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Objectives: Metronidazole central nervous system toxicity is a rare finding in patients receiving the medication. We report a peculiar case of metronidazole central nervous system toxicity in which both the underlying condition (Crohn disease) and the drugs used to treat it are potential causes of encephalopathy., Methods: A 26-year-old female with 6-year history of Crohn's disease for 6 years presented acute-onset encephalopathy. We provide bibliographic evidence to support metronidazole toxicity and potential Crohn disease-associated neurologic involvement., Results: The patient presented dystonia, cerebellar ataxia, and altered mental status. Magnetic resonance imaging of the brain revealed typical findings of metronidazole toxicity and white matter involvement of the centrum semiovale. Immunoelectrophoresis and immunofixation of serum and cerebrospinal fluid proteins were consistent with a systemic inflammatory process. We concluded on an association between drug toxicity and probable Crohn-associated neurologic involvement. Metronidazole was stopped and the patient was placed on vitamin therapy and diazepam to control dystonia. She deteriorated and was transferred to the intensive care unit where she expired., Conclusions: Acute behavioral changes in a young patient constitute an emergency and differential diagnoses should include infective, inflammatory, metabolic, and toxic causes. Metronidazole is a potential toxic etiology., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Iodinated contrast agents are extensively employed in clinical settings, with allergic reactions and renal impairment being the most prevalent adverse events. Contrast-induced encephalopathy (CIE) can present with heterogeneous clinical features, making diagnosis challenging. Prior studies on CIE have primarily documented rapid recovery within several days. However, this paper describes a case of CIE in a patient whose clinical symptoms took 3 months to fully abate., Patient Concerns: A female patient, aged 54 years, received drug-coated balloon therapy for stenosis in a branch of the anterior descending coronary artery. Unfortunately, the patient developed CIE, which initially manifested as visual disturbances and subsequently progressed to gastrointestinal and limb movement issues, as well as an altered mental status, all of which occurred within a 24-hour period during hospitalization., Diagnoses: The patient was diagnosed with CIE after cerebral hemorrhage, and cerebral edema was ruled out based on the history of contrast medium administration and radiographic exams., Interventions and Outcomes: Dexamethasone (10 mg/d), mannitol (100 mL/d), betahistine (500 mL), trazodone (25 mg), and hydration supplementation were given to treat CIE-related symptoms. Aspirin and clopidogrel were administered for the management of the cardiovascular ailment. The neurologist prescribed neurotrophic agents, namely, cytarabine and methylcobalamin, based on the cerebral magnetic resonance imaging findings. Despite the treatment, the patient's ocular symptoms, including blurry vision, diplopia, and impaired intraocular retraction, persisted. Furthermore, the patient's mental state was altered, and she continued to exhibit a depressive state during her 1-month follow-up visit., Lessons: CIE is a comparatively infrequent ailment, and its prompt identification and management are of paramount importance. Although the treatments for CIE are primarily symptomatic, it is crucial to acknowledge that the symptoms may not always subside quickly within a short duration. In conjunction with pharmacotherapy, counseling should be offered to address patients' mental health., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ifosfamide is an important chemotherapeutic agent used in the therapeutic protocols of many malignant tumors. Central nervous system toxicity of ifosfamide manifests with encephalopathy in 10% to 30% of patients treated with ifosfamide. Thiamine and methylene blue have been reported beneficial in the treatment and prevention of ifosfamide-induced encephalopathy (IIE). We describe an episode of encephalopathy developed at the third cycle of ifosfamide treatment in a child with Ewing sarcoma. With the administration of thiamin, the encephalopathy resolved and no episode was noted during subsequent courses of ifosfamide. Previous use of cisplatin, concomitant use of opioids, low levels of serum albumin and hemoglobin, and elevated levels of serum creatinine are potential risk factors for IIE. The current case illustrates the possibility of IIE even in the absence of such additional risk factors, treated successfully with thiamin and draws attention to the need for close neurological monitorization of patients treated with ifosfamide., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Metronidazole has been used to treat a broad range of infections over the decades, and its safety profile has been presumably well studied. However, neurological severe adverse events after prescription and nonprescription use of metronidazole is well recognized but underdiagnosed., Case Presentation: We report the case of a 48-year-old Indian man who presented with unremitting symptoms of peripheral neuropathy along with a silent callosal lesion in the splenium ("boomerang" sign). Because he had visited 3 neurologists previously, there were many targeted and nontargeted investigations, which failed to reach an etiological diagnosis and hence to provide relief. The patient was questioned about a potential neurotoxin exposure, and at that point, he said that he had been taking metronidazole for a long time, without any supervision, as an over-the-counter remedy for self-diagnosed "chronic amebiasis." On stopping metronidazole, he recovered gradually. In the sixth month of follow-up, brain magnetic resonance imaging showed disappearance of the callosal lesion and significant improvement in the nerve conduction studies., Conclusions: Clinicians should keep metronidazole toxicity in mind while dealing with a case of cytotoxic lesion of the corpus callosum with splenium involvement and peripheral neuropathy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Childhood encephalopathy comprises a wide range of etiologies with distinctive distribution in different age groups. We reviewed the pattern of encephalopathy admitted to the pediatric intensive care unit (PICU) of a tertiary children's hospital., Methods: We reviewed the medical records and reported the etiologies, clinical features, and outcomes of children with encephalopathy., Results: Twenty-four admissions to the PICU between April 2019 and May 2020 were reviewed. The median (interquartile range) age was 10.0 (14.7) years and 62.5% were boys. Confusion (66.7%) was the most common presentation. Adverse effects related to medications (33.3%) and metabolic disease (20.8%) were predominant causes of encephalopathies in our study cohort. Methotrexate was responsible for most of the medication-associated encephalopathy (37.5%), whereas Leigh syndrome, pyruvate dehydrogenase deficiency and Wernicke's encephalopathy accounted for those with metabolic disease. The median Glasgow Coma Scale (GCS) on admission was 12.5 (9.0). Antimicrobials (95.8%) and antiepileptic drugs (60.9%) were the most frequently given treatment. Children aged 2 years or younger were all boys (P = 0.022) and had a higher proportion of primary metabolic disease (P = 0.04). Intoxication or drug reaction only occurred in older children. The mortality was 8.3%, and over half of the survivors had residual neurological disability upon PICU discharge. Primary metabolic disease (P = 0.002), mechanical ventilation (P = 0.019), failure to regain GCS back to baseline level (P = 0.009), and abnormal cognitive function on admission (P = 0.03) were associated with cerebral function impairment on PICU discharge., Conclusions: Primary metabolic encephalopathy was prevalent in younger children, whereas drug-induced toxic encephalopathy was common among older oncology patients. Survivors have significant neurologic morbidity. Failure to regain baseline GCS was a poor prognostic factor for neurological outcomes., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare the efficacy of four therapeutic methods to modify gut microbiota dysbiosis and brain dysfunction in septic rats., Methods: Rats were treated with fecal microbiota transplantation, prebiotics, probiotics, and synbiotics after exposure to lipopolysaccharide. The diversity and composition of gut microbiota, electroencephalogram values, and the concentrations of TNF-α, IL-1β, and IL-6 in the cortex were analyzed., Results: Fecal microbiota transplantation was the most efficacious method to restore intestinal microbial diversity and exert the best corrective effects in modulating microbial composition in septic rats. More interestingly, fecal microbiota transplantation exerted the best protective effects in brain dysfunction in septic rats., Conclusion: Among the four methods, fecal microbiota transplantation was the most useful method to modify the dysbiosis of intestinal microbiota and improve brain function in septic rats. These findings reveal the protective consequence of microbiota modification, and the findings suggest opportunities to improve brain function in sepsis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2021 International Anesthesia Research Society.)

Introduction: Acyclovir (ACV)-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, an ACV metabolite, and is often reported in patients with renal dysfunction. We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral administration of valacyclovir (VACV) and review literature of previous ACV-associated encephalopathy cases., Patient Concerns: An 88-year-old man was diagnosed with herpes zoster. VACV (3000 mg/day) treatment was initiated. Serum creatinine (Cr) level was 0.80 mg/dL. However, irritability, memory impairment, and decreased responsiveness occurred after 3 days. The Cr level was 6.76 mg/dL on admission., Diagnosis: He was diagnosed with ACV-associated encephalopathy with acute kidney injury., Interventions: VACV was discontinued, hemodialysis was initiated on the day of admission, and then the signs and symptoms improved approximately 72 hours after the admission., Conclusion: Worsening of renal function and encephalopathy should be a focus when using VACV or ACV, regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary during VACV treatment., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Contrast-induced encephalopathy (CIE) is a rare complication caused by administration of intravascular contrast media and characterized by acute reversible neurological disturbance. Most of the CIE cases are reported after arterial administration of contrast media such as during cerebral or coronary angiographies, yet only a few articles have reported CIE secondary to intravenous contrast. A case of CIE secondary to intravenous contrast administration is reported here., Patient Concerns: A 68-year-old man was admitted to our hospital for contrast-enhanced chest computed-tomography (CT) examination due to suspected pulmonary nodules. After CT examination, the patient lost consciousness and experienced a cardiorespiratory arrest. An emergency plain brain CT was done immediately which showed abnormal cortical contrast enhancement and cerebral sulci hyperdensity., Diagnoses: After excluding other differential diagnoses such as electrolytes imbalance, hypo/hyperglycemia, cardiogenic pathologies and other neurological emergencies such as cerebral hemorrhage, cerebral infarction, the final diagnosis of CIE was made., Interventions: The patient was admitted to the intensive care unit for further management. A series of supportive treatments were arranged., Outcomes: Follow-up visits at the outpatient clinic showed no lasting neurological deficits., Lessons: CIE should be considered as 1 of the differential diagnoses for a patient with acute neurologic symptoms after iodinate contrast administration. Neuroradiological imaging examinations are essential to rule out other etiologies such as acute cerebral infarction or intracranial hemorrhage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Contrast-induced encephalopathy (CIE) is a rare and underrecognized complication after endovascular thrombectomy (EVT) for acute ischemic stroke. This study investigated the incidence and risk factors of CIE in patients who underwent EVT., Methods: Consecutive patients with acute ischemic stroke who received EVT between September 2014 and December 2019 at 2 medical centers were included. CIE was diagnosed on clinical criteria of neurological deterioration or delayed improvement within 24 hours after the procedure that was unexplained by the infarct or hemorrhagic transformation and radiological criterion of edematous change extending beyond the infarct core accompanied by contrast staining., Results: Of 421 patients with acute ischemic stroke who received EVT, 7 (1.7%) developed CIE. The manifestations included worsening of focal neurological signs, coma, and seizure. Patients with CIE were more likely to experience contrast-induced acute kidney injury than were those without CIE, but the volume of contrast medium was comparable between the two groups. The independent risk factors for CIE included renal dysfunction (defined as an estimated glomerular filtration rate <45 mL/min per 1.73 m 2 ; odds ratio, 5.77 [95% CI, 1.37-24.3]; P =0.02) and history of stroke (odds ratio, 4.96 [95% CI, 1.15-21.3]; P =0.03). Patients with CIE were less likely to achieve favorable functional outcomes (odds ratio, 0.09 [95% CI, 0.01-0.87]; P =0.04)., Conclusions: CIE should be suspected in patients with clinical worsening after EVT accompanied by imaging evidence of contrast staining and edematous changes, especially in patients with renal dysfunction or history of stroke.

A 42-year-old woman with reversible splenial lesion syndrome (RESLES) and rectal adenocarcinoma presented with sudden-onset delirium after the sixth cycle of her chemotherapy drug, oral tegafur-uracil (300 mg/m/day, days 1-14, with treatment cycle repeated every 21 days). Accompanied by the anti-CV2 antibody, paraphasia, and a loss of bimanual coordination, the patient's etiology and clinical manifestations of RESLES are unlike those of other reported cases of RESLES. Tegafur-uracil is an oral fluoropyrimidine that has a similar effect to 5-fluorouracil as an adjuvant treatment for colorectal cancer. The possibility that the toxicity of chemotherapeutic drugs may play a role in the pathogenesis of cytotoxic edema in the splenium of the corpus callosum and extracallosal white matter should be investigated further.

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 μmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 μmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.

Background: Obstructive sleep apnea (OSA) patients are at increased risk for pulmonary and cardiovascular complications; perioperative mortality risk is unclear. This report analyzes cases submitted to the OSA Death and Near Miss Registry, focusing on factors associated with poor outcomes after an OSA-related event. We hypothesized that more severe outcomes would be associated with OSA severity, less intense monitoring, and higher cumulative opioid doses., Methods: Inclusion criteria were age ≥18 years, OSA diagnosed or suspected, event related to OSA, and event occurrence 1992 or later and <30 days postoperatively. Factors associated with death or brain damage versus other critical events were analyzed by tests of association and odds ratios (OR; 95% confidence intervals [CIs])., Results: Sixty-six cases met inclusion criteria with known OSA diagnosed in 55 (83%). Patients were middle aged (mean = 53, standard deviation [SD] = 15 years), American Society of Anesthesiologists (ASA) III (59%, n = 38), and obese (mean body mass index [BMI] = 38, SD = 9 kg/m); most had inpatient (80%, n = 51) and elective (90%, n = 56) procedures with general anesthesia (88%, n = 58). Most events occurred on the ward (56%, n = 37), and 14 (21%) occurred at home. Most events (76%, n = 50) occurred within 24 hours of anesthesia end. Ninety-seven percent (n = 64) received opioids within the 24 hours before the event, and two-thirds (41 of 62) also received sedatives. Positive airway pressure devices and/or supplemental oxygen were in use at the time of critical events in 7.5% and 52% of cases, respectively. Sixty-five percent (n = 43) of patients died or had brain damage; 35% (n = 23) experienced other critical events. Continuous central respiratory monitoring was in use for 3 of 43 (7%) of cases where death or brain damage resulted. Death or brain damage was (1) less common when the event was witnessed than unwitnessed (OR = 0.036; 95% CI, 0.007-0.181; P < .001); (2) less common with supplemental oxygen in place (OR = 0.227; 95% CI, 0.070-0.740; P = .011); (3) less common with respiratory monitoring versus no monitoring (OR = 0.109; 95% CI, 0.031-0.384; P < .001); and (4) more common in patients who received both opioids and sedatives than opioids alone (OR = 4.133; 95% CI, 1.348-12.672; P = .011). No evidence for an association was observed between outcomes and OSA severity or cumulative opioid dose., Conclusions: Death and brain damage were more likely to occur with unwitnessed events, no supplemental oxygen, lack of respiratory monitoring, and coadministration of opioids and sedatives. It is important that efforts be directed at providing more effective monitoring for OSA patients following surgery, and clinicians consider the potentially dangerous effects of opioids and sedatives-especially when combined-when managing OSA patients postoperatively.

Rationale: Metronidazole is widely used for treating infection of anaerobic bacteria and protozoa. Metronidazole is generally well tolerated, although metronidazole-associated peripheral neuropathy (PN) and metronidazole-induced encephalopathy (MIE) have been reported as rare side effects. The most common sites of MIE involve the bilateral dentate nucleus of the cerebellum. Herein, we present a rare case of MIE with isolated corpus callosum involvement, with concomitant metronidazole-associated PN., Patient Concerns: A middle-aged man with ulcerative colitis was diagnosed with amoebic dysentery because of unhygienic eating. After receiving metronidazole (1.8 g/d, cumulative dose 61.2 g) for >1 month, he started to complain of continuous paresthesia of the limbs, and intermittent speech problems. Magnetic resonance imaging demonstrated an isolated lesion in the splenium of the corpus callosum., Diagnosis: A diagnosis of reversible splenial lesion syndrome and PN was made. Given the patient's medical history, MIE and metronidazole-associated PN were considered., Interventions: Metronidazole was stopped. Mecobalamine and vitamin B1 were used for adjuvant treatment., Outcomes: At 1.5 months after stopping metronidazole, his symptoms of numbness and hyperesthesia had not improved, although he felt less ill. The isolated lesion disappeared on follow-up magnetic resonance imaging. At 6 months later, the hyperesthesia symptoms remained, and he was unable to resume his previous work., Conclusions: Physicians should consider MIE in their differentials for reversible splenial lesion syndrome when encountering a patient with a history of metronidazole medication and symptoms of encephalopathy, especially with concomitant PN. Early identification of this metronidazole-related complication and early cessation of the drug are essential for treatment.

Background: Contrast-induced encephalopathy (CIE) is a rare disease, whose etiology and risk factors remain unclear and need investigation., Methods: We collected 7 CIE cases from 2646 patients injected with ioversol and 5 CIE cases from 526 patients injected with iopromide, all of whom underwent neurointervention surgery in our regional centers. The incidence of CIE, its characteristics, and risks were analyzed in both groups., Results: The overall incidence of CIE was 0.38%, specifically 0.95% and 0.26% in the iopromide and ioversol groups, respectively; the former incidence was significantly higher than the latter (P = 0.029). The risk of CIE with iopromide was 3.567 to 3.618 times higher than that with ioversol (single-factor analysis odds ratio [OR], 3.618; 95% confidence interval [CI], 1.144-11.443; P = 0.029; multifactor analysis OR, 3.567 (95% CI, 0.827-15.379); P = 0.088). Moreover, acute cerebral infarction was an independent risk factor for CIE (OR, 4.024; 95% CI, 1.137-14.236; P = 0.031). Contrast-induced encephalopathy could occur within 5 minutes after injecting contrast media. The CIE characteristics differed according to the medium. In the ioversol group, the most common characteristic was visual disorder (71.43%), whereas in the iopromide group, the most common characteristic was delirium (100%)., Conclusions: Compared with ioversol, iopromide appeared more likely to lead to CIE. Acute cerebral infarction was an independent risk factor for CIE. The earliest CIE onset was within 5 minutes after injecting contrast. The characteristics of CIE varied significantly for different contrast media.

Objectives: Neuropsychiatric symptoms have been reported in people living with HIV (PLWH) on integrase strand transfer inhibitors (INSTIs) in postmarketing analysis. Limited data exist regarding brain integrity (function and structure) in PLWH prescribed INSTIs compared with other HIV treatment regimens., Design: A cross-sectional analysis of PLWH on combined antiretroviral therapy aged more than 18 years at a single institution., Methods: Neuropsychological tests were administered to calculate domain deficit scores in learning/memory, executive function and motor/psychomotor domains. Cortical and subcortical volumes from MRI were obtained using the FreeSurfer software suite (v5.3)., Results: Of 202 participants, median age 55 (48, 60) years old, 49% were on INSTI-based combined antiretroviral therapy. PLWH on INSTIs were similar to individuals on non-INSTIs in terms of age, sex, race, education years, smoking history, depression scores, psychiatric medication use, presence of hepatitis C infection, history of substance use, HIV infection duration and recent or nadir CD4 T-cell count. Participants in the INSTI group performed worse than non-INSTI users in the verbal learning and memory domain [1.5 (interquartile range 0, 2.5) versus 1 (0, 2); P = 0.016]. The INSTI and non-INSTI groups were similar for other cognitive domains. Frontal, brain stem and cerebellar volumes were reduced in INSTI compared with non-INSTI users (all P = <0.05)., Conclusion: We demonstrated modest differences in learning/memory performance and smaller brain volumes in PLWH on INSTI-based regimens compared with non-INSTI users. Prospective studies are needed to define mechanisms and the clinical significance of reduced brain integrity in PLWH on INSTIs.

For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand-foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy.

Purpose of Review: The literature on air pollution and brain health is rapidly expanding and it is a universal finding that greater exposure to air pollution is associated with worse outcomes, whatever the measure of brain health used (clinical dementia, neuroimaging correlates, or cognitive impairment). However, there are a number of important questions which the studies currently published are not able to answer: when in the life course does exposure to air pollution most have the most impact?; which pollutant(s) or components are most important?; and since dementia describes a heterogeneous group of conditions, which is most affected by exposure to air pollution?, Recent Findings: We briefly review and discuss the nine articles which have been published so far in 2018, so recently that they were not included in the four review articles also published this year. We highlight the variation in estimates of air pollution used but the consistency in deriving them from residential address (with or without some knowledge of an individual's previous home locations)., Summary: We are now at the stage when the research agenda needs to be agreed and we believe these three questions should be the focus of future research.

Hyperammonemic encephalopathy secondary to the use of valproate is rare without evidence of hepatotoxicity, and it usually presents with confusion, agitation, irritability, cognitive disturbances, lethargy, coma, and death. We present the case of a 21-year-old woman presenting with catatonia as a manifestation of hyperammonemic encephalopathy that resolved with the normalization of ammonia and suspension of valproate.

A 74-year-old man with peripheral neuropathy due to diabetes presented with deliberate ingestion of 450 mg of pregabalin (PBG) over a period of 8 hours followed by altered mental status. A bedside electroencephalogram was performed to rule out nonconvulsive status epilepticus, which showed continuous triphasic waves (TWs) with slow background activity. He recovered after 48 hours of stopping PBG, and his repeat electroencephalogram after 72 hours did not show any TWs. We present a rare case of PBG-induced TWs thereby highlighting the extent of the etiologic spectrum of TWs and discussing the literature related to this association.

Acute hyperammonemic encephalopathy induced by fluoropyrimidines (FPs) is a rare complication. Its pathophysiology remains unclear, especially given the currently used regimens, including intermediate-doses of 5-fluorouracil (5-FU) or oral FP agents. We aimed to characterize the clinical manifestations in cancer patients who developed hyperammonemic encephalopathy after receiving FP-based chemotherapy.We retrospectively reviewed 1786 patients with gastrointestinal or primary-unknown cancer who received FP-based regimens between 2007 and 2012. Eleven patients (0.6%) developed acute hyperammonemic encephalopathy. The incidence according to the administered anticancer drugs were as follows: 5-FU (8 of 1176, 0.7%), S-1 (1 of 679, 0.1%), capecitabine (2 of 225, 0.9%), and tegafur-uracil (UFT) (0 of 39, 0%). Ten patients (90.9%) had at least 1 aggravating factor, including infection, dehydration, constipation, renal dysfunction, and muscle loss. All the 10 patients met the definition of sarcopenia. Median time to the onset of hyperammonemic encephalopathy in the cycle was 3 days (range: 2-21). Three patients (27.3%) developed encephalopathy during the first cycle of the regimen and the remaining 8 patients during the second or more cycles. Seven patients (63.6%) had received at least 1 other FP-containing regimen before without episodes of encephalopathy.All patients recovered soon after immediate discontinuation of chemotherapy and supportive therapies, such as hydration, infusion of branched-chain amino acids, and oral lactulose intake, with a median time to recovery of 2 days (range: <1-7). Four patients (36.4%) received FP-based regimens after improvement of symptoms; 3 patients were successfully managed with dose reduction, and 1 patient, who had developed encephalopathy due to S-1 monotherapy, received modified FOLFOX-6 therapy without encephalopathy later.FP-associated acute hyperammonemic encephalopathy is extremely rare, but a possible event at any time and even during the administration of oral FP agents. Particular attention is warranted when giving FP-based therapy for patients with aggravating factors, such as sarcopenia. This complication can be properly managed with early detection.

Delayed encephalopathy after carbon monoxide (CO) poisoning (DEACMP) is still a clinical challenge. This study aimed to investigate the efficacy of combined therapy of mesenchymal stem cell (MSC) transplantation and butylphthalide in DEACMP patients.Forty-two DEACMP patients were treated with 1 of the 3 therapies: combined therapy of MSC transplantation and butylphthalide; MSC transplantation alone; or hyperbaric oxygen therapy. The MSCs were alternatively injected into the subarachnoid space and the carotid artery using a self-made high-pressure injector. The Mini-Mental State Examination and the Barthel index of activities of daily living were administered before the treatment, and at 1 month, 3 months, and 6 months after the treatment. Computed tomography and magnetic resonance imaging results before and after the treatment were compared.At 1 month, 3 months, and 6 months after the treatment, the Mini-Mental State Examination scores and the Barthl scores were significantly higher in patients with the combined therapy of MSC transplantation and butylphthalide than those in patients with MSC transplantation alone or hyperbaric oxygen therapy (all P < 0.0001). No significant adverse events occurred.The combination of MSC transplantation and butylphthalide is safe and effective in treating DEACMP., Competing Interests: The authors report no conflicts of interest.

Encephalopathy is a common side effect of ifosfamide, occurring in up to 30% of patients. Although self-resolving in most cases, death secondary to severe encephalopathy has been reported. Methylene blue and thiamine have been occasionally successful as treatment. We report a case of an 11-year-old girl with relapsed neuroblastoma who developed grade 4 ifosfamide-induced encephalopathy. She showed no initial response to methylene blue and thiamine. She remained neurologically impaired and continuous veno-venous hemodiafiltration was started, with rapid resolution of encephalopathy. This is the first report of continuous veno-venous hemodiafiltration use for suspected ifosfamide-induced encephalopathy in the pediatric population.

Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state., (© 2016 American Academy of Neurology.)

Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 μg/dL and 27.27 μIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 μg/dL and thyroid stimulating hormone level decreased 22.34 μIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC.

Background: In previous studies in virologically suppressed patients, protease inhibitor monotherapy has shown trends for more low-level elevations in HIV-1 RNA compared with triple therapy, but no increase in the risk of drug resistance., Methods: A total of 273 patients with HIV-1 RNA less than 50 copies/ml on first-line antiretrovirals switched to darunavir/ritonavir (DRV/r) 800/100 mg once daily, either as monotherapy (n = 137) or as triple therapy with two nucleoside analogues (n = 136). Treatment failure was defined as HIV-1 RNA levels 50 copies/ml or above, or discontinuation of study treatment by week 48 (FDA Snapshot algorithm)., Results: Patients were 83% male and 88% white, with mean age 42 years. In the primary efficacy analysis, HIV-1 RNA less than 50 copies/ml by week 48 [intention-to-treat (ITT)] was 118 of 137 (86%) in the DRV/r monotherapy arm versus 129 of 136 (95%) in the triple therapy arm (difference = -8.7%, 95% confidence interval -15.50, -1.80). In a post-hoc analysis, for patients with nadir CD4 cell count 200 cells/μl or above, rates of HIV-1 RNA suppression were 91 of 96 (95%) in the DRV/r monotherapy arm and 100 of 106 (94%) in the triple therapy arm. There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy. Two patients in the monotherapy arm with CD4 nadir less than 200 cells/μl developed viraemia in both cerebrospinal fluid (CSF) and plasma, with one symptomatic case., Conclusions: In this study for patients with HIV-1 RNA less than 50 copies/ml at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple therapy at week 48 in the primary ITT switch equals failure analysis, with two cases of viraemia in the CSF in the protease inhibitor monotherapy arm.

Five-year survival from childhood acute lymphoblastic leukemia (ALL) approaches 90%, but 40% of survivors experience central nervous system (CNS) treatment-related cognitive problems. Despite considerable evidence for cognitive problems, less is known about mechanisms of neurological injury. Our purpose was to investigate oxidative stress, measured by lipid peroxidation, as a mechanism of CNS treatment-related neurological injury. The sample included 55 children (mean age at diagnosis=6.84 y, SD=3.40) who received intrathecal and intravenous chemotherapy for CNS-directed treatment according to Children's Oncology Group protocols. Glycerophospholipids were extracted from cerebrospinal fluid samples obtained at diagnosis and during intrathecal chemotherapy administration. Unoxidized and oxidized phosphatidylcholine (PC) and phosphatidylinositol (PI) were measured by normal phase high-performance liquid chromatography with diode array detection, and analyzed with a general linear model for repeated measures analysis of variance. Compared with the diagnostic cerebrospinal fluid sample, unoxidized and oxidized PC and PI increased significantly across treatment phases. Amount of intravenous methotrexate received was significantly correlated with oxidized PI, and age at time of ALL diagnosis was significantly associated with oxidized PC. These findings support our hypothesis that oxidative stress is a mechanism of neurological injury associated with CNS-directed treatment for ALL.

Donepezil and memantine are commonly prescribed antidementia drugs. There is a paucity of literature concerning pediatric ingestions of these drugs. We describe a case of a 2-year-old child who developed encephalopathy after an unintentional ingestion of donepezil and memantine. A 2-year-old girl was found by her family members agitated and reporting visual hallucinations. In the emergency department, she became sedated and had rightward eye deviation. She was hospitalized and had extensive neurological and infectious disease testing that was unremarkable, except for an electroencephalogram, which showed a nonspecific encephalopathy. She recovered with supportive care for 72 hours. Serum concentrations of donepezil and memantine measured on arrival were 470 ng/mL (therapeutic range, 25-50 ng/mL) and 32 ng/mL (therapeutic range, 70-150 ng/mL), respectively. This case demonstrates that unintentional ingestions of memantine and donepezil can potentially cause significant and prolonged neurological symptoms in pediatric patients.

Ifosfamide and methotrexate are widely used for the treatment of pediatric osteosarcoma. However, both these chemotherapeutic drugs can cause encephalopathy. A 17-year-old girl presented with profound hearing loss and dizziness during a postoperative course of ifosfamide, 20 days after a course of methotrexate. Cerebral magnetic resonance imaging (MRI) showed bilateral white matter hypersignal in Fluid Attenuated Inversion Recovery sequences. The clinical evolution was rapidly favorable after methylene blue infusion. This is the second reported case of acute deafness, possibly associated with ifosfamide, whereas MRI data revealed unnoticed chronic methotrexate toxicity. Systematic MRI screening and hearing evaluation may be useful in such cases.

We describe an adolescent case of Guillain-Barré syndrome (GBS) mimicking acute methotrexate-associated encephalopathy during chemotherapy for lymphoblastic lymphoma. Although initial presentations of hemiparesis and irritability were suggestive of acute encephalopathy, the diminished deep tendon reflexes and subsequent rapid progression to flaccid triparesis with bulbar palsy were consistent with GBS. After the initiation of intravenous immunoglobulin therapy her symptoms improved rapidly, and the diagnosis of GBS was confirmed by nerve conduction studies and cerebrospinal fluid examination in recovery phase. GBS should be considered in the differential diagnosis of acute methotrexate-associated encephalopathy, although GBS is a rare neurologic complication.

Purpose: The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity., Methods: A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed., Results: A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy., Conclusion: Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss approximately 1 month after treatment.

Objective: To evaluate the currently available evidence for the deleterious effects of sedatives and anesthetics on developing brain structure and neurocognitive function., Design: A computerized, bibliographic search of the literature regarding neurodegenerative effects of sedatives and anesthetics in the developing brain., Measurements and Main Results: A growing number of animal studies demonstrate widespread structural damage of the developing brain and long-lasting neurocognitive abnormalities after exposure to sedatives commonly used in neonatal and pediatric critical care medicine. These studies reveal a dose and exposure time dependence of neuronal cell death, characterize its molecular pathways, and suggest a potential early window of susceptibility in humans. Several clinical studies document neurologic abnormalities in neonatal intensive care unit graduates, usually attributed to comorbidities. Emerging human epidemiologic data, however, do not exclude prolonged or repetitive exposure to sedatives and anesthetics in early childhood as contributing factors to some of these abnormalities., Conclusions: Neuronal cell death after neonatal exposure to sedatives and anesthetics has been clearly demonstrated in developing animal models. Although the relevance for human medicine remains speculative, the phenomenon's serious implications for public health necessitate further preclinical and clinical studies. Intensivists using sedatives and anesthetics in neonates and infants need to stay informed about this rapidly emerging field of research.

A patient with valproate-induced hyperammonemic encephalopathy presented with altered mental status and hyperammonemia in the context of normal liver functions. Fortunately, altered mental status and elevated plasma ammonia level normalized 1 day after discontinuation of divalproex sodium (Depakote). The case analysis suggests a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy in the context of normal liver functions. Possible mechanisms of the encephalopathy and hyperammonemia are discussed. For example, valproate has diverse metabolic effects that include regulating levels of ammonia by altering activity of the urea cycle, whose first step uses HCO3 in the synthesis of carbamoylphosphate. Topiramate's inhibition of carbonic anhydrase activity may be the basis of its possible synergy with valproate by affecting levels of HCO3.

We describe a patient who was in a stupor for several days after combined general-spinal anesthesia. Both clinical manifestations and magnetic resonance imaging findings were consistent with posterior reversible encephalopathy syndrome and resolved after the patient recovered spontaneously.

Although delayed hemolytic transfusion reaction (DHTR) has been widely recognized as a serious complication of red blood cell transfusion in patients with sickle cell disease (SCD), there is no consensus on its optimal management. Discontinuation of transfusion is recommended, whereas corticosteroids and immunoglobulins are considered to be beneficial. We report 2 children with sickle cell anemia who were diagnosed with DHTR and experienced a subsequent neurologic event in the course of treatment with corticosteroids. The role of corticosteroids as possible precipitating factors of neurologic complications is discussed. Pending a better understanding of the chain of events of DHTR, SCD children with DHTR should receive steroids with great caution.

Background and Purpose: Sublethal injury induces tolerance to a subsequent lethal insult, a phenomenon termed preconditioning (PC). PC occurs within hours (early tolerance) or days (delayed tolerance) after the inducing stimulus. In the brain, delayed tolerance has been studied extensively, but very little is known about early tolerance. We investigated whether the proinflammatory agent lipopolysaccharide (LPS), a well-established inducer of delayed tolerance, can also induce early tolerance and, if so, whether nitric oxide (NO) is involved in its mechanisms., Methods: In C57BL/6 mice, LPS was administered and N-methyl-D-aspartate (NMDA) was microinjected into the neocortex 30 minutes to 24 hours later. Lesion volume was assessed 24 hours after NMDA administration in thionine-stained sections., Results: LPS reduced NMDA lesions when administered 1 hour (-25+/-1%; P<0.05, n=5 per group) or 24 hours (-25+/-4%; P<0.05, n=5 per group) before NMDA application. LPS administration 30 minutes or 2 to 4 hours before NMDA administration was not neuroprotective (P>0.05). The protection at 1 hour was independent of protein synthesis and was blocked by inhibition of neuronal NO synthase or soluble guanylyl cyclase. Furthermore, early protection was not observed in neuronal or endothelial NO synthase-null mice, but it was present in inducible NO synthase-null mice., Conclusions: The data demonstrate that LPS induces both early and late tolerance. At variance with delayed tolerance, which depends on inducible NO synthase and peroxynitrite, early tolerance is mediated by endothelial and neuronal NO through production of cGMP. The findings suggest that LPS can trigger signaling between endothelial cells and neurons, leading to NO production and cGMP-dependent neuroprotection.

A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later.