Neurotoxic Manifestations Research Articles

Ifosfamide-Induced Encephalopathy in Relapsed Lymphoma: Report of Two Cases

Objective: Ifosfamide is a chemotherapeutic drug available for various malignancy, including lymphoma. Ifosfamide has adverse effects including myelosuppression, nephrotoxicity, hemorrhagic cystitis, and neurotoxicity. Encephalopathy is a severe manifestation of neurotoxicity due to ifosfamide, with an incidence of 10-40%. This study aimed to report two cases of ifosfamide-induced encephalopathy. Case: This case studies reported two relapsed lymphoma patients with almost similar characteristics who received ifosfamide chemotherapy. The first case of 48-year-old woman with relapsed High-Grade B-cell lymphoma stage IIIBE while the second case of 38-year-old woman with relapsed non-hodgkin lymphoma.Results: The first case showed a good outcome with improvement in consciousness 48 hours after stopping ifosfamide and thiamine, while the second case experienced tumor lysis syndrome, leading to the death of the patient.Conclusion: Mechanism of ifosfamide-induced encephalopathy remains unclear, with the hypothesis from the neurotoxic effects of the resultant metabolite chloracetyldehide. Radiology examination of the brain and electroencephalography is required to rule out other differential diagnoses. Early recognition of adverse effects, followed by immediate discontinuation of ifosfamide, administration of therapy, such as methylene blue and/or thiamine, and supportive treatment usually produced good outcomes.

Core outcome set for intervention research on snakebite envenomation in South Asia

BackgroundThe 2019 WHO strategy to reduce snakebite burden emphasises the need for fostering research on snakebite treatments. A core outcome set (COS) is a consensus minimal list of outcomes that...

Polymyxin B neurotoxicity as manifestation of a serious life-threatening adverse reaction: clinical case

The aim of this work is to describe a clinical case of a serious life-threatening adverse reaction in the form of neurotoxicity (convulsions, apnea requiring mechanical ventilation) to the polymyxin B drug, and also to remind that manifestations of neurotoxicity can be extremely varied and nonspecific, and do not occur after every administration, can be delayed, require vigilance and careful monitoring both from the attending physicians and from anesthesiologistsresuscitators, neurologists, ophthalmologists, etc.A 62-year-old female patient diagnosed with stage IIIB T4G3N0M0 pleomorphic soft tissue sarcoma of the right thigh, condition after combination treatment, developed infection and necrosis of the postoperative wound (recto-abdominal flap). According to the results of a microbiological study and an antibiogram, the patient received polymyxin B as part of combination antibacterial therapy. On days 4, 5, 6, 7 of polymyxin administration, the patient experienced the following symptoms in various combinations: weakness, numbness of the face, paresthesia, paresis of the limbs, partial convulsions, respiratory depression, and apnea.After establishing a connection between neurologicalsymptoms and intravenous administration of polymyxin B (the total score on the Naranjo scale was 6 points, the degree of reliability of the “adverse reaction–drug” relationship was probable) and drug withdrawal, manifestations of neurotoxicity completely disappeared and did not reoccur. The patient was discharged in satisfactory condition.In a patient with symptoms of damage to the nervous system, it is necessary to conduct multiple differential diagnostic search to exclude stroke, epilepsy, encephalitis, hereditary and acquired neurodegenerative diseases, as well as side effects of medications. At the slightest suspicion of the likelihood of an adverse reaction to polymyxin B/colistimethate sodium, the Naranjo algorithm must be used to establish a cause-and-effect relationship between the adverse reaction and the drug.

Possibilities of Using Nootropic Drugs to Reduce Neurotoxic Reactions Caused by Anti-tuberculosis Drugs in Experimental Conditions

The objective: to evaluate the neuroprotective activity of cytoflavin and combinations of mexidol with vitamin B6 or Magne B6 by changes in behavioral reactions in rats during in-take of a neurotoxic combination of anti-tuberculosis drugs.Subjects and Methods. Non-linear female rats divided in 4 groups were used in this study. For 14 days, all rats received a combination of Mxf+Lzd+Cs+Pto daily. Additionally, rats of Group 2 were administered cytoflavin before administration of the basic combination; Group 3 – Mexidol + vitamin B6; Group 4 - Mexidol + Magne B6. Doses of anti-tuberculosis drugs, cytoflavin, Mexidol, vitamin B6 and Magne B6 correspond to the recommended doses for humans. The manifestation of neurotoxicity was assessed by changes in behavioral reactions by Open Field Test.Results. Neurotoxicity caused by the combination Mxf+Lzd+Cs+Pto was manifested by a decrease in motor activity, exploratory activity and grooming. With cytoflavin administration, all parameters of behavioral reactions in rats improved. When using Mexidol with vitamin B6, only a slight decrease in grooming versus the baseline level was observed. There was a less qualitative decrease in neurotoxicity manifestations with administration of Mexidol in combination with Magne B6.

Patterns of neurotoxicity among patients receiving chimeric antigen receptor T-cell therapy: A single-centre cohort study.

Immune effector cell-associated neurotoxicity syndrome (ICANS) is an important complication of chimeric antigen receptor T-cell (CAR-T) therapy. This study aims to identify the patterns of neurotoxicity among patients with ICANS at a tertiary referral centre in Australia. This single-centre, prospective cohort study included all consecutively recruited patients who underwent CAR-T therapy for eligible haematological malignancies. All patients underwent a comprehensive neurological assessment and cognitive screening before CAR-T infusion, during the development of ICANS, and 1 month after treatment. Baseline demographic characteristics, incidence, and neurological patterns of neurotoxicity management were evaluated. Over a 19-month period, 23% (12) of the 53 eligible patients developed neurotoxicity (10/12 [83%] being grade 1). All patients showed changes in handwriting and tremor as their initial presentation. Changes in cognition were manifested in most of the patients, with a more substantial drop noted in their Montreal Cognitive Assessment compared to immune effector cell-associated encephalopathy scores. All manifestations of neurotoxicity were short-lived and resolved within a 1-month period, with a mean duration of 8.2 days (range = 1-33). The patterns of CAR-T-related neurotoxicity often include change in handwriting, tremor, and mild confusional state, especially early in their evolution. These may remain undetected by routine neurological surveillance. These features represent accessible clinical markers of incipient ICANS.

Azithromycin induces neurotoxicity in zebrafish by interfering with the VEGF/Notch signaling pathway

Azithromycin (AZM) is a widely used antibiotic in both human and veterinary medicine, and its use has significantly increased during the COVID-19 pandemic. However, potential adverse effects of AZM on aquatic organisms have not been well studied. In this study, we explored the neurotoxicity of AZM in zebrafish and delved into its underlying mechanisms. Our results showed that AZM exposure resulted in a spectrum of detrimental effects in zebrafish, encompassing abnormal behaviors, damaged neuronal development, aberrant lateral line nervous system development, vascular malformations and perturbed expression of genes related to neural development. Moreover, we observed a concentration-dependent exacerbation of these neurotoxic manifestations with increasing AZM concentrations. Notably, AZM induced excessive cell apoptosis and oxidative stress damage. In addition, alterations in the expression levels of the genes involved in the VEGF/Notch signaling pathway were evident in AZM-exposed zebrafish. Consequently, we hypothesize that AZM may induce neurotoxicity by influencing the VEGF/Notch signaling pathway. To validate this hypothesis, we introduced a VEGF signaling inhibitor, axitinib, and a Notch signaling agonist, valproic acid, alongside AZM exposure. Remarkably, the administration of these rescue compounds significantly mitigated the neurotoxic effects induced by AZM. This dual verification provides compelling evidence that AZM indeed induces neurotoxicity during the early developmental stages of zebrafish, primarily through its interference with the VEGF/Notch pathway. Innovatively, our study reveals the molecular mechanism of AZM-induced neurotoxicity from the perspective of the close connection between blood vessels and nervous system. These findings provide new insights into the potential mechanisms underlying the neurotoxic effect of antibiotics and highlight the need for further investigation into the ecotoxicological effects of antibiotics on aquatic organisms and the potential risks to human health.

TREM2 expression on the microglia resolved lead exposure-induced neuroinflammation by promoting anti-inflammatory activities

Neurotoxicity caused by environmental lead (Pb) pollution is a worldwide public health concern, and developing a therapeutic strategy against Pb-induced neurotoxicity is an important area in the current research. Our prior research has demonstrated the significant involvement of microglia-mediated inflammatory responses in the manifestation of Pb-induced neurotoxicity. Additionally, the suppression of proinflammatory mediator activity significantly mitigated the toxic effects associated with Pb exposure. Recent studies have highlighted the critical role of the triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of neurodegenerative disorders. TREM2 exerted protective effects on inflammation, but whether TREM2 is involved in Pb-induced neuroinflammation is poorly understood. In the present study, cell culture experiments and animal models were designed to investigate the role of TREM2 in Pb’s neuroinflammation. We examined the impact of pro- and anti-inflammatory cytokines involved in Pb-induced neuroinflammation. Flow cytometry and microscopy techniques were applied to detect microglia phagocytosis and migration ability. Our results showed that Pb treatment significantly downregulated TREM2 expression and altered the localization of TREM2 expression in microglia. The protein expression of TREM2 was restored, and the inflammatory responses provoked by Pb exposure were ameliorated upon the overexpression of TREM2. Furthermore, the phagocytosis and migratory capabilities of microglia, which were impaired due to Pb exposure, were alleviated by TREM2 overexpression. Our in vitro findings were corroborated in vivo, demonstrating that TREM2 regulates the anti-inflammatory functions of microglia, thereby mitigating Pb-induced neuroinflammation. Our results provide insights into the detailed mechanism by which TREM2 alleviates Pb-induced neuroinflammation and suggest that activating the anti-inflammatory functions of TREM2 may represent a potential therapeutic strategy against environmental Pb-induced neurotoxicity.

Isoimperatorin therapeutic effect against aluminum induced neurotoxicity in albino mice.

Background: Although aluminum (Al) is not biologically crucial to the human body, classical studies have demonstrated that excessive human exposure to Al can induce oxidative damage, neuroinflammatory conditions and neurotoxic manifestations implicated in Alzheimer's disease (AD). Exposure to Al was reported to be associated with oxidative damage, neuroinflammation, and to enhance progressive multiregional neurodegeneration in animal models. Several plant-derived natural biomolecules have been recently used to reduce the toxic effects of Al through decreasing the oxidative stress and the associated diseases. A good candidate still to be tested is an active natural furanocoumarin, the isoimperatorin (IMP) that can be extracted from Lemon and lime oils and other plants. Here, we examined the neuroprotective effects of IMP on aluminum chloride (AlCl3)-induced neurotoxicity in albino mice. Methods: Twenty-four male albino mice were used in this study. Mice were randomly devided into 5 groups. The first group was given distilled water as a control, the second group was given AlCl3 orally (10mg/wt/day) starting from the 2nd week to the end of the 6th week, the third group received AlCl3 orally and IMP interperitoneally, i. p. (30mg/wt/day) starting from week 2 till week 6 where IMP was supplement 1st and then 4h later AlCl3 was given to mice. The fourth group received the control (IMP 30mg/wt, i. p.) from the 2nd week till the end of the experiment. Rodent models of central nervous system (CNS) disorders were assessed using object location memory and Y-maze tests in 6th week began. Essential anti-inflammatory and oxidative stress indicators were evaluated, including interleukin-1 β (IL-1β), tumor necrosis factor α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity (CAT). In addition, serum levels of brain neurotransmitters such as corticosterone, acetylcholine (ACh), dopamine and serotonin in brain homogenates were measured calorimetrically. Results: The study results revealed that the daily treatment of AlCl3 upregulated the TNF-α and IL-1β levels, increased MDA accumulation, and decreased TAC and CAT activity. In addition, aluminum induced a reduction in concentrations of ACh, serotonin and dopamine in the brain. However, IMP significantly ameliorates the effect of AlCl3 through modulating the antioxidant and regulating the inflammatory response through targeting Nrf2 (NF-E2-related factor 2) and mitogen-activated protein kinase (MAPK). Conclusion: Thus, IMP might be a promising treatment option for neurotoxicity and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which are associated with neuro-inflammation and oxidative stress.

Current understanding of chemotherapy-induced peripheral neuropathy (literature review)

This review focuses on chemotherapy-induced polyneuropathy, which is a fairly common side effect and affects not only the quality of life of patients with malignancies, but can also lead to a change in patient management tactics, namely dose modification, delay of drug administration to complete cessation of treatment, which threatens the life of the patient. Chemotherapy-induced polyneuropathy is based on different mechanisms of damaging effects depending on the type of cytotoxic agent. The most neurotoxic drugs are platinum drugs, taxanes, periwinkle alkaloids, bortezomib, and thalidomide. As a result of neurotoxic effects, damage occurs to thin and thick fibers of peripheral nerves. However, it is still a mystery why one patient develops manifestations of neurotoxicity and another does not. Therefore, the modern medical community is faced with the urgent question of further study of the mechanisms of development, risk factors, as well as the search for biomarkers and the development of prevention and treatment of chemotherapy-induced polyneuropathy. The results of studies on the mechanism of onset, clinic, diagnosis, prevention and treatment of chemotherapy-induced polyneuropathies are summarized.

Specific Manifestations of Neurotoxicity of Some Drug Combinations for Treatment of Drug Resistant Tuberculosis from the Perspective of Experimental Studies

The objective: to evaluate comparative neurotoxicity of combinations of anti-tuberculosis and antimicrobial drugs with different and similar toxic potentials assessing behavioral changes in rats.Subjects and Methods: non-linear female rats divided in 3 groups were used in this study. For 14 days, the rats received a daily combinations of drugs: Group 1 – Mxf + Lzd + Cs + Pto, Group 2 – Mxf + Bdq + Cs + Z , and Group 3 – Bdq + Lzd + Cfz + Z. Neurotoxicity was assessed by changes in behavioral responses using Open Field Test. The number of crossed squares and racks was recorded which characterized horizontal and vertical activity, also peeping into burrows (exploratory activity), the number of groomings (washing and scratching) and physiological functions were registered.Results. In rats of Group 1 versus baseline parameters, we observed a significant limitation of horizontal motor activity and a sharp decrease (by 5 times) in exploratory activity, a 2.8-fold decrease in the number of groomings which indicated emotional suppression. In rats of Groups 2 and 3, the decrease in motor and exploratory activity was insignificant but there was a more pronounced emotional depression. The use of the Mxf + Lzd + Cs + Pto combination in which all drugs possessed a neurotoxic potential, led to diverse and profound changes in behavioral responses which indicated a pronounced neurotoxic effect.

Neuroprotective potential of ferulic acid against cyclophosphamide-induced neuroinflammation and behavioral changes.

In the present study, ferulic acid (FRA) has been explored for possible neuroprotective effects against cyclophosphamide (CP)-induced neurotoxicity in the Swiss Albino mice. Animals were divided into five groups and treated with FRA for fourteen days and a single dose of CP was administered on the seventh day. Animals were subjected to neurobehavioral tests such as the forced swim test and Morris Water Maze test. On day fifteenth, the brain was removed and used for biochemical analysis. The outcome of the study showed that CP administration induced significant neurotoxicity in the form of depression, anxiety, and cognitive dysfunction. Cyclophosphamide administration also reduced the activity of antioxidant enzymes, reduced the level of neurotransmitters (i.e., dopamine, 5-HT, and BDNF), anti-inflammatory cytokines (IL-10), and increased lipid peroxidation and proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Additionally, CP administration increased the level of acetylcholine esterase. Treatment with FRA significantly reversed these behavioral, and biochemical markers towards normal and mitigated CP-induced neurotoxic manifestation. PRACTICAL APPLICATIONS: Ferulic acid has a variety of pharmacological activities viz. anti-inflammatory, antioxidant, antimicrobial activity, anti-cancer, and anti-diabetic effects. The results of the present study showed that FRA mitigates the neurotoxicity (i.e., alteration of neurotransmitters, inflammation, and oxidative stress) induced by CP in mice. Treatment with FRA knowingly overturned the behavioral and biochemical markers in the direction of the moderated CP-influenced neurotoxic demonstration. Thus, FRA can be useful in the prevention of anticancer drugs induced neurotoxicity. Contrariwise, supplementary in-depth studies are obligatory to bring FRA from bench to bedside that it be used as an adjuvant among chemotherapeutically treated patients.

Antioxidant Supplementation with N-Acetylcysteine as a Protection Against Cisplatin-Induced Motor Impairment in Rats

Abstract The aim of this study was to estimate a potential beneficial influence of N-acetylcysteine (NAC) in the treatment of cisplatin-induced motor impairment. We included 32 male Wistar albino rats, divided into 4 equal groups: control (received saline on the 1st and 5th day), cisplatin – CIS (received saline on the 1st and cisplatin 7.5 mg/kg i.p. on the 5th day), NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p.), and CIS+NAC (received NAC on the 1st and 5th day, 500 mg/kg i.p. and cisplatin 7.5 mg/kg i.p. on the 5th day) group. Motor performance was estimated by rotarod, grip wire, open field (OF), elevated plus maze (EPM) and beamwalking (BW) tests on the 10th day. Cisplatin administration resulted in decreased motor performance in all tests, except for BW test, compared to the control group. NAC supplementation on its own had no significant effect on motor performance parameters. However, simultaneous administration of NAC along with cisplatin reversed negative impact of cisplatin in rotarod, OF and EPM tests, with no significant effect on the results obtained in grip wire test. The results of this study confirmed numerous motoric manifestations of cisplatin-induced neurotoxicity in rats. However, the decline in most of the estimated parameters was successfully prevented by antioxidant supplementation with NAC.

