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INTRODUCTION/AIMS: Femoral neuropathies can cause severe, prolonged debility, yet there have been few clinical and electrodiagnostic (EDx) studies addressing this condition. The aim of this study was to better understand the etiologies, EDx features, and clinical course of femoral neuropathy. METHODS: We identified patients evaluated at Mayo Clinic Rochester between January 1, 1999 and July 31, 2019, with possible new femoral neuropathy ascertained via International Classification of Diseases-versions 9 and 10 diagnosis codes presenting within 6 months of symptom onset. RESULTS: A retrospective review of 1084 records was performed and we ultimately identified 159 patients with isolated femoral neuropathy for inclusion. The most common femoral neuropathy etiologies were compressive (40%), perioperative stretch (35%), and inflammatory (6%). Presenting symptoms included weakness (96%), sensory loss (73%), and pain (53%). Presenting motor physical exam findings demonstrated moderate weakness (34%) or no activation (25%) of knee extension and mild (32%) or moderate (35%) weakness of hip flexion. Seventy-two percent of patients underwent EDx testing, including 22 with femoral motor nerve conduction studies. Treatment often involved physical therapy (89%) and was otherwise etiology-specific. In patients with follow-up data available (n = 154), 83% had subjective clinical improvement at follow-up with a mean time to initial improvement of 3.3 months and mean time to recovery at final follow-up of 14.8 months. Only 48% of patients had nearly complete or complete recovery. DISCUSSION: In our cohort, the most common etiologies of femoral neuropathy were compression or perioperative stretch with high initial morbidity. Although motor recovery is common, improvement is often prolonged and incomplete.
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Neuropatía Femoral , Humanos , Neuropatía Femoral/diagnóstico , Neuropatía Femoral/etiología , Estudios Retrospectivos , Dolor/complicaciones , Modalidades de FisioterapiaRESUMEN
INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.
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Esclerosis Amiotrófica Lateral , Biomarcadores , Proteínas de Neurofilamentos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Método Doble Ciego , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Resultado del TratamientoRESUMEN
PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.
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Antineoplásicos , Supervivientes de Cáncer , Síndromes de Neurotoxicidad , Enfermedades del Sistema Nervioso Periférico , Humanos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Antineoplásicos/efectos adversos , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Personal AdministrativoRESUMEN
PURPOSE: Prior studies reported evidence of autonomic involvement in motor neuron disease and suggested more severe dysfunction in upper motor neuron predominant syndromes. Hence, we sought to characterize autonomic impairment in primary lateral sclerosis. METHODS: Neurological evaluations, thermoregulatory sweat tests, and autonomic reflex screens were analyzed retrospectively in 34 primary lateral sclerosis patients (28 definite and 6 probable). Patients with other potential causes of autonomic failure and patients with autonomic testing results compromised by artifact were excluded. RESULTS: A total of 17 patients reported autonomic symptoms. Orthostatic lightheadedness was most frequent (8 patients), followed by bladder (7), bowel (5), and erectile dysfunction (3). The autonomic reflex screens of 33 patients were reviewed; 20 patients had abnormal studies. The thermoregulatory sweat tests of 19 patients were reviewed; 11 patients had abnormal studies. Composite Autonomic Severity Score was calculated for 33 patients and found abnormal in 20/33 patients (60.6%): 15/20 patients (75%) had mild impairment, and 5/20 patients (25%) had moderate impairment. The frequencies of testing abnormalities were: sudomotor 18/20 (90%), cardiovagal 9/20 (45%), and adrenergic 6/20 (30%). Sweat loss pattern analysis showed global, regional, and mixed patterns to be more common than length-dependent and distal patterns. CONCLUSION: We found evidence of frequent autonomic dysfunction in primary lateral sclerosis, which is generally of modest severity akin to prior reports for amyotrophic lateral sclerosis, but more commonly in a pattern consistent with preganglionic/ganglionic localization. This suggests that primary lateral sclerosis, as with amyotrophic lateral sclerosis, is a multisystem disease that affects the autonomic nervous system.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anticancer agents. There are few predictable risk factors with which to identify susceptible patients. Effective preventive measures or treatments are not available. Here, we have used a model of CIPN in Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for the creation of RNAi lines, is resistant to cisplatin damage compared with the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplatin. The mitochondria of attP40 flies function similarly to control attP2 mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but attP40 mitochondria are able to retain function and even increase basal respiration rates in response to this stress. This retained mitochondrial activity is likely mediated by Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α, and is key to cisplatin resistance. Our findings represent the potential for both identification of susceptible patients and prevention of CIPN through the targeting of mitochondria.