI). After 29 days in the inpatient unit and 120 days of rehabilitation, the patient was discharged home with moderate neurological impairment. Opioid misuse can cause serious life-threatening consequences especially in children resulting in death or severe neurological impairment. When dealing with cases of fentanyl overdose, doctors should keep in mind not only respiratory depression and hypotension, but the presence of toxic leukoencephalopathy as well. These cases may be preventable through better education of prescribers and patients.

NCMP-22. FLUDARABINE NEUROTOXICITY IN PATIENTS UNDERGOING CAR T-CELL THERAPY - A REPORT OF 2 CASES

Abstract Fludarabine is a purine analog used in the treatment of chronic lymphocytic leukemia (CLL) and as part of immunosuppressive/lymphodepleting regimens in allogeneic stem cell transplant and chimeric antigen receptor (CAR) T-cell therapy. It induces cellular cytotoxicity through multiple mechanisms, ultimately leading to the inhibition of DNA synthesis. Although myelosuppression is the primary dose-limiting side effect of fludarabine, there have been reported cases of delayed-onset neurological symptoms, such as progressive visual impairments, dementia, ataxia, hemiparesis, quadriparesis, and blindness. These symptoms have been observed in patients receiving fludarabine alone or as part of preconditioning treatments for CAR T-cell therapy. The neurological abnormalities are characterized by leukoencephalopathies and can manifest as posterior reversible encephalopathy (PRES), acute toxic leukoencephalopathy (ATL), or other leukoencephalopathy (OLE). We present two cases of patients who underwent fludarabine conditioning before CAR T-cell therapy, exhibiting late-onset and progressive changes in vision and encephalopathy. These symptoms differ in timing and pattern from the neurotoxicities commonly associated with CAR T-cell therapy. Nonetheless, given the overlapping neurological toxicities seen with both CAR-T cell therapy and fludarabine, it is important to consider implementing thorough screening measures to modify preconditioning fludarabine dose intensity, particularly for patients with advanced disease, renal insufficiency, or other risk factors to limit fludarabine-associated adverse effects.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

FOLFIRI-bevacizumab-induced acute toxic leukoencephalopathy.

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. 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. 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. 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.

Imaging Findings in Children Presenting with CNS Nelarabine Toxicity.

Nelarabine is a nucleoside analog critical for the treatment of patients with T-cell acute lymphoblastic leukemia/lymphoma. However, clinical peripheral and central neurologic adverse events associated with nelarabine administration have been reported. Neuroimaging of brain neurotoxicity has only been described in very few reports in pediatric patients so far. Six children with diagnosed T-cell acute lymphoblastic leukemia who clinically experienced possible, probable, or definite nelarabine-induced toxicity and underwent spine and/or brain MR imaging were reviewed. Neuroimaging findings showed a mixture of patterns including features of acute toxic leukoencephalopathy (seen in 6 cases), posterior reversible encephalopathy syndrome (2 cases), involvement of deep gray structures (1 case) and brainstem (2 cases), cranial and spinal neuropathy (2 cases each), and myelopathy (2 cases). Even though neuroimaging findings are nonspecific, the goal of this article was to alert the pediatric neuroradiologists, radiologists, and clinicians about the possibility of nelarabine-induced neurotoxicity and its broad neuroimaging spectrum.

Transient Mutism Related to Capecitabine-Induced Acute Toxic Leukoencephalopathy

Capecitabine, a precursor of 5-fluorouracil (5-FU), is a well-tolerated and safe chemotherapy that has been used to treat breast, pancreatic, and colorectal cancers. Albeit rare, both 5-FU and capecitbine have been reported to be associated with acute central nervous system toxicity, including cerebellar dysfunction, posterior reversible encephalopathy syndrome, and transient leukoencephalopathies. Here we present a case of 32-year-old female, demonstrating transient mutism related to capecitabine induced acute toxic leukoencephalopathy.

