Capecitabine-induced leukoencephalopathy in a patient with triple-negative breast cancer: A case report and review of the literature.

INTRODUCTION: Capecitabine is an orally administered prodrug that converts preferentially to 5-fluorouracil within tumors, resulting in enhanced concentrations of 5-fluorouracil in tumor tissue. The use of capecitabine has shown efficacy in the metastatic setting for breast cancer, and more recently, efficacy as adjuvant therapy for triple-negative breast cancer (TNBC). Capecitabine has been shown to be well tolerated with minimal side effects, but the incidence of leukoencephalopathy is rare with a risk of less than one percent. CASE REPORT: We report on a 34-year-old female patient with left TNBC, moderately differentiated, stage IIB that experienced symptoms of neurotoxicity following initiation of adjuvant chemotherapy with capecitabine. MANAGEMENT AND OUTCOME: Naranjo Algorithm Assessment score of nine indicated patient had drug-induced leukoencephalopathy leading to discontinuation of capecitabine and resolution of the neurotoxicity symptoms. DISCUSSION: Early detection of capecitabine-induced neurotoxicity by magnetic resonance imaging is crucial as symptoms may be reversible to the condition that capecitabine is immediately discontinued.

Altered Mental Status: A Case Report of Toxic Leukoencephalopathy Following Heroin Exposure.

: Toxic leukoencephalopathy is a rare illness that causes diffuse white matter destruction, and as a result may mimic psychiatric disorders. Multiple causes have been identified including nerve related injury from exposure to a toxin. When symptoms present, they typically improve after the offending agent is eliminated. However, the clinical presentation in this report is unique in that the syndrome got worse several weeks after the toxin was removed. Research indicates that supportive supplements and vitamins can be used to facilitate neurological recovery. This report outlines a case of toxic leukoencephalopathy following heroin overdose that was treated with vitamin supplementation.

Cytotoxic Lesions of the Corpus Callosum Caused by Thermogenic Dietary Supplements.

Consumption of over-the-counter dietary supplements to reduce body weight is common among the population. Thermogenics are herbal combinations that claim to produce a fat-burning process through an increase in the cellular metabolic rate and greater cellular energy consumption, having a high risk for patients developing toxic leukoencephalopathy. We present a series of 6 patients with acute neurologic symptoms and MR imaging showing restricted diffusion and decreased apparent diffusion coefficient values (mean value, 400 mm2/s × 10-6) in the entire corpus callosum compatible with a cytotoxic lesion of the corpus callosum. Although patients responded favorably to the product discontinuation with rapid recovery of neurologic symptoms, there was a more prolonged resolution on imaging alterations. Because of the widespread availability and unregulated nature of thermogenic dietary supplements, physicians must be aware of the clinical and radiologic characteristics of these potential complications of their use.

A Callosal Catastrophe: Toxic Leukoencephalopathy Associated with Thermogenic Weight Loss Supplement Use.

BACKGROUND: The use of weight loss drugs and dietary supplements is common, but safety profiles for these drugs are largely unknown. Reports of toxicity have been published, and the use of these agents should be considered in clinical differential diagnoses. METHODS: We report the case of a patient with toxic leukoencephalopathy and hyponatremia associated with oral consumption of a thermogenic dietary supplement and essential oils. RESULTS: A 30-year-old woman presented after 2 days of headache, blurred vision, photophobia, vomiting, and hand spasms. She was taking a thermogenic dietary supplement daily for 6 months as well as a number of essential oils. Examination revealed mild right sided ataxia and diffuse hyperreflexia. Neuroimaging demonstrated bilaterally symmetric T2 hyperintensities of the corpus callosum and periventricular white matter. Approximately 18 h after admission she became unresponsive with brief extensor posturing and urinary incontinence. She partially recovered, but 1 h later became unresponsive with dilated nonreactive pupils and extensor posturing (central herniation syndrome). She was intubated, hyperventilated, and given hyperosmotic therapy. Emergent imaging showed diffuse cerebral edema. Intracranial pressure was elevated but normalized with treatment; she regained consciousness the following day. She was extubated one day later and discharged on hospital day 5. She was seen 2 months later with no further symptoms and a normal neurologic examination. CONCLUSIONS: The pathophysiology of this patient's hyponatremia and toxic leukoencephalopathy is unknown. However, physicians must be aware of the association between thermogenic dietary supplements and toxic leukoencephalopathy. Vigilance for life-threatening complications including hyponatremia and cerebral edema is critical.

