Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity

The aim of this multi-center study was to assess with reduced versions of the Total Neuropathy Score (TNS), the severity of chemotherapy-induced peripheral neurotoxicity (CIPN), and to compare the results with those obtained with common toxicity scales. An unselected population of 428 cancer patients was evaluated at 11 different centers using a composite (clinical + neurophysiological, TNSr) or clinical (TNSc) examination and with the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) 2.0 and Eastern Cooperative Oncology Group (ECOG) scores. A highly significant correlation was demonstrated between the TNSr and the NCI-CTC 2.0 and ECOG scores; but the TNSr evaluation was more accurate in view of the more extended score range. Also, the simpler and faster TNSc (based only on the clinical neurological examination) allowed to grade accurately CIPN and correlated with the common toxicity scores. The correlation tended to be closer when the sensory items were considered, but also the TNSr motor items, which were not specifically investigated in any other previous study, significantly correlated with the results of the common toxicity scales. In conclusion, this study suggests that the TNSr is a reliable tool for accurately grading and reporting CIPN, with the additional and so far unique support of a formal comparison with known and widely used common toxicity scales. The TNSc is a valid alternative if neurophysiological examination is not feasible. The longer time needed to calculate the TNSr and TNSc in comparison to the ECOG or the NCI-CTC 2.0 scales is offset by the more detailed knowledge of the CIPN characteristics.     

The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy-induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI-CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.     

A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale

A new peripheral neuropathy activities measure, the Overall Neuropathy Limitations Scale (ONLS), was derived by modifying the Overall Disability Sum Score (ODSS) slightly. Its inter-rater reliability was found to be high and its correlation with the ODSS (r = 0.97), 36-item Short Form Questionnaire Physical Component Summary Score, and participation and impairment measures was significant. Acceptable responsiveness (standardised response mean 0.76) was shown by the ONLS. The results obtained from the questionnaire agreed closely with those obtained from observation of the tasks on the ONLS, but were not equivalent. The simplicity of the ODSS is shared by the ONLS, but the ONLS has better content validity and less ceiling effect, which may make it more useful for clinical practice and research.     

Neurophysiologic assessment of small fibre damage in chemotherapy-induced peripheral neuropathy

ObjectiveIn patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects.MethodsThirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli.ResultsFor LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively.ConclusionsIn patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together.SignificanceLEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.     

Measures of chemotherapy-induced peripheral neuropathy: a systematic review of psychometric properties

Chemotherapy-induced peripheral neuropathy (CIPN) remains the principal dose-limiting toxicity of many agents. This systematic review evaluates available CIPN measures and provides rationale for selection of measures in this field. Searches of Medline (1966-2010), CINAHL (1966-2010), Embase (1966-2010), and Cochrane (1988-2010) databases were performed. To be selected, studies had to include (1) subjects receiving peripheral neurotoxic chemotherapy for cancer and (2) a primary purpose of psychometric evaluation of CIPN measures. A modified Quality of Diagnostic Accuracy Studies (QUADAS) tool coded psychometric study quality, with 0-7 score overall possible (higher score indicating better quality). A total of 15 studies qualified for evaluation. Overall studies were of moderate quality, with 10 of 15 receiving a 4-5 QUADAS score. Averaged quality scores for two repeatedly studied measures, Total Neuropathy Score (TNS) versions and Functional Assessment of Cancer-Gynecologic Oncology Group, neurotoxicity (FACT/GOG-Ntx), were 5.4 and 4.5, respectively. Two measures emerged as potentially useful for clinical trials and patient care. The FACT/GOG-Ntx is a subjective measure of CIPN-related quality of life (QoL). TNS clinical versions incorporate both subjective measures and objective examinations of nerve function. However, to improve QUADAS scoring, additional research is needed focusing on other psychometric aspects such as responsiveness of CIPN outcome measures.     