Chemotherapy-induced acute reversible toxic leukoencephalopathy

Acute toxic leukoencephalopathy can be due to a variety of endogenous and exogenous agents. Chemotherapy-induced toxic leukoencephalopathy is often encountered in clinical practice with the widespread use of various chemotherapeutic agents. Since initial clinical findings may be nonspecific, magnetic resonance imaging can be useful in the pattern recognition of white matter injury as well as to rule out its close differentials. Early diagnosis is important since prompt removal of the inciting agent and supportive therapy can reverse this condition, while delay can result in a poor prognosis. Here, we report a case of chemotherapy-induced toxic leukoencephalopathy in a patient with metastatic adenocarcinoma of the rectum from an imaging perspective.

Potentially Reversible and Recognizable Acute Encephalopathic Syndromes: Disease Categorization and MRI Appearances.

"Encephalopathy" is a vague term that encompasses varying definitions, often with a nonspecific clinical presentation and numerous possible pathophysiologic causes. Hence, MR imaging plays a crucial role in the early diagnosis and treatment by identifying imaging patterns when there is limited clinical history in such patients with acute encephalopathy. The aim of this review was to aid in remembrance of etiologies of potentially reversible acute encephalopathic syndromes on MR imaging. The differential includes vascular (reversible cerebral vasoconstriction syndrome, transient global amnesia, disseminated intravascular coagulation, and thrombotic microangiopathy), infection (meningitis, encephalitis), toxic (posterior reversible encephalopathy syndrome, acute toxic leukoencephalopathy; carbon monoxide, alcohol-related, medication- and illicit drug-related toxic encephalopathies), autoimmune, metabolic (osmotic demyelination syndrome, uremic, acute hepatic encephalopathy), idiopathic/inflammatory (stroke-like migraine attacks after radiation therapy syndrome), neoplasm-related encephalopathy, and seizure-related encephalopathy.

Pediatric Acute Toxic Leukoencephalopathy: Prediction of the Clinical Outcome by FLAIR and DWI for Various Etiologies.

Pediatric acute toxic leukoencephalopathy is a clinicoradiologic entity comprising various etiologies. This study aimed to identify the MR imaging appearance of pediatric acute toxic leukoencephalopathy from various etiologies and determine whether the etiology correlates with clinical outcome. We retrospectively reviewed the electronic records of patients with pediatric acute toxic leukoencephalopathy younger than 19 years of age who had MR imaging within <2 weeks of presentation, including DWI and FLAIR sequences. Two neuroradiologists scored the DWI and FLAIR severity and measured the percentage ADC reduction within the visibly affected regions and normal-appearing WM. The percentage ADC reduction and DWI and FLAIR severity were correlated with clinical outcome using the Spearman correlation. Of 22 children, 3 were excluded due to a nontoxic cause or incomplete examination. Regarding the included 19 children (mean age, 13 years), the etiologies of pediatric acute toxic leukoencephalopathy were the following: methotrexate (n = 6), bone marrow transplantation (n = 4), fludarabine (n = 3), cytarabine (n = 1), carboplatin (n = 1), vincristine (n = 1), cyclosporine (n = 1), uremia (n = 1), and bevacizumab (n = 1). Three subgroups were analyzed (chemotherapy, n = 12; immunosuppression, n = 5; others, n = 2). There was a strong correlation of FLAIR (r = 0.773, P < .001) and DWI (r = 0.851, P < .001) severity with clinical outcome, and patients treated with fludarabine had the worst outcomes. High percentage ADC reduction values were associated with adverse outcomes, and lower percentage ADC reduction values were associated with favorable outcomes (r = 0.570, P = .011). The DWI and FLAIR severity scores appear highly prognostic, whereas percentage ADC reduction is moderately prognostic for clinical outcomes in pediatric acute toxic leukoencephalopathy. Immunosuppressive pediatric acute toxic leukoencephalopathy tends toward favorable outcomes, and fludarabine tends toward worse outcomes.

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients.