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy is a major, debilitating side effect of many platinum-based cancer drugs. There are few available screening tools to identify patients at risk, and there are no effective treatments. Here, we report a novel genetic change that confers resistance to cisplatin-induced neurotoxicity in a Drosophila model while preserving the toxic effect in rapidly dividing cells. This work has the potential to influence patient susceptibility testing and development of novel CIPN preventive treatments.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Proteínas de Drosophila/genética , Complejo I de Transporte de Electrón/genética , Síndromes de Neurotoxicidad/genética , Enfermedades del Sistema Nervioso Periférico/genética , Animales , Drosophila melanogaster , Síndromes de Neurotoxicidad/etiología , Enfermedades del Sistema Nervioso Periférico/etiologíaRESUMEN
INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder of motor neurons in which the cause is mostly unknown. Early identification of genetic ALS cases, of which C9ORF72 (C9ALS) is the most frequent, can have important implications for evaluation, prognosis, and therapeutics. Here, we aimed to characterize the clinical and electrophysiological hallmarks of C9ALS and investigate differences from C9ORF72 negative ALS (non-C9ALS). METHODS: We retrospectively reviewed clinical and electrodiagnostic (EDX) data for all genetically confirmed C9ALS cases seen between 1/1/2012 and 10/1/2020 who met Gold Coast criteria and compared them 1:1 with non-C9ALS patients within the same time frame. RESULTS: A total of 99 C9ALS and 99 non-C9ALS cases were identified. Compared to non-C9ALS, C9ALS demonstrated higher prevalence in women, lesser racial variability, stronger family history of ALS, and higher frequency of upper motor neuron signs. EDX testing of C9ALS showed higher median sensory nerve and lower fibular compound muscle action potential amplitudes. DISCUSSION: Although the differences between C9ALS and non-C9ALS reached statistical significance in certain nerve conduction parameters, they were not sufficient to discriminate between groups on a case-by-case basis. Genetic testing is required to identify C9ALS patients.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Femenino , Humanos , Neuronas Motoras , Pronóstico , Estudios RetrospectivosRESUMEN
INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.
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Esclerosis Amiotrófica Lateral , Células Madre Mesenquimatosas , Esclerosis Amiotrófica Lateral/diagnóstico , Método Doble Ciego , Humanos , Factores de Crecimiento Nervioso/metabolismo , Trasplante AutólogoRESUMEN
BACKGROUND AND AIMS: Premature commercialization of unproven stem cell interventions (SCIs) has received significant attention within the regenerative medicine community. Patients considering SCIs may encounter misinformation and seek out guidance from their physicians who are trusted brokers of health information. However, little is known about the perspectives of academic physician specialists toward the SCI industry. The purpose of this study was to capture the attitudes of physician specialists with experience addressing patient questions about unproven SCIs. METHODS: The authors undertook 25 semi-structured interviews with academic physicians in cardiology, ophthalmology, orthopedics, pulmonology and neurology primarily from one academic center. RESULTS: The authors identified two major themes: concerns and mediators of appropriateness of offering SCIs as therapies to patients. Specialists were generally aware of the industry and reported scientific and commercial concerns, including the scientific uncertainty of SCIs, medical harms to patients, misleading marketing and its impact on patient informed consent and economic harms due to large out-of-pocket costs for patients. All specialists outside of orthopedics voiced that it was inappropriate to be offering SCIs to patients today. These views were informed by previously expressed concerns surrounding safety and properly informing patients, levels of evidence needed prior to offering SCIs therapeutically and desired qualifications for clinicians. Among the specialties, orthopedists reported that under certain conditions, SCIs may be appropriate for patients with limited clinical options but only when safety is adequate, expectations are managed and patients are well informed about the risks and chances of benefit. Most participants expressed a desire for phase 3 studies and Food and Drug Administration approval prior to marketing SCIs, but some also shared the challenges associated with upholding these thresholds of evidence, especially when caring for out-of-option patients. CONCLUSIONS: The authors' results suggest that medical specialists are aware of the industry and express several concerns surrounding SCIs but differ in their views on the appropriateness and clinical evidence necessary for offering SCIs currently to patients. Additional educational tools may help physicians with patient engagement and expectation management surrounding SCIs.
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Médicos , Especialización , Humanos , Células MadreRESUMEN
PURPOSE: The current project was developed to obtain natural history information regarding cisplatin-induced peripheral neuropathy in males with testicular/germ cell cancers and to compare such neuropathy data with similarly obtained data in patients receiving other chemotherapy drugs in similarly conducted clinical trials. METHODS: Patients without baseline neuropathy symptoms, who were initiating cisplatin-based chemotherapy, completed the EORTC CIPN 20 patient-reported instrument to evaluate chemotherapy-induced peripheral neuropathy (CIPN). Results were compared with EORTC CIPN 20 data obtained from independent study sets regarding patients receiving (1) paclitaxel, (2) combined paclitaxel and carboplatin, (3) oxaliplatin, or (4) a combination of doxorubicin and cyclophosphamide (AC). The last study set of patients on AC was selected to evaluate the use of EORTC CIPN 20 data in patients receiving chemotherapy not known to cause CIPN. RESULTS: Cisplatin-induced neuropathy was more similar to neuropathy in patients receiving oxaliplatin than in those receiving paclitaxel. The cisplatin and oxaliplatin groups exhibited the coasting phenomenon and more prominent upper extremity symptoms than lower extremity symptoms during chemotherapy administration weeks. In contrast, paclitaxel-treated patients did not, on average, exhibit the coasting phenomenon; additionally, lower extremity symptoms were more prominent during the weeks when paclitaxel was administered. Cisplatin-induced neuropathy was less severe than was seen in patients in the other two groups, potentially because the cisplatin-receiving patients were younger. Patients receiving AC did not report substantial EORTC CIPN 20 changes. CONCLUSION: Understanding neuropathy similarities and differences with various chemotherapy agents may help elucidate CIPN processes and facilitate means to prevent and/or treat established CIPN. TRIAL REGISTRATION: NCT02677727.
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Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Cisplatino/administración & dosificación , Ensayos Clínicos como Asunto , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Oxaliplatino/efectos adversos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/patología , Neoplasias Testiculares/tratamiento farmacológico , Adulto JovenRESUMEN
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Variación Biológica Poblacional , Biomarcadores , Ensayos Clínicos como Asunto/métodos , Evaluación de Resultado en la Atención de Salud , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Progresión de la Enfermedad , Desarrollo de Medicamentos , Humanos , Fuerza Muscular , Rendimiento Físico Funcional , Medicina de Precisión , Pronóstico , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria , Medición de Riesgo , Habla , Estimulación Magnética TranscranealRESUMEN
Brain-computer interfaces (BCIs) provide a way for the brain to interface directly with a computer. Many different brain signals can be used to control a device, varying in ease of recording, reliability, stability, temporal and spatial resolution, and noise. Electrocorticography (ECoG) electrodes provide a highly reliable signal from the human brain surface, and these signals have been used to decode movements, vision, and speech. ECoG-based BCIs are being developed to provide increased options for treatment and assistive devices for patients who have functional limitations. Decoding ECoG signals in real time provides direct feedback to the patient and can be used to control a cursor on a computer or an exoskeleton. In this review, the authors describe the current state of ECoG-based BCIs that are approaching clinical viability for restoring lost communication and motor function in patients with amyotrophic lateral sclerosis or tetraplegia. These studies provide a proof of principle and the possibility that ECoG-based BCI technology may also be useful in the future for assisting in the cortical rehabilitation of patients who have suffered a stroke.