Delayed leukoencephalopathy after acute carbon monoxide intoxication.

Delayed leukoencephalopathy is an uncommon complication of hypoxic-ischemic events of different etiologies, including carbon monoxide intoxication. We present a case of a 40-year-old male patient who was admitted with rapidly progressive neurocognitive and behavioral deficits. There was a history of accidental carbon monoxide intoxication one month before, presenting with loss of consciousness and short hospitalization, followed by a complete clinical recovery. The imaging studies in the delayed phase depicted confluent, symmetric supra-tentorial white matter lesions in keeping with diffuse demyelinization. Restricted diffusion and metabolite abnormalities in magnetic resonance proton spectroscopy were also seen. The diagnosis of CO-mediated delayed post-hypoxic leukoencephalopathy was assumed after exclusion of other mimickers. Hyperbaric oxygen therapy was tentatively performed and the patient had a favorable clinical and radiological evolution.

[Early diagnosis of capecitabine-induced acute leukoencephalopathy by using diffusion-weighted MRI].

A 63-year-old woman with colon cancer who was treated with capecitabine as adjuvant chemotherapy presented with vertigo on day 5, and dysarthria and dysphagia on day 7 of the treatment. Diffusion-weighted magnetic resonance imaging of the brain revealed high signal intensity in the corpus callosum and corona radiata. The patient was diagnosed with acute leukoencephalopathy, and the capecitabine treatment was discontinued. Her symptoms recovered immediately. On the basis of these findings, it can be concluded that diffusion-weighted imaging is useful for the early detection and diagnosis of acute leukoencephalopathy.

Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia.

PURPOSE: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. PATIENTS AND METHODS: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. RESULTS: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. CONCLUSION: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy.

OBJECTIVES: To date, only four small studies have investigated the effects of adjuvant chemotherapy for breast cancer on the microstructure of cerebral white matter with magnetic resonance imaging (MRI). These studies, which were conducted shortly up to 10 years post-treatment, showed that chemotherapy is associated with focal loss of microstructural white matter integrity. We investigated the long-term effect of chemotherapy on white matter microstructural integrity by comparing the brains of chemotherapy-exposed breast cancer survivors to those of a population-based sample of women without a history of cancer. EXPERIMENTAL DESIGN: Diffusion tensor imaging (DTI) MRI (1.5 T) was performed in 187 CMF (cyclophosphamide, methotrexate, and 5-flourouracil) chemotherapy-exposed breast cancer survivors, mean age 64.2 (sd = 6.5) years, who had been diagnosed with cancer on average 21.2 (sd = 4.4) years before, and 374 age-matched cancer-free reference subjects from a population-based cohort study. Outcome measures were whole-brain microstructural integrity as measured by fractional anisotropy and mean/axial/radial diffusivity and focal white matter integrity, which was analyzed with tract-based spatial statistics. All analyses were adjusted for age, cardiovascular risk factors, education, and symptoms of depression. PRINCIPAL OBSERVATIONS: No significant group differences were observed in white matter integrity. However, within the breast cancer survivors, time since treatment was inversely associated with lower global and focal white matter integrity. CONCLUSIONS: This cross-sectional study suggests that among chemotherapy-exposed breast cancer survivors white matter microstructural integrity deteriorates with accumulating time since treatment. This warrants further investigation.

Protective effects of pentoxifylline on lipopolysaccharide-induced white matter injury in a rat model of periventricular leukomalasia.