Prior studies regarding acute toxic leukoencephalopathy (ATL) are either small, or preliminary. Our aim was to evaluate etiologies of and differences in imaging severity and outcomes among various etiologies of ATL. MRIs of patients with suspected ATL over 15 years were retrospectively reviewed; inclusion criteria were: MRI <3 weeks of presentation with both DWI and FLAIR. These were jointly graded by two neuroradiologists via a previously described score of severity. Clinical outcome was evaluated via both modified Rankin (mRS) and ATL outcome (ATLOS) scores, each being correlated with the DWI and FLAIR scores. Etiologic subgroups of n > 6 patients were statistically compared. Of 101 included patients, the 4 subgroups of n > 6 were the following: chemotherapy (n = 35), opiates (n = 19), acute hepatic encephalopathy (n = 14), and immunosuppressants (n = 11). Other causes (n = 22 total) notably included carbon monoxide (n = 3) metronidazole (n = 2), and uremia (n = 1). The mean DWI/FLAIR severity scores were 2.6/2.3, 3.3/3.3, 2.1/2.1 and 2.0/2.5 for chemotherapeutics, opiates, AHE and immunosuppressants, respectively, with significant differences in both imaging severity and outcome (P = .003-.032) among subgroups, particularly immunosuppressant versus chemotherapy-related ATL and immunosuppressants versus opiates (P = .004-.032) related ATL. DWI and FLAIR severity weakly correlated with outcome (ρ = 0.289-.349, P < .005) but correlated stronger in the chemotherapy (ρ = 0.460-.586, P < .010) and opiate (ρ =.472-.608, P < .05) subgroups, which had the worst outcomes. ATL clinically resolved in 36%, with severe outcomes in 23% (coma or death, 9/16 deaths from fludarabine). Notable laboratory results were elevated CSF myelin basic protein levels in 8/9 patients and serum blood urea nitrogen levels in 24/91. Clinical outcomes of ATL vary on the basis of etiology, being worse in chemotherapeutic- and opiate-related ATL. Uremia may be a predisposing or exacerbating factor.

Toxic‐Metabolic Neurologic Disorders in Children: A Neuroimaging Review

There are multiple causes of neurotoxicity in children including medications, extrinsic toxins and insults, illicit drugs, built up of toxic metabolites due to genetic or acquired disorders, and metabolic abnormalities. The review is centered on causes of neurotoxicity affecting the pediatric brain and producing typical and easily recognized imaging manifestations. Early identification of common and less common imaging findings may point toward the correct direction, and may facilitate early diagnosis and institution of appropriate treatment to reverse or at least limit the injury to the developing brain. Two common imaging patterns of neurotoxicity in children are the posterior reversible encephalopathy syndrome and acute toxic leukoencephalopathy that are usually related to chemotherapy and immunosuppression for common pediatric malignancies. Another well-described imaging pattern of injury in children involves reversible splenial lesions with or without associated white matter abnormalities. Multiple additional extrinsic causes of neurotoxicity are presented including radiation and chemoradiation, various medications and treatment regimens, poisoning, illicit drug use or accidental exposure, and the respective characteristic neuroimaging findings are highlighted. Intrinsic neurotoxicity may occur in the setting of inborn errors of metabolism or acquired progressive organ failure leading to build up of toxic metabolites. Additional intrinsic causes of neurotoxicity include metabolic derangements and characteristic imaging findings in all instances are reviewed. The goal of the article is to enhance familiarity of neurologists and neuroradiologists with the imaging appearance of common and less common toxic insults to the pediatric brain.

Capecitabine-induced acute toxic leukoencephalopathy

A 45-year-old woman was treated by Capecitabine (Xeloda®) during 6days for breast cancer with metastatic bone lesions when she presented with nausea, headaches, muscle cramps, dysarthria and swallowing disorders. A stroke was first suspected. Brain CT was normal. MRI showed bilateral and symmetric high signal intensities of deep white matter, corpus callosum and corticospinal tracts on diffusion-weighted imaging and T2 fluid-attenuated inversion recovery (FLAIR) sequence, similar to 5-FU acute leukoencephalopathy. An acute toxic leukoencephalopathy was diagnosed prompting to discontinue capecitabine, which allowed a regression of the symptoms. Though acute toxic leukoencephalopathies with pseudo-stroke presentation have been reported with other chemotherapy agents such as methotrexate or 5-fluorouracil (5-FU), cases of leukoencephalopathy induced by capecitabine are less reported and less well known. This oral precursor of 5-FU is commonly used to treat colorectal, stomach or breast cancers. Neurotoxicity of other 5-FU derivates like cormafur and tergafur have rarely been depicted as well.Although 5-FU-induced leukoencephalopathy is known, the potential toxicity of its precursor should be acknowledged as well. Early detection of chemotherapy-induced toxicity by MRI is crucial as symptoms may be reversible to the condition that chemotherapy is immediately discontinued.