Unmasking the ties of snake bite poisoning and COVID-19

BackgroundSnake bite envenoming is a neglected tropical disease with variable clinical presentation, neurotoxic manifestations (respiratory paralysis), rhabdomyolysis, cardiotoxicity, autonomic hyperactivity, and/or coagulation abnormalities. There is limited data on the clinical course of the envenomation in an incidentally diagnosed COVID-19 patient.Case presentationA 17-year-old male with history of snake bite and neuroparalysis developed shortness of breath. He was treated with lyophilized polyvalent anti-snake venom (ASV) on admission in the emergency department and mechanical ventilation. Subsequently, he tested positive for COVID-19 infection. No immunomodulatory therapy was administered, and patient was extubated on the 5th day of ICU admission without any neurological deficit.ConclusionsCoinfections of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus with snake bite poisoning lead to diagnostic dilemmas and controversies in management practices. Abnormalities of coagulation need to be cautiously addressed, and cause of development of pneumonia needs to be identified. The rapid recovery of the patient in our case theoretically can be explained on the organ-protective potential of snake-derived peptides; a large case series is however needed to prove the same.

Prevalence and management of methotrexate-induced neurotoxicity in pediatric patients with osteosarcoma: a single-center experience.

To determine the incidence, clinical presentation, and outcome of methotrexate (MTX) associated neurotoxicity in pediatric patients treated for osteosarcoma, with the aim of identifying possible risk factors and suggesting recommended treatment for these sequelae. All medical files of patients treated for osteosarcoma in a single pediatric haemato-oncology center between November 2011 and August 2021 were retrospectively reviewed. All patients were treated according to the EURAMOS AOST0331 protocol, using cisplatin, doxorubicin, and high-dose MTX at a dose of 12g/m2 over 4h. Seventy-eight patients with osteosarcoma were identified (age range 5 to 23years, 42 males). Seven patients (9%) sustained neurotoxicity following treatment with high-dose MTX. Manifestations of neurotoxicity included among others, generalized seizures, confusion, encephalopathy, dysarthria, and choreiform movements. All but one episode occurred following two sequential cycles of high-dose MTX. All 7 had subacute toxicity, 5-10days following MTX administration, and 1 had both acute and subacute toxicity. Brain MRI was performed for all patients and demonstrated typical MRI changes attributed to MTX neurotoxicity in 4 of them. Two patients received aminophylline; one patient received dextromethorphan. Patients with normal MRI imaging resumed MTX therapy without any sequels. No risk factors were found for high-dose MTX-related toxicity occurrence. The time of risk of neurotoxicity due to high-dose MTX treatment for osteosarcoma is days 5-10 following two sequential treatment cycles. These findings together with treatment options for these adverse effects should be detailed in the therapeutic protocol of MTX use among pediatric patients with osteosarcoma.

Pathogenic mechanisms and therapeutic promise of phytochemicals and nanocarriers based drug delivery against radiotherapy-induced neurotoxic manifestations

Radiotherapy is one of the extensively used therapeutic modalities in glioblastoma and other types of cancers. Radiotherapy is either used as a first-line approach or combined with pharmacotherapy or surgery to manage and treat cancer. Although the use of radiotherapy significantly increased the survival time of patients, but its use has been reported with marked neuroinflammation and cognitive dysfunction that eventually reduced the quality of life of patients. Based on the preclinical and clinical investigations, the profound role of increased oxidative stress, nuclear translocation of NF-kB, production of proinflammatory cytokines such as TNF-α, IL-6, IL-β, increased level of MMPs, increased apoptosis, reduced angiogenesis, neurogenesis, and histological aberrations in CA1, CA2, CA3 and DG region of the hippocampus have been reported. Various pharmacotherapeutic drugs are being used as an adjuvant to counteract this neurotoxic manifestation. Still, most of these drugs suffer from systemic adverse effect, causes interference to ongoing chemotherapy, and exhibit pharmacokinetic limitations in crossing the blood-brain barrier. Therefore, various phytoconstituents, their nano carrier-based drug delivery systems and miRNAs have been explored to overcome the aforementioned limitations. The present review is focused on the mechanism and evidence of radiotherapy-induced neuroinflammation and cognitive dysfunction, pathological and molecular changes in the brain homeostasis, available adjuvants, their limitations. Additionally, the potential role and mechanism of neuroprotection of various nanocarrier based natural products and miRNAs have been discussed.

