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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.

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.

Composite scales such as the Total Neuropathy Score clinical version (TNSc(©) ) have been widely used to measure neurological impairment in a standardized manner but they have been criticized due to their ordinal setting having no fixed unit. This study aims to improve impairment assessment in patients with chemotherapy-induced peripheral neuropathy (CIPN) by subjecting TNSc(©) records to Rasch analyses. In particular, we wanted to investigate the influence of factors affecting the use of the TNSc(©) in clinical practice. TNSc(©) has 7 domains (sensory, motor, autonomic, pin-prick, vibration, strength, and deep tendon reflexes [DTR]) each being scored 0-4. Data obtained in 281 patients with stable CIPN were subjected to Rasch analyses to determine the fit to the model. The TNSc(©) did not meet Rasch model's expectations primarily because of misfit statistics in autonomic and DTR domains. Removing these two, acceptable model fit and uni-dimensionality were obtained. However, disordered thresholds (vibration and strength) and item bias (mainly cultural) were still seen, but these findings were kept to balance the assessment range of the Rasch-Transformed TNSc(©) (RT-TNSc(©) ). Acceptable reliability findings were also obtained. A 5-domains RT-TNSc(©) may be a more proper assessment tool in patients with CIPN. Future studies are needed to examine its responsive properties.

Objective: cerebral Amyloid Angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined Amyloid-Related Imaging Abnormalities (ARIA) reported in Alzheimer’s disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid beta (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: we used a novel ultra-sensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibodies concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau and APOE4 genotype were also investigated. Results: during the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. Interpretation: our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebro-vascular Aβ, directly related to autoantibodies concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA

Objective: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid β (Aβ) autoantibodies in the acute and remission phases of CAA-ri. Methods: We used a novel ultrasensitive technique on patients from a retrospective multicenter case-control study, and evaluated the anti-Aβ autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Aβ40, Aβ42, tau, P-181 tau, and APOE genotype were also investigated. Results: During the acute phase of CAA-ri, anti-Aβ autoantibodies were specifically increased and directly correlated with Aβ mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Aβ and axonal degeneration markers decreased in parallel. Interpretation: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. The CSF dosage of anti-Aβ autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Aβ autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.

Cerebral amyloid angiopathy (CAA) is pathologically characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries and capillaries in the cerebral cortex and overlying leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. Interestingly, a subgroup of CAA patients has been shown to develop vascular inflammation of the affected vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline. This condition, known as CAA-related inflammation (CAA-ri), presents with acute or subacute neurological impairment, behavioral changes, seizures and focal neurological deficits. A definite diagnosis of CAA-ri requires brain and leptomeningeal biopsy that shows perivascular inflammation associated with Aβ laden vessels and signs of vasculitis. This distinct syndrome has parallels with what observed in about 5-10% of patients affected by Alzheimer’s disease (AD) who developed reversible VE after passive immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of the therapeutic protocol. Moreover, recent imaging data on the location of ARIA-E have shown that up to 17% of the treated patients showed signs of VE, even if in the absence of clinical correlates and directly related to the drug dose. Herein, thanks to a novel technique for the ultra sensitive evaluation of anti-Aβ (patent application pending), for the first time, we confirmed a direct involvement of these antibodies during the course Pag. of disease in the CSF of 10 CAA-ri, compared to 8 CAA and 20 healthy subjects, demonstrating that the concentration of anti-Aβ is specifically increased during the acute phase of the disease. Moreover, we reported a progressive reduction of autoantibodies concentration following steroid treatment, according to clinical-radiological improvement. As a further proof, a spontaneous decrease of anti-Aβ in patients without any immunosuppressant treatment was observed, finally proving that this event is not secondary to an unspecific effect of treatment, but strictly related to the disease progression. Our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction directed against Aβ, directly mediated by anti-Aβ autoantibodies. The outcomes implied by antibodies dosage in the CSF may be proposed to support future accessible targets for early diagnosis and follow-up, and as a novel surrogate biomarkers for clinical trials of disease modifying therapies.

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries of cerebral cortex and leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. A subgroup of CAA patients develop perivascular inflammation linked to the Aβ laden vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline, leading to a condition known as CAA-related inflammation (CAA-ri). This syndrome has parallels with what observed in about 10% of patients affected by Alzheimer's disease (AD) who developed reversible VE after immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of therapeutic protocols. Recent MRI data have also shown that up to 17% of the treated patients have signs of VE directly related to the drug dose, even if in the absence of clinical correlates. Methods: thanks to a novel technique for the ultra sensitive evaluation (patent application pending), we followed the concentration of anti-Aβ antibodies in the CSF of 10 CAA-ri patient during the acute phase (acCAA-ri) and after the remission phase (rpCAA-ri), compared to 8 non-inflammatory CAA, 10 AD, 10 MS and 20 healthy control subjects. Results: we demonstrated that the concentration of anti-Aβ antibodies is specifically increased in the CSF of acCAA-ri patients, followed by a progressive reduction of their concentration after steroid treatment, accordingly to clinical-radiological improvements. Moreover, we observed a spontaneous decrease of these autoantibodies in rpCAA-ri patients without any immunosuppressant treatment, finally proving that the event is not secondary to an unspecific effect of treatment, but strictly related to disease progression. Conclusions: our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction against Aβ, directly mediated by anti-Aβ autoantibodies. Since an invasive procedure such as brain biopsy is still needed for a definite diagnosis of CAA-ri, the outcomes implied by anti-Aβ dosage in CSF may be proposed to support future targets for early diagnosis and follow-up, in association with clinical and radiological features, and as a surrogate biomarker for clinical trials of disease modifying therapies.

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.

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.

The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compared, since no animal models of docetaxel peripheral neurotoxicity have yet been reported. In this experiment, we examined the effect of the chronic administration of these two taxanes in the Wistar rat using neurophysiological, neuropathological and morphometrical methods. Our results showed that both paclitaxel and docetaxel induced a significant, equally severe and dose-dependent reduction in nerve conduction velocity. On the contrary, the morphometric examination demonstrated that the effect on the nerve fibres was more severe after paclitaxel administration when the same schedule was used. However, the overall severity of the pathological changes was milder than expected on the basis of the neurophysiological results. Our results support the hypothesis that taxanes (and particularly docetaxel) may exert their neurotoxic effect not only on the microtubular system of the peripheral nerves, but also on other less obvious targets. © 2005 Elsevier Ltd. All rights reserved.

The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient’s entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17.

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a frequent, potentially severe and dose-limiting side-effect of cancer treatment. Despite its clinical relevance that limits the use of several antineoplastic agents and even the future development of new anticancer drugs, several crucial aspects of CIPN remain unsolved, one of which is how to assess its occurrence and severity in the most effective and reliable way. CIPN severity is generally assessed using Common Toxicity Criteria (CTC) scales, although it is well known that significant inter-observer disagreement exists using these scales. Moreover, most CTC scores mix impairment, disability and quality of life measures, which could lead to misinterpretation of the results and unpredictable under- or overestimation of the effect. This uncertainty may lead to different interpretations of the results of the same clinical trials by clinicians and also by regulatory agencies. The use of other types of scale based on clinical and instrumental examinations, or the use of self-administered questionnaires for patients, has not yet really improved the accuracy of CIPN assessment, although some of these tools are promising and deserve to be further validated. As a result, there is a general recognition that CIPN has still not been properly assessed and that improvements should be made. In this review, the available data regarding the different tools used to assess CIPN