Leukoencephalopathic Changes on Magnetic Resonance Imaging Associated with a Thermogenic Dietary Supplement (Thermatrim)

Acute toxic leukoencephalopathy can be caused by exposure to many compounds. Reversibility has been described in some cases with prompt recognition and withdrawal of the offending agent. Its association with a thermogenic supplement has never been reported. We describe two such cases in young women taking a commercially available thermogenic dietary supplement who presented with acute neurologic deficits and a common magnetic resonance imaging pattern.

Severe fludarabine neurotoxicity after reduced intensity conditioning regimen to allogeneic hematopoietic stem cell transplantation: a case report

Key Clinical MessageWe present a case of severe, irreversible neurotoxicity in a 55-year-old-patient with myelofibrosis undergoing hematopoietic stem cell transplantation following a reduced intensity conditioning including fludarabine. The patient developed progressive sensory-motor, visual and consciousness disturbances, eventually leading to death. MRI imaging pattern was unique and attributable to fludarabine neurotoxicity.

Acute reversible toxic leukoencephalopathy due to the chemotherapeutic agent folfox in a patient with negative IVS14+1G&gt;A mutation in the DPD (dihydropyrimidine dehydrogenase) gene (P3.142)

Acute reversible toxic leukoencephalopathy due to the chemotherapeutic agent folfox in a patient with negative IVS14+1G&gt;A mutation in the DPD (dihydropyrimidine dehydrogenase) gene (P3.142)

Methadone-Induced Acute Toxic Leukoencephalopathy

Methadone-Induced Acute Toxic Leukoencephalopathy

Retraction Note: The sequential magnetic resonance images of tri-methyl tin leukoencephalopathy.

Organotin compounds are commonly used in industrial and agriculture. It causes toxic effects on skin, eyes, respiratory system, gastrointestinal system, and nervous system. After cleaning a di-methyl tin tank, 43-year-old man showed a dizziness, disorientation, visual hallucination, and agitation. Through a measurement by liquid chromatography and inductively coupled plasma-mass spectrometry, di-methyl tin and tri-methyl tin was detected. Although magnetic resonance (MR) image 3 days after exposure showed no abnormal signal intensity, follow-up MR images 15 days after exposure revealed abnormal extensive signal intensities in the white matter that was not ever coincident with previous reports. It was hardly explainable that previous abnormal signal intensities of MR image nearly disappeared 4 months later. We present a case of a patient who developed acute toxic leukoencephalopathy from an acute inhalational exposure to methyl tin with sequential MR images showing an involvement of white matter that was not ever reported.

Methotrexate-induced acute toxic leukoencephalopathy

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year period.

Medication neurotoxicity in children

Medication neurotoxicity may have a variety of imaging manifestations in children. In this pictorial essay, we review the two most common brain injury patterns, posterior reversible encephalopathy syndrome (PRES) and acute toxic leukoencephalopathy (ATL). Proposed etiologies, salient features on neurological imaging, and methods for differentiating these entities and their implications will be discussed. Certain agents do not fall into these two broad patterns but instead characteristically involve central structures. We individually review several medications and their respective neurotoxic appearances including methotrexate, cyclosporine A, tacrolimus, metronidazole and vigabatrin. Diagnosis of medication neurotoxicity may be achieved by the combination of new-onset neurological deficits, recent initiation of a new therapy agent and distinctive findings on magnetic resonance imaging. Clinical and radiological improvement and/or resolution are frequently observed after the agent is discontinued.

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging