Incidence and risk factors for developing chemotherapy-induced neuropathic pain in 500 cancer patients: A file-based observational study.

OBJECTIVE: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP). METHODS: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN. RESULTS: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001). CONCLUSION: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies.

Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients.

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel-induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12-weekly paclitaxel-based regimen. Patients were clinically examined by means of the Total Neuropathy Score-clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0-1 and 26 (44%) grade 2-3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week-12 was determined, whereas patients with TNSc grade 2-3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0-1. receiver-operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2-3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2-3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro-axonal injury in PIPN. An early increase of this biomarker after a 3-weekly chemotherapy course can be a predictive marker of final PIPN severity.

Duloxetine against symptomatic chemotherapy-induced peripheral neurotoxicity in cancer survivors: a real world, open-label experience.

The objective of this observational study was to evaluate the efficacy and safety of duloxetine in a cohort of 100 cancer survivors with chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN was graded employing the TNSc and the NCI-CTCv4. The Patient Global Impression of Change (PGIC) scale measured the efficacy of duloxetine (1: no benefit; to 7: excellent response). A clinically meaningful response was considered a PGIC > 4. Median age was 62 (29-81) years and 42% were male. CIPN was graded as grades 1, 2 and 3 in 20, 66, and 14% of patients, respectively. Median time to duloxetine initiation was 6 (1-63) months after chemotherapy. Fifty-seven patients early dropped out from duloxetine, due to lack of efficacy (20%) or side effects (37%). Male patients more frequently discontinued duloxetine due to lack of efficacy (35.7 vs. 8.6% P = 0.001). PGIC scores were higher in female patients (4 vs. 1, P = 0.001), taxane-treated patients (4 vs. 1, P = 0.042) and with short-lasting (<6 months) CIPN (4 vs. 1, P = 0.008). Patients with long-lasting CIPN had a higher rate of adverse events (47 vs. 27%, P = 0.038) and discontinuation (54.8 vs. 45.1%, P = 0.023). In the multivariate analysis, female gender and short-lasting CIPN were independently associated with a favorable response to duloxetine. Low tolerability, male gender, and long-lasting CIPN significantly limited duloxetine use in daily practice setting. A minority of cancer survivors with CIPN treated with duloxetine had a meaningful CIPN improvement, and tolerability was overall low. Female gender and short-term CIPN were independently associated with a favorable response to duloxetine.

Incidence and characteristics of neurotoxicity in immune checkpoint inhibitors with focus on neuromuscular events: Experience beyond the clinical trials.

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.

Assessing risk factors of falls in cancer patients with chemotherapy-induced peripheral neurotoxicity.

AIM: To identify the risk factors of falls in a well-characterized cohort of cancer patients with chemotherapy-induced peripheral neurotoxicity (CIPN). PATIENTS AND METHODS: We studied 122 cancer patients experiencing any grade of CIPN, following completion of different chemotherapeutic regimens for various non-hematological malignancies. The results of the clinical examination were summarized by means of the Total Neuropathy Score-clinical version (TNSc®). A neurophysiological examination was also carried out. RESULTS: Among 122 patients, 21 (17.2%) of them reported falls. These were 7 males and 14 females with a mean age of 57.3 ± 8.1 years. All of them (21; 100%) had grade 3 CIPN, according to TNSc® with a median value of 15. Univariate analysis showed that the following variables were strongly associated with falls: TNSc® score of > 14 corresponding to grade 3 CIPN, evidence of motor impairment, evidence of sensory ataxia with positive Romberg sign, and decrease of sural a-SAP > 50% from the baseline value. Multivariate regression analysis failed to define independent predictors of falls. However, ROC analysis demonstrated that a discriminative TNSc® cutoff value of > 14 predicted falls with a sensitivity of 100% and specificity of 87%, whereas sensory ataxia predicted falls with a sensitivity of 95% and specificity of 83%. CONCLUSION: Grade 3 CIPN, as assessed with TNSc®, and evidence of sensory ataxia with a positive Romberg sign were strongly associated with an increased risk of falls. Although our results need further validation, the TNSc® scale appears to be a practical and easy tool for identifying patients at higher risk of falling.

Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications. CIPN may involve multiple areas of the peripheral nervous system from the autonomic and dorsal root ganglia (DRG) to the axon and any peripheral nerve fibre type. Large diameter sensory myelinated (Aß) fibres are more frequently involved, but motor, small myelinated (Aδ), unmyelinated (C) or autonomic fibres may also be affected. Here, we review the current evidence on techniques for the CIPN assessment in the clinical and experimental settings. Nerve conduction studies (NCS) may be used at the subclinical and early CIPN stage, to assess the extent of large nerve fibre damage and to monitor long-term outcomes, with the sural or dorsal sural nerve as the most informative. The quantitative sensory neurological examination provides valuable data alongside NCS. Quantitative sensory testing and nerve excitability studies add information regarding pathophysiology. Nerve MRI and ultrasound may provide information on enlarged nerve, increased nerve signal intensity and DRG or spinal cord changes. Skin biopsy, corneal confocal microscopy, laser-evoked potentials, contact heat-related potentials and microneurography may reveal the extent of damage to small unmyelinated nerve fibres that go undetected by NCS. The information on the role of these latter techniques is preliminary. Hence, the use of multimodal testing is recommended as the optimal CIPN assessment strategy, employing objective NCS and other specialised techniques together with subjective patient-reported outcome measures.

Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: From pathogenesis to treatment.

Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length-dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre-existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs-induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.

Immune checkpoint inhibitors-induced neuromuscular toxicity: From pathogenesis to treatment.

Immune checkpoint inhibitors (ICIs) are increasingly used and are becoming the standard of care in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Neurological irAEs are rare but potentially severe. Neuromuscular disorders represent the most common neurological irAEs following anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment, and include myositis, myasthenia gravis, and demyelinating polyradiculoneuropathy. Instrumental findings may differ from typical neuromuscular disorders occurring outside ICIs treatment. Despite initial severity, neurological irAEs often respond to immune-modulating therapies. Prompt irAEs diagnosis, ICIs discontinuation, and early treatment with corticosteroids, together with patient education and a multi-disciplinary approach, are important for optimizing clinical outcomes. Intravenous immunoglobulin, plasma exchange, and other immune-modulating treatments should be considered in more severe cases. Consideration of re-challenging with the same immunotherapy drug may be given in some cases, based on clinical picture and initial severity of irAEs.

Liability of the voltage-gated potassium channel KCNN3 repeat polymorphism to acute oxaliplatin-induced peripheral neurotoxicity.

Thus far, there are conflicting results on the causal role of K+ channels in the pathogenesis of acute oxaliplatin-induced peripheral neurotoxicity (OXAIPN). As such, we tested the hypothesis that the voltage-gated K+ channel KCNN3 repeat polymorphism confers liability to acute OXAIPN. DNA from 151 oxaliplatin-treated patients for colorectal cancer was extracted and genotyped. The incidence of acute OXIPN was measured by the OXA-neuropathy questionnaire, while the severity of acute OXAIPN was scored basing on the number of symptoms reported by the patients at each clinical assessment. The increased number of acute symptoms was considered as being suggestive of an increased severity of acute OXAIPN. A total of 130/151 (86.1%) patients developed any grade of acute OXAIPN. Grade I acute neurotoxicity was revealed in 43 (28.5%) patients; grade II in 34 (22.5%); and grade III in 53 (53.1%) patients. Genotyping revealed alleles carrying 11 to 20 CAG repeats. The majority of patients were heterozygous (131; 89.4%). The most common numbers of CAG repeats were 15 (n = 46), 16 (n = 53), and 17 (n = 95). Patients carrying alleles with either 15 to 17 CAG repeats (P = .601) did not experience a higher incidence of grade III (treatment-emergent) acute OXAIPN. Likewise, no increased incidence of acute treatment-emergent OXAIPN was noted in heterozygous patients carrying either two short alleles (<19 CAG repeats) or one short and one long (≥19 CAG repeats) allele (P = .701). Our results do not support a causal relationship between the KCNN3CAG repeat polymorphism and acute OXΑIPN.

Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.

To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.

Risk stratification of oxaliplatin induced peripheral neurotoxicity applying electrophysiological testing of dorsal sural nerve.

PURPOSE: We aimed to verify the predictiveness of dorsal sural nerve neurophysiological monitoring in obtaining risk stratification for oxaliplatin-induced peripheral neurotoxicity (OXAPN). METHODS: We conducted a secondary analysis on a cohort of 110 colorectal cancer patients who were evaluated clinically and neurophysiologically before chemotherapy, at mid-treatment and at discontinuation. We applied the classification tree analysis method to predict the end-of-treatment OXAPN neurophysiological diagnosis, using data recorded at mid-treatment. We then ascertained the correlation between the obtained classes and neurological impairment at the end of treatment (Fisher's exact test). RESULTS: Dorsal sural nerve monitoring enabled us to stratify oxaliplatin-treated patients into risk classes with an implemented approach to neurophysiology application in this setting. Neurological outcome at discontinuation was predicted by neurophysiological monitoring performed during chemotherapy administration. CONCLUSIONS: We demonstrated the role that neurophysiology may play in clinical trials as an early surrogate marker that can predict OXAPN development at the end of treatment. Specifically, we propose abnormal dorsal sural sensory nerve testing as an early biomarker in identifying patients at high risk of eventually developing OXAPN.

Serum micronutrients and prealbumin during development and recovery of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse event. Nutritional status can become impaired in cancer patients, potentially contributing to neuropathy's evolution. Our aim was to evaluate serum micronutrients and prealbumin in a cohort of 113 solid-cancer patients receiving platinum and taxane compounds during the development and recovery of neuropathy, up to 1 year after finishing treatment. CIPN was graded according to Total Neuropathy Score(©) and NCI.CTCv3 at T0 (baseline), T1 (1-3 months), and T12 (12 months) after chemotherapy. CIPN was classified as asymptomatic (< grade 2) or symptomatic (≥2). CIPN recovery was defined as ≥1 grade improvement at T12. Symptomatic CIPN developed in 52% of patients. Symptomatic patients presented a higher increase in TNSc (p < 0.001), in TNSr(©) (p < 0.001), and decrease in sural (p < 0.001) and radial nerve conduction (p < 0.001). No significant differences with any of the micronutrients were observed along T0-T1 period between severity or chemotherapy groups. By T12, symptomatic patients without recovery had a decrease in vitamin E levels (p = 0.019) and prealbumin (p = 0.062) compared with those symptomatic that improved. A correlation between the variation of vitamin E and prealbumin at T0-T1 (r = 0.626, p = 0.001) and T1-T12 (r = 0.411, p = 0.06) was observed. After chemotherapy treatment, the improvement of patients displaying symptomatic neuropathy is related to vitamin E and prealbumin serum levels. Our results suggest that nutritional status can play a role in CIPN recovery.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis.

We aimed at validating the role of genetic variants identified by a recent genome-wide association study (GWAS) as determinants of chronic oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin-based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI-CTC criteria and the clinical version of the Total Neuropathy Score(©) (TNSc(©) ). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI-CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc(©) scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10-0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI-CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI-CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40-5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P-value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta-analysis for validation of GWAS findings.

Refractory status epilepticus due to SMART syndrome.

INTRODUCTION: Stroke-like migraine attacks after radiation therapy (SMART) is a late-onset complication of brain irradiation of unknown physiopathology. Our aim was to present three patients with SMART syndrome who had clinical and neuroimage studies suggestive of status epilepticus. PATIENTS: Patient 1. A 69-year-old woman, who was treated with radiation therapy 14 years before her first admission to the Neurology Department, presented with several episodes of headache, speech disturbances, and weakness of left limbs with altered awareness. Patient 2. A 49-year-old man, who was treated with whole brain radiation 20 years before the onset of symptoms, developed some episodes consisting of headache and numbness of the right side of face and right arm; the latest episodes were accompanied by visual disturbances followed by generalized tonic-clonic seizures. Patient 3. A 40-year-old man, who received cranial irradiation 20 years before, suffered three episodes of behavioral disturbance, aphasia, headache, and visual aura followed by left homonymous hemianopia. RESULTS: All three patients suffered seizures mostly with visual aura. Electroencephalography showed interictal epileptiform discharges or focal slowing. Brain magnetic resonance image (MRI), positron emission tomography (PET), or ictal-single-photon emission computed tomography (SPECT) showed focal cortical hyperperfusion. Focal diffusion restriction and focal gadolinium-enhancement were observed on MRI. All patients were treated with antiepileptic drugs, being effective in one of them. One patient needed anesthesic coma, and the other patient responded to therapy with corticosteroids. CONCLUSIONS: Taking into account clinical evolution and ictal neuroimaging studies, status epilepticus could explain the origin of these episodes in SMART syndrome. Although most patients have reversible symptoms, in some cases, aggressive treatment to avoid sequelae is needed. This article is part of a Special Issue entitled "Status Epilepticus".

Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients.

OBJECTIVES: Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN). METHODS: 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded. RESULTS: According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow-up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN. CONCLUSIONS: High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid-treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN.

Long-term course of oxaliplatin-induced polyneuropathy: a prospective 2-year follow-up study.

This prospective study sought to identify the potential reversibility of oxaliplatin-induced peripheral neuropathy (OXAIPN) by following-up its long-term course 2 years after discontinuation of oxaliplatin (OXA)-based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA-based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow-up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2-15) at T1 vs. four (range: 2-12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes.

Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. Early diagnosis and initiation of immunosuppressive therapy are likely to be crucial in preventing the accumulation of neurological disability. Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.