Nasal administration of mesenchymal stem cells reverses chemotherapy-induced peripheral neuropathy in mice

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequently reported adverse effects of cancer treatment. CIPN often persists long after treatment completion and has detrimental effects on patient’s quality of life. There are no efficacious FDA-approved drugs for CIPN. We recently demonstrated that nasal administration of mesenchymal stem cells (MSC) reverses the cognitive deficits induced by cisplatin in mice.Here we show that nasal administration of MSC after cisplatin- or paclitaxel treatment- completely reverses signs of established CIPN, including mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. Nasally administered MSC enter rapidly the meninges of the brain, spinal cord and peripheral lymph nodes to promote IL-10 production by macrophages.MSC-mediated resolution of mechanical allodynia, recovery of IENFs and restoration of DRG mitochondrial function critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, WT MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons. In conclusion, only two nasal administrations of MSC fully reverse CIPN and the associated mitochondrial abnormalities via an IL-10 dependent pathway. Since MSC are already applied clinically, we propose that nasal MSC treatment could become a powerful treatment for the large group of patients suffering from neurotoxicities of cancer treatment.     

Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry. At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of the follow-up period. Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vacuolization due to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells. Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal cord was morphologically normal. This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity.     

Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies

Cisplatin, paclitaxel and bortezomib belong to some of the most effective families of chemotherapy drugs for solid and haematological cancers. Epothilones represent a new family of very promising antitubulin agents. The clinical use of all these drugs is limited by their severe peripheral neurotoxicity. Several in vivo rat models have reproduced the characteristics of the peripheral neurotoxicity of these drugs. However, since only a very limited number of cancer types can be studied in immunocompetent rats, these animal models do not represent an effective way to evaluate, at the same time, the antineoplastic activity and the neurotoxic effects of the anticancer compounds. In this study, we characterized the neurophysiological impairment induced by chronic chemotherapy treatment in BALB/c mice, a strain suitable for assessing the activity of anticancer treatments. At the end of a 4-week period of treatment with cisplatin, paclitaxel, epothilone-B or bortezomib, sensory and sensory/motor nerve conduction velocities (NCV) were determined in the caudal and digital nerves and dorsal root ganglia (DRG) and sciatic nerves were collected for histopathological analysis.The electrophysiological studies revealed that all the compounds caused a statistically significant reduction in the caudal NCV, while impairment of the digital NCV was less severe. This functional damage was confirmed by the histopathological observations evidencing axonal degeneration in the sciatic nerve induced by all the drugs associated with pathological changes in DRG induced only by cisplatin and bortezomib.These results confirm the possibility to use our models to combine the study of the antineoplastic activity of anticancer drugs and of their toxic effects on the peripheral nervous system in the BALB/c mouse strain.     

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.     

Pilot study of repetitive transcranial magnetic stimulation in patients with chemotherapy-induced peripheral neuropathy

ObjectiveChemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients.Materials and methodsEleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes’ Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2).ResultsrTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed.ConclusionThis is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN.     

External validation of the Epilepsy Surgery Grading Scale in a Japanese cohort of patients with epilepsy

Objective: The Epilepsy Surgery Grading Scale (ESGS) is a simple method to predict the likelihood of a patient with epilepsy proceeding to surgery and achieving seizure freedom. Usefulness of the ESGS has been confirmed in established epilepsy centres in the United States and Belgium for adult patients with drug‐resistant focal epilepsy undergoing presurgical evaluation. However, the applicability of the ESGS has not yet been evaluated in a wider range of epilepsy patients that may reflect the general spectrum of epilepsy. The present study validated the ESGS in a Japanese epilepsy centre in which admission‐based comprehensive epilepsy studies were indicated beyond presurgical evaluation. Methods: This single‐centre retrospective study included adult patients with epilepsy admitted to the Epilepsy Monitoring Unit from 2010 to June 2019. Patients were classified as ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favourable). Patients were grouped into three cohorts: all patients, patients with drug‐resistant focal epilepsy, and patients who underwent resective epilepsy surgery. We assessed progression to surgery and seizure freedom at one year after surgery. Results: Of the 1,158 total admissions, 670 patients met the inclusion criteria and formed the total cohort. Of these, 435 (64.9%) had drug‐resistant focal epilepsy and 78 (11.6%) proceeded to resective surgery. Overall, progression to surgery was observed in 41.3%, 16.6%, and 4.8% of patients with Grade 1, 2, and 3, respectively. In the surgical cohort, seizure freedom was observed in 85.2%, 65.2%, and 31.3% of patients with Grade 1, 2, and 3, respectively. Significance: Our results indicate that the ESGS is effective in predicting whether a patient proceeds to epilepsy surgery and achieves seizure freedom even in the general population of epilepsy patients, regardless of type or resistance to antiepileptic drugs.     

On ethylene oxide neurotoxicity: report of two cases of peripheral neuropathy

Two cases of clinically and electromyographically proven ethylene oxide neuropathy occurred among 12 workers at the Lecco Hospital Sterilization Center. Cessation of exposure to the gas, which had lasted for two years, was followed by swift remission of the symptoms and complete normalisation of the EMG record at follow-up six months later. The paucity of published data on the subject may well mean that the real risk of ethylene oxide toxicity is being underrated.

---

Sommario Vengono descritti due casi di neuropatia da ossido di etilene, con sintomatologia clinica ed alterazione dei parametri elettrografici investigati, insorti in un gruppo di dodici lavoratori addetti al Centro di Sterilizzazione dell'Ospedale di Lecco. L'allontanamento dalla esposizione al gas (che datava da due anni) ha determinato una pronta remissione dei sintomi ed una normalizzazione completa del quadro elettrografico, ad un controllo eseguito sei mesi dopo. Si sottolinea la scarsità dei dati della letteratura al riguardo (sette casi in tutto, compresi quelli da noi descritti), possibile espressione, a nostro avviso, di una sottovalutazione del reale pericolo di neurotossicità dell'ossido di etilene.

     

The Neurotoxicity Scale: The validity of a patient-based scale, assessing neurotoxicity

The validity of a patient-based scale, presumably measuring adverse effects of drugs on cognitive function, was examined in a normal volunteer study. Thirty subjects were randomly assigned to placebo or one of two doses of a benzodiazepine, temazepam (10 mg and 20 mg), in a double-blind placebo-controlled parallel group design. Plasma samples were taken before the scale was completed and up to 8 hours post-dose. After administration of the medication the subjects were asked to maintain their normal daily routine as much as possible (reading, studying, conversations). The inventory was administered twice, at 50 minutes and 2 hours post-dose (peak level). The overall score was different between the three groups, only for the second assessment, 2 h post-dose ( , P<0.02). Multiple t-testing between the three groups revealed statistically significant differences between placebo and the 10 mg temazepam group (P = 0.02) and between placebo and the 20 mg temazepam group (P = 0.006). No significant difference was found between the two temazepam groups. Analysis of the separate questions showed least sensitivity for questions related to the domain of ‘hyperexcitability’ and most sensitivity for ‘fatigue’ and ‘slowing’. The overall score appeared to be sensitive already for the lower toxicity range suggesting an ‘all or nothing effect’. The subjective reports, collected by using this scale, may therefore be used for the detection of gross overall changes in cognitive functioning.     

Epidemiological case definitions of peripheral neuropathy: experience from two neurotoxicity studies

OBJECTIVE: The purpose of this investigation was to develop and apply case definitions of peripheral neuropathy (PN) derived from a set of individual measures of peripheral nerve function obtained in two epidemiological studies. METHODS: In the first study, retired workers of an industrial plant who were either previously exposed to mercury or not underwent a set of peripheral neurological tests. In the second study, persons living in an arsenic contaminated community in rural Georgia, USA, and unexposed comparison subjects were tested. In both studies all participants received a neurological physical examination, functional quantitative tests of vibrotactile thresholds and standing stability, and nerve conduction measurements. Two types of analyses were performed. First, the effect of exposure group status was examined for each individual test. For tests with continuous outcomes, the effect of exposure group was estimated while controlling for covariates. For tests with categorical outcomes (all of the neurological examination outcomes), exposure group effects were estimated by comparison of the proportion of abnormal test results among the exposed and unexposed groups. Second, case definitions of PN were constructed using combinations of results of the tests performed. Each of the continuous measures was categorized as normal, equivocal, or abnormal on the basis of adjusted standardized scores. Separate "abnormality scores" were constructed for 1) the nerve conduction tests and 2) the functional quantitative tests and physical examination findings. Five case definitions for PN were constructed based on combinations of these two abnormality scores. RESULTS: Generally, small differences were observed between exposed (n=79 arsenic exposed and 85 mercury exposed) and unexposed (n=84 arsenic unexposed and 118 mercury unexposed) groups when results of each clinical, functional or electrophysiological test were examined separately. Clearer group differences were observed in the proportions of each group who met case definitions for PN, however. For example, for both studies, the largest difference in nerve conduction measures between exposed and unexposed groups was approximately 0.33 SD, while the composite case definition showed an odds ratio of more than 3.1 for the mercury study and 5.1 for the arsenic study. CONCLUSIONS: These results suggest improved efficiency (and avoidance of the multiple-comparisons problem) for detecting peripheral nerve effects when case definitions of PN are constructed rather when results of individual tests of PN function are compared.     

The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity

To evaluate the utility of the peripheral benzodiazepine receptor (PBR) as a biomarker of neurotoxicity, we measured receptor levels after sub-seizure doses of domoic acid (0–3.0 mg/kg) in rats using [³H]PK-11195 autoradiography. PBR expression in limbic structures was significantly increased 5 days, but not 24 or 48 h after injection of 3.0 mg/kg domoic acid. The largest increase in [³H]PK-11195 binding (>500% above control) was found in the CA3 subfield of the hippocampus. Other limbic structures including the CA1 hippocampal subfield, subiculum, dentate gyrus and amygdala also showed significant increases in PBR expression, as did the striatum and substantia nigra pars reticulata. Smaller but significant increases were also observed 5 days after injection of 1.5 mg/kg, but not in animals treated with 0.75 mg/kg domoic acid. No pathology was observed after routine histological staining of brain tissue. Spatial learning and memory, a process thought to be associated with the hippocampus, was assessed in the Morris water maze. Groups treated with 1.5 and 3.0 mg/kg, but not 0.75 mg/kg domoic acid were significantly impaired in water maze performance. These findings suggest that the PBR could provide a sensitive and specific biomarker of neurotoxicity. © 1997 Elsevier Science B.V. All rights reserved.     

RAT in vivo models of taxanes'' peripheral neurotoxicity following chronic intravenous administration

Case Report: A 20‐year‐old man presented for evaluation following an episode of painless injury in which he almost amputated his thumb. Upon further questioning, the patient reported he rarely experienced physical (including visceral) pain and his mother provided support to his history recalling incidents occurring as a child. He does not experience itching either. His neurologic and general medical history was otherwise negative. His neurologic and general examination were unremarkable except for the inability to perceive painful (pinprick, pressure on Achilles' tendons), hot and cold stimuli over his entire body, with some relative sparing over his chest, abdomen and back. Nerve conduction studies and needle examinations were normal. Quantitative sensory testing revealed normal threshold to vibration, relatively elevated threshold to cold and insensitivity to heat and pain. Autonomic reflex screen and thermoregulatory sweat test were normal. Sural nerve biopsy showed normal myelinated and unmyelinated fibers. MRI of head and cervical spine, and extensive laboratory testing were unremarkable. Conclusion: This patient differs from any other case described in the literature of pain insensitivity or pain indifference. Suspecting a central pathology, we prescribed naltrexone and retested his heat‐pain sensation after treatment. He perceived the probe as hotter. Unfortunately, he suffered unacceptable dysthymia from the medication and stopped it.     

Chemotherapy-induced peripheral neurotoxicity can be misdiagnosed by the National Cancer Institute Common Toxicity scale

The assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) is still uncertain as several of the most frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. The aim of this study was to compare the assessment of CIPN using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale and a formal neurological assessment scored with the Total Neuropathy Score (TNS, i.e., a composite scale designed to grade the impairment in neuropathy patients) to identify possible discrepancies in the diagnosis. In this prospective study, 155 patients treated with cisplatin/carboplatin or with paclitaxel/docetaxel and CIPN were examined in a collaborative oncological/neurological multi-center trial using the NCI-CTC scale and the TNS; the results were then extensively compared. We evidenced that the TNS allows possible misdiagnosed neuropathies to be revealed. In fact, the NCI-CTC evaluation performed by experienced examiners overestimated the occurrence of motor neuropathy, possibly because of the presence of confounding factors (e.g., fatigue, depression, cachexia), which might be difficult to be ruled out without a formal neurological examination. This study strongly indicates that a more formal neurological assessment of patients with CIPN than that achievable with the common toxicity scales (e.g., NCI-CTC) is advisable.