Polystyrene nanoplastics penetrate across the blood-brain barrier and induce activation of microglia in the brain of mice

Microplastics (MPs) have been well demonstrated as potential threats to the ecosystem, whereas the neurotoxicity of MPs in mammals remains to be elucidated. The current study was designed to investigate whether 50 nm polystyrene nanoplastics (PS-NPs) could pass through the blood-brain barrier (BBB), and to elucidate the underlying mechanisms and the following neurotoxic manifestation. In vivo study showed that PS-NPs (0.5–50 mg/kg. bw PS-NPs for 7 days) significantly induced the increase of permeability of BBB, and dose-dependently accumulated in the brain of mice. In addition, PS-NPs were found to be present in microglia, and induced microglia activation and neuron damage in the mouse brain. In vitro studies using the immortalized human cerebral microvascular endothelial cell (hCMEC/D3), the most commonly used cell model for BBB-related studies, revealed that PS-NPs could be internalized into cells, and caused reactive oxygen species (ROS) production, nuclear factor kappa-B (NF-κB) activation, tumor necrosis factors α (TNF-α) secretion, and necroptosis of hCMEC/D3 cells. Furthermore, PS-NPs exposure led to disturbance of the tight junction (TJ) formed by hCMEC/D3, as demonstrated by the decline of transendothelial electrical resistance (TEER) and decreased expression of occludin. Lastly, PS-NPs exposure resulted in the activation of murine microglia BV2 cells, and the cell medium of PS-NPs-exposed BV2 induced obvious damage to murine neuron HT-22 cells. Collectively, these results suggest that PS-NPs could pass through BBB and induce neurotoxicity in mammals probably by inducing activation of microglia.

Lysosphingolipid urine screening test using mass spectrometry for theearly detection of lysosomal storage disorders.

Background: Sphingolipidoses are caused by a defective sphingolipid catabolism, leading to an accumulation of several glycolipid species in tissues and resulting in neurotoxicity and severe systemic manifestations. Methods & results: Urine samples from controls and patients were purified by solid-phase extraction prior to the analysis by ultra-high-performance liquid chromatography (UPLC) combined withMS/MS. A UPLC-MS/MS method for the analysis of 21 urinary creatinine-normalized biomarkers for eight diseases was developed and validated. Conclusion: Considering the growing demand to identify patients with different sphingolipidoses early and reliably, this methodology will be applied for high-risk screening to target efficiently patients with various sphingolipidoses.

Prescription Stimulant-Induced Neurotoxicity: Mechanisms, outcomes, and relevance to ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a relatively prevalent neuropsychiatric and neurodevelopmental condition characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5 ) as difficulty sustaining attention and maintaining tasks at hand, heightened distractibility, and other deficits in executive functioning. Prescription stimulants—amphetamine (AMP) and methylphenidate (MPH)—are the first-line treatment(s) for ADHD in both pediatric and adult populations and exist in many formulations. Troublingly, the non-medical use (NMU) of amphetamine and methylphenidate is more prevalent in the American population, especially on college and university campuses, than the condition of interest. The neurotoxicological profile and NMU epidemiology of prescription stimulants is of direct relevance to primary care physicians and psychiatrists as they are the providers most frequently tasked with the treatment of ADHD and the surveillance of substance misuse behaviors in the young adult population. As comprehensive literature reviews of the mechanisms and potential adverse sequelae of prescription stimulant-induced neurotoxicity intended for medical clinicians have been quite sparse in the last decade—especially given the gravity of the issue—this article includes a brief primer on ADHD etiology and pathophysiology; considers the current state of NMU epidemiology; reviews the mechanisms of action of AMP and MPH; and, finally, summarizes known molecular and clinical manifestations of AMP and MPH neurotoxicity.

Psychosis as a Neurotoxic Manifestation of Extended-Release Tacrolimus

Psychosis as a Neurotoxic Manifestation of Extended-Release Tacrolimus

Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity.

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.