OBJECTIVE: To investigate the potential neuroprotective effect of maternal pentoxifylline (PNTX) treatment in endotoxin-induced periventricular leukomalasia (PVL) in the developing rat brain. METHOD: Intraperitoneal injection of lipopolysaccharide was administered on two of three Wistar pregnant rats to establish PVL. To obtain PNTX-treated group, one of the two dams were injected with PNTX. The control group was treated with saline. Rat pups were grouped as control, maternal LPS-treated group and PNTX + LPS-treated group. At 7th postnatal days, apoptosis and hypomyelination were evaluated. Apoptosis was evaluated by caspase-3 and terminal deoxynucleotidyl transferase [TdT] dUTP nick endlabelling reaction (TUNEL) immunostaining. To assess hypomyelination, myelin basic protein (MBP) staining, as a marker of myelination, was evaluated. RESULTS: MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the PNTX-treated group. PNTX treatment significantly reduced the number of apoptotic cells in the periventricular WM shown on Tunel and caspase-3. CONCLUSIONS: Presented study is first indicated that PNTX may provide protection against an LPS-induced inflammatory response and WMI in the developing rat brain. Our results also suggest that PNTX treatment in pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.

Maternal omega-3 fatty acid supplementation protects against lipopolysaccharide-induced white matter injury in the neonatal rat brain.

OBJECTIVES: Periventricular leukomalacia (PVL) is the predominant form of brain injury in premature infants, and no specific treatment currently exists for this condition. We have evaluated whether maternal omega-3 fatty acid (ω3 FA) treatment reduces endotoxin-induced PVL in the developing rat brain. METHODS: Wistar rats with dated pregnancies were fed a standard diet or a diet enriched in ω3 FA (70% docosahexaenoic acid + 30% eicosapentaenoic acid mixture) during gestation. Intraperitoneal injection of lipopolysaccharide (LPS) was administered consecutively on the 18th and 19th embryonic days to establish the endotoxin-induced PVL rat model. The animals were divided into four groups: (i) control, (ii) PVL, (iii) PVL+low-dose ω3 FA and (iv) PVL+high-dose ω3 FA. At day P7, apoptosis and hypomyelination in periventricular white matter were evaluated by immunohistochemical assessments. RESULTS: High-dose maternal ω3 FA treatment reduced brain weight loss. Maternal ω3 FA treatment given either in low or high doses greatly decreased caspase-3 immunoreactivity and increased myelin basic protein immunoreactivity, indicating a decrease in apoptosis and hypomyelination. CONCLUSION: Considering that no specific treatment is available for PVL, maternal ω3 FA supplementation may provide a nutritional strategy to limit periventricular white matter damage caused by infections during pregnancy.

[Posterior reversible encephalopathy related to tacrolimus in a liver transplanted HIV patient]. / Encéphalopathie postérieure réversible liée au tacrolimus chez un patient transplanté hépatique infecté par le VIH.

Tacrolimus-related posterior reversible leukoencephalopathy (PRLE) is a rare complication which should be recognized by clinicians who regularly use immunosuppressive therapy. We report the case of an HIV-positive, hepatitis C-positive liver transplant patient who presented with this complication. Immunosuppression with tacrolimus was started after postsurgery. On the 20th day, the patient suffered two tonic-clonic convulsive attacks against a background of hypertension. Cerebral magnetic resonance imaging and lumbar puncture led to diagnosis of tacrolimus-related PRLE after eliminating other possible diagnoses. Therapeutic management consisted of withdrawing tacrolimus and initiating treatment with antiepileptogenic and antihypertensive drugs, supplemented with magnesium sulphate. The symptoms regressed in the days following withdrawal of tacrolimus and the majority of lesions on magnetic resonance imaging disappeared within two weeks. The aim of which should be to identify patients at risk of developing this complication. This would enable targeted prevention involving magnesium supplementation, strict control of blood pressure and serial monitoring of tacrolimus blood concentrations.