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Interfaces Cerebro-Computador , Encéfalo/fisiopatología , Electroencefalografía , Cuadriplejía/fisiopatología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/rehabilitación , Electroencefalografía/métodos , Dispositivo Exoesqueleto , Humanos , Habla/fisiología , Accidente Cerebrovascular/fisiopatología , Rehabilitación de Accidente CerebrovascularRESUMEN
BACKGROUND: Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Specifically, activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. We explore whether connections exist between ALS and retroviruses through protein interaction networks (PIN) and pathway analysis, and consider the potential roles in drug target discovery. Protein database and pathway/network analytical software including Ingenuity Pathway BioProfiler, STRING, and CytoScape were utilized to identify overlapping protein interaction networks and extract core cluster (s) of retroviruses and ALS. RESULTS: Topological and statistical analysis of the ALS-PIN and retrovirus-PIN identified a shared, essential protein network and a core cluster with significant connections with both networks. The identified core cluster has three interleukin molecules IL10, Il-6 and IL-1B, a central apoptosis regulator TP53, and several major transcription regulators including MAPK1, ANXA5, SQSTM1, SREBF2, and FADD. Pathway enrichment analysis showed that this core cluster is associated with the glucocorticoid receptor singling and neuroinflammation signaling pathways. For confirmation purposes, we applied the same methodology to the West Nile and Polio virus, which demonstrated trivial connectivity with ALS, supporting the unique connection between ALS and retroviruses. CONCLUSIONS: Bioinformatics analysis provides evidence to support pathological links between ALS and retroviral activation. The neuroinflammation and apoptotic regulation pathways are specifically implicated. The continuation and further analysis of large scale genome studies may prove useful in exploring genes important in retroviral activation and ALS, which may help discover new drug targets.
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Esclerosis Amiotrófica Lateral/virología , Biología Computacional , Retroviridae/genética , Regulación de la Expresión Génica , Humanos , Estudios Longitudinales , Mapas de Interacción de Proteínas , Proteínas/genéticaRESUMEN
INTRODUCTION: Neuropathy after total knee arthroplasty (TKA) can cause significant morbidity but is inconsistently reported. METHODS: We reviewed the clinical, electrodiagnostic and perioperative features of all patients who underwent primary TKA at our institution and developed a new neuropathy within 8 weeks postoperatively. RESULTS: Fifty-four cases were identified (incidence 0.37% [95% confidence interval, 0.28-0.49]) affecting the following nerve(s): peroneal (37), sciatic (11), ulnar (2), tibial (2), sural (1), and lumbosacral plexus (1). In all cases with follow-up data, motor recovery typically occurred within 1 year and was complete or near-complete. CONCLUSIONS: Post-TKA neuropathy is uncommon, typically does not require intervention and usually resolves within 1 year. Post-TKA neuropathy most often affects the nerves surgically at risk. Anesthesia type does not correlate with post-TKA neuropathy. An inflammatory etiology for post-TKA neuropathy is rare but should be considered in specific cases. Muscle Nerve 59:679-682, 2019.
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Artroplastia de Reemplazo de Rodilla , Enfermedades del Sistema Nervioso Periférico/epidemiología , Complicaciones Posoperatorias/epidemiología , Anciano , Femenino , Humanos , Plexo Lumbosacro , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Neuropatías Peroneas/epidemiología , Neuropatías Peroneas/fisiopatología , Complicaciones Posoperatorias/fisiopatología , Recuperación de la Función , Estudios Retrospectivos , Neuropatía Ciática/epidemiología , Neuropatía Ciática/fisiopatología , Nervio Sural , Neuropatía Tibial/epidemiología , Neuropatía Tibial/fisiopatología , Neuropatías Cubitales/epidemiología , Neuropatías Cubitales/fisiopatologíaRESUMEN
Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.
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Antineoplásicos/efectos adversos , Síndromes de Neurotoxicidad/terapia , Compuestos Organoplatinos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/terapia , Cisplatino/efectos adversos , Clorhidrato de Duloxetina/uso terapéutico , Humanos , Síndromes de Neurotoxicidad/diagnóstico , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Inhibidores de Captación de Serotonina y Norepinefrina/uso terapéutico , Resultado del TratamientoRESUMEN
Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.
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Antineoplásicos/efectos adversos , Furanos/efectos adversos , Cetonas/efectos adversos , Síndromes de Neurotoxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Talidomida/efectos adversos , Alcaloides de la Vinca/efectos adversos , Estudios de Cohortes , Humanos , Inmunosupresores/efectos adversos , Neoplasias/tratamiento farmacológico , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/terapia , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/terapiaRESUMEN
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a potentially dose-limiting side effect of several commonly used cytotoxic chemotherapy agents. The main pharmacological classes that may cause CIPN include classical anticancer drugs, as well as the recently introduced immune checkpoint inhibitors and antibody drug conjugates. The absence of a complete knowledge of CIPN pathophysiology is only one of the several unsolved issues related to CIPN. Among some of the most relevant aspects of CIPN deserving further attention include the real number of patients exposed to the risk of CIPN, the long-term impact on cancer survivors' quality of life due to incomplete recovery from CIPN, the economic burden related to acute and chronic CIPN, and the different perspective and education of the healthcare specialists in charge of managing patients with CIPN. Overall, CIPN remains a very challenging area of research as there are still several unresolved issues to be addressed in the future. In this special issue, the multifaceted profile of CIPN will be presented, with particular emphasis on bolstering the need to develop more optimized outcome measures than the existing ones to accurately evaluate the extent of CIPN, but also to ascertain the differences in the incidence, risk factors, clinical phenotype, and management of CIPN, according to the most commonly used neurotoxic chemotherapy classes. Perspectives for future research to pursue in order to cover the gaps in knowledge in the CIPN field will also be discussed.
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Antineoplásicos/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Humanos , Síndromes de Neurotoxicidad/epidemiología , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/prevención & control , Factores de RiesgoRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.
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Antineoplásicos/efectos adversos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/genética , Bortezomib/efectos adversos , Predisposición Genética a la Enfermedad/genética , Humanos , Taxoides/efectos adversos , Alcaloides de la Vinca/efectos adversosRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect experienced by patients receiving treatment for cancer. Approximately 30 to 40% of patients treated with neurotoxic chemotherapy will develop CIPN, and there is considerable variability in its severity between patients. It is often sensory-predominant with pain and can lead to long-term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. Ann Neurol 2017;81:772-781.
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Antineoplásicos/toxicidad , Neoplasias/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Humanos , Síndromes de Neurotoxicidad/terapia , Enfermedades del Sistema Nervioso Periférico/terapiaRESUMEN
OBJECTIVE: To assess disease burden of chemotherapy-induced peripheral neuropathy (CIPN), which is a common dose-limiting side effect of neurotoxic chemotherapy. Late effects of CIPN may increase with improved cancer survival. METHODS: Olmsted County, Minnesota residents receiving neurotoxic chemotherapy were identified and CIPN was ascertained via text searches of polyneuropathy symptoms in the medical record. Clinical records were queried to collect data on baseline characteristics, risk factors, signs and symptoms of CIPN, medications, impairments and International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes for all subjects. RESULTS: A total of 509 individuals with incident exposure to an inclusive list of neurotoxic chemotherapy agents between 2006 and 2008 were identified. 268 (52.7%) of these individuals were determined to have CIPN. The median time from incident exposure to first documented symptoms was 71 days. Patients with CIPN received a neuropathy ICD-9 diagnosis in only 37 instances (13.8%). Pain symptoms and use of pain medications were observed more often in patients with CIPN. Five-year survival was greater in those with CIPN (55.2%) versus those without (36.1%). Those with CIPN surviving greater than 5 years (n=145) continued to have substantial impairments and were more likely to be prescribed opioids than those without CIPN (OR 2.0, 1.06-3.69). CONCLUSIONS: Results from our population-based study are consistent with previous reports of high incidence of CIPN in the first 2 years following incident exposure to neurotoxic chemotherapeutic agents, and its association with significant pain symptomatology and accompanied long-term opioid use. Increased survival following exposure to neurotoxic chemotherapy and its long-term disease burden necessitates further study among survivors.