Upper-limb dysfunction in cancer survivors with chemotherapy-induced peripheral neurotoxicity.

INTRODUCTION: Upper-limb symptoms are often reported in the context of chemotherapy-induced peripheral neurotoxicity (CIPN), but objective quantification of functional deficits is often lacking. We examined and compared a range of neurophysiological and functional assessments of the upper-limb in the assessment of CIPN severity. METHODS: Cross-sectional assessment of neurotoxic chemotherapy-treated patients was undertaken using patient-reported and clinically-graded CIPN measures. Upper-limb functional assessments comprised of assessing fine motor skills, sensory perception, and neurophysiological measures of the median nerve. Group comparisons between participants who reported absence or presence of upper-limb functional deficits were investigated. RESULTS: 60 participants who were 11.5 (IQR = 4.0-26.0) months post-neurotoxic chemotherapy treatment reported CIPN. 65% (n = 39) reported upper-limb CIPN symptoms. Reduction in fine motor skills, sensory perception and median nerve SNAP amplitudes were associated with higher CIPN severity. Participants who self-reported presence of upper-limb functional deficits had worse CIPN severity across all measures, compared to participants who reported no upper-limb functional deficits. CONCLUSIONS: Participants who reported upper-limb symptoms and functional deficits had worse CIPN severity and quality-of-life. There is a high burden of upper-limb dysfunction long after neurotoxic chemotherapy treatment cessation. Focus on research into supportive care and rehabilitation options to improve upper-limb function is warranted to improve patient quality-of-life.

Neurologic Complications of Cancer Immunotherapy.

OBJECTIVE: Immunotherapeutic approaches have revolutionized cancer treatment with immune checkpoint inhibitors and adoptive T-cell therapy now approved to treat a variety of solid and hematologic malignancies. This article summarizes the distinctive neurologic side effects of these therapies as well as their management. LATEST DEVELOPMENTS: Neurologic immune-related adverse events are rare but potentially serious complications of immune checkpoint inhibitors. Both peripheral and central nervous system disorders have been described, often necessitating a pause or cessation of immunotherapy. Immune effector cell-associated neurotoxicity syndrome is a potentially serious complication of chimeric antigen receptor T-cell therapy. While symptoms may be mild and self-limited, delirium, encephalopathy, seizures, focal neurologic deficits, and fulminant cerebral edema can be seen. Close neurologic monitoring is imperative. The mainstay of treatment for neurologic complications includes high-dose corticosteroids, although other immunomodulatory strategies may be used in severe or refractory cases. ESSENTIAL POINTS: The spectrum of neurologic complications of cancer immunotherapy is broad, encompassing both central and peripheral nervous system disorders, indolent as well as fulminant clinical presentations, and wide-ranging severity with variable response to treatment. Early identification and multidisciplinary management are crucial to balance neurologic recovery and antitumor control.

Post-CART-T Cell Infection: Etiology, pathogenesis, and therapeutic approaches.

Chimeric antigen receptor (CAR) T cell therapy targeting CD-19 has revolutionized the treatment of refractory B-cell malignancies. However, patients undergoing this therapy face an increased risk of infections due to compromised immune function, lymphodepleting chemotherapy, hospitalization, and therapy-related complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Patients with systemic corticosteroid use, low immunoglobulin levels, and severe CRS, are at higher risk of infection. This review article highlights the spectrum of infections encountered in CAR T cell therapy, including bacterial, viral, and fungal infections. Following consensus guidelines for vaccination and immunoglobulin replacement is recommended. Clear criteria for antibiotic usage and vaccinating household members against respiratory viruses are crucial. Understanding the risk factors, spectrum of infections, and implementing appropriate prophylactic measures are essential to optimize outcomes in patients undergoing CAR T cell therapy. By prioritizing infection prevention strategies, healthcare professionals can effectively improve patient care.

Valproate overdose leading to hyperammonaemic encephalopathy.

Sodium valproate is a commonly prescribed anticonvulsant medication; however, it can cause uncommon side effects such as hyperammonaemia and encephalopathy. We present the case of a male in his early 50s brought to the emergency department after being found collapsed by his wife, with an empty bottle of sodium valproate tablets. The patient developed hyperammonaemic encephalopathy due to sodium valproate overdose and was treated with supportive care and renal replacement therapy. This case highlights the importance of recognising the potential complications of sodium valproate and its prompt treatment.

Metabolic and lifestyle risk factors for chemotherapy-induced peripheral neuropathy in taxane and platinum-treated patients: a systematic review.

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN. METHODS: Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included. RESULTS: Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk. CONCLUSIONS: Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection.

[A suspected case of delayed encephalopathy after acute hydrogen sulfide poisoning].

The main component of the gas in the fish storage tank is hydrogen sulfide. Hydrogen sulfide poisoning is a common occupational chemical poisoning among fishermen in summer, and acute hydrogen sulfide poisoning can manifest as toxic encephalopathy. This paper analyzes a patient with delayed encephalopathy suspected of acute hydrogen sulfide poisoning. The patient was unconscious for 18 days after waking up for 5 days after acute hydrogen sulfide poisoning. After waking up again, there were symptoms such as decreased limb muscle strength, ataxia, swallowing, dysarthria, and the clinical characteristics were significantly different from those of delayed encephalopathy caused by acute carbon monoxide poisoning, such as decreased cognitive function and damage to extrapyramidal system.

Incidence of Neurotoxic Symptoms in Iranian Anesthesiology Staff: Psychometric Properties of Persian Version of the Euroquest Questionnaire.

BACKGROUND: With the increase in the number of people exposed to anesthetic gases, there is a critical need to examine the prevalence of neurotoxic symptoms in these individuals using reliable tools. The aim of this study was to evaluate the psychometric characteristics of EUROQUEST questionnaire and to measure the rate of neurotoxic symptoms in the anesthesiology personnel. METHODS: This research was a cross-sectional study. This study was a cross-sectional one. Participants included 404 personnel of the operating room in western Iran. EUROQUEST questionnaire was translated into Persian and used to measure the rate of neurotoxic symptoms. Reliability of the questionnaire was examined by Cronbach's alpha, while face and construct validities were evaluated using SPSS 16 (SPSS Inc., Chicago, IL, USA) and AMOS 18 (IBM, Chicago, IL, USA) software. RESULTS: The results indicated that EUROQUEST questionnaire had acceptable reliability and validity. The most prevalent symptoms were observed in memory and concentration, fatigue, and sleepiness. The prevalence of fatigue was higher than other dimensions, with 28% of participants in the third and fourth quartiles. Also, there was no relationship between symptoms and work experience. CONCLUSIONS: EUROQUEST questionnaire can be applied in studies of the neurotoxic symptoms. The study of the prevalence of symptoms also indicated that most participants complained about memory and concentration, fatigue, and sleepiness, and these symptoms were observed in all individuals regardless of their work experience.

Asiatic acid attenuates aluminium chloride-induced behavioral changes, neuronal loss and astrocyte activation in rats.

Aluminium (Al) is a potent neurotoxic metal known to cause neurodegeneration. Al exposure causes oxidative stress by accumulation of reactive oxygen species, followed by the activation of neuronal cell death in the brain. Asiatic acid (AA), the major bioactive compound of Centella asiatica (a medicinal plant), act as multifunctional drug as well as an antioxidant. Thus, the present study aimed to investigate the potential neuroprotective effect of AA against Al neurotoxicity. Rats were orally administered aluminium chloride (AlCl3; 100 mg/kg b. wt.) dissolved in distilled water for 8 weeks or AA (75 mg/kg b. wt.) in combination with AlCl3. The results showed that AlCl3-intoxication causes significant impairment of memory, enhances anxiety-like behavior, acetyl cholinesterase (AChE) activity, malondialdehydes (MDA) level, and concomitant decrease in the activities of superoxide dismutase (SOD) and catalase (CAT) in the cortex and hippocampus regions of rat brain. In addition, AlCl3-intoxication enhanced neuronal loss and reactive astrogliosis in both regions. However, co-administration of AA with AlCl3 significantly attenuated the behavioral alterations, restored SOD and CAT activities, while reduced AChE activity and MDA content. Further, the study demonstrated that AA attenuates neuronal loss and reactive astrogliosis in rat brain. In conclusion, the study suggests that AA protects rat brain from Al neurotoxicity by inhibiting oxidative stress, neuronal loss and reactive astrogliosis.

Inhibition of ROCK2 kinase activity improved behavioral deficits and reduced neuron damage in a DEACMP rat model.

The main pathological changes that occur in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) are extensive demyelination of brain white matter and neuron damage. Previous studies suggested that demyelination and neuron injury are related to activating the Rho/ROCK signaling pathway. Inhibition of the Rho/ROCK signaling pathway can alleviate neuron injury and promote myelin repair. This study utilized a DEACMP model in which rats were prepared by space injection of CO gas intraperitoneally (CO group), and the association between the Rho/ROCK signaling pathway and DEACMP was investigated. The ROCK2 kinase inhibitor Y-27632 was used to prevent the effects of the DEACMP model to elucidate its protective mechanism. The results demonstrated that the cognitive and motor functions were significantly impaired, and the GFAP, NSE, RhoA, and ROCK2 protein levels were significantly increased in the CO group within three weeks after the model was established. After Y-27632 intervention, the cognitive and motor functions of the CO+Y-27632 group were significantly improved within three weeks after the model was established. In the CO+Y-27632 group, the RhoA, ROCK2, GFAP, and NSE (indicating neuron injury) protein levels decreased significantly, and the MBP protein levels (indicating myelin repair) increased significantly within three weeks after the model was established. These results suggested that the pathogenesis of DEACMP was associated with activation of the Rho/ROCK pathway and that Y-27632 inhibited ROCK2 kinase activity in the CO exposed rats, resulting in improved behavioral deficits, reduced neuron damage, and promotion of myelin repair. Therefore, Y-27632 might be a potentially effective drug for the treatment of DEACMP-induced brain damage.

The impact of obesity on neuropathy outcomes for paclitaxel- and oxaliplatin-treated cancer survivors.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m2) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment. METHODS: Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m2) were compared to those within the normal BMI range (< 25 kg/m2). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity. RESULTS: Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p < .001), larger waist circumference (B = .030, 95%CI = .001-.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models. CONCLUSIONS: Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment. IMPLICATIONS FOR CANCER SURVIVORS: Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions.

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl3), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.

Exposure to anesthesia is not associated with development of α-synucleinopathies: A nested case-control study.

INTRODUCTION: Preclinical studies suggest that inhalational anesthetics may induce neuropathology changes in the nigrostriatal system, leading to development of α-synucleinopathies. We explored the role of general anesthesia in the development of Parkinson disease (PD) and other α-synucleinopathies. METHODS: All α-synucleinopathy cases in Olmsted County, Minnesota, from January 1991, to December 2010, were identified from diagnostic codes, and then reviewed for type and index date of diagnosis. Cases were matched by sex and age (±1 year) to a referent control, a resident living in Olmsted County, and free of α-synucleinopathies before the index date (year of onset of the α-synucleinopathy). Medical records of both cases and controls were reviewed for lifetime exposure to anesthesia prior to the index date. RESULTS: A total of 431 cases with clinically defined α-synucleinopathies were identified. Of these, 321 (74%) underwent 1,069 procedures under anesthesia before the diagnosis date, and in the control group, 341 (79%) underwent 986 procedures. When assessed as a dichotomous variable, anesthetic exposure was not significantly associated with α-synucleinopathies (odds ratio [OR], 0.75; 95% CI, 0.54-1.05; P=.094). No association was observed when anesthetic exposure was quantified by the number of exposures (OR, 0.64, 0.89, and  0.74, for 1, 2-3, and ≥4 exposures, respectively, compared to no exposure as the reference; P=.137) or quantified by the cumulative duration of exposure assessed as a continuous variable (OR, 1.00; 95% CI, 0.97-1.02 per 1-h increase of anesthetic exposure; P=.776). CONCLUSIONS: We did not observe a significant association between exposure to general anesthesia and risk for the development of α-synucleinopathies.

Possible roles of mitochondrial dysfunction in neuropathy.

OBJECTIVES: The present review aims to present and discuss the consistent and inconsistent evidence regarding the associations between mitochondrial dysfunction and several neuropathic models, including trauma-induced, chemotherapy-induced, diabetes-induced and HIV-associated sensory neuropathy. METHODS: The searching strategy and inclusion criteria for this review are all research articles in the PubMed database published before July 2019. We used the search terms 'mitochondria' and 'neuropathy' for the present review and non-English articles were excluded. RESULTS: Damage to mitochondria via trauma, chemotherapy drugs, hyperglycaemia and HIV infection has been widely discussed to play an important role in the pathogenesis of neuropathy. Several mechanisms of mitochondrial damages have been proposed. CONCLUSION: The damage of mitochondria results in cellular apoptosis, which appears to be one of the key factors in the pathogenesis of neuropathy. Novel therapeutic strategies targeting mitochondria could be a potential therapeutic target in neuropathy.

Toxin-Induced Parkinsonism.

Toxins identified as causing parkinsonism and being related to overall idiopathic Parkinson disease risk range from heavy metals to pesticides to contaminants in synthetic heroin. Several described in this article exhibit significant oxidative stress on neurons of the central nervous system and have a particular predilection toward damage of dopaminergic neurons. Although many of these toxins have well-established connections with Parkinson disease risk, a few continue to be studied with data still being produced. The parkinsonisms caused by these agents have variable responses to dopaminergic therapies. This article discusses manganese, mercury, MPTP, organochlorines, organophosphates, paraquat, rotenone, and Agent Orange.

Toxin-Induced Seizures.

New toxins are emerging all the time. In this article, the authors review common toxins that cause seizure, their mechanisms, associated toxidromes, and treatments. Stimulants, cholinergic agents, gamma-aminobutyric acid antagonists, glutamate agonists, histamine and adenosine antagonists, and withdrawal states are highlighted. Understanding current mechanisms for common toxin-induced seizures can promote understanding for future toxins and predicting if seizure may occur as a result of toxicity.

Neurotoxicity and Chemoreception: A Systematic Review of Neurotoxicity Effects on Smell and Taste.

Several different types of exposure have the potential to produce olfactory and gustatory deficits related to neurotoxicity. Although the literature contains relatively few studies of such chemoreceptive dysfunction in the context of toxic exposure, this review explores the strength of such published associations. Several studies collectively demonstrated moderately strong evidence for an association between manganese dust exposure and olfactory deficits. Evidence of associations between individual chemicals, therapeutics, and composites, such as World Trade Center debris, and olfactory and gustatory deficits remains limited or mixed. Further need for controlled studies for clinical management, exposure limits, and policy development is identified.

Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and Medications.

PURPOSE OF REVIEW: Vitamin and mineral deficiencies, neurotoxins, and, particularly, prescription medications, are some of the most common causes of peripheral neuropathy. Recognition and prompt treatment of these neuropathies require a high index of suspicion and an accompanied detailed history. This article provides a comprehensive approach and list of items that must be considered in the setting of new-onset neuropathy. RECENT FINDINGS: Although many of the neuropathies described in this article have decreased in prevalence in developed countries because of public health interventions and occupational/environmental regulations, new causes for this class of neuropathy continue to be uncovered. SUMMARY: The peripheral nervous system is susceptible to a broad array of metabolic and toxic abnormalities, which most often lead to a length-dependent sensory-predominant axonal peripheral neuropathy. A careful history accompanied by recognition of multisystem clues can increase recognition of these neuropathies, which is important as many have specific treatments that may either improve the neuropathy or halt its progression.

Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic Mice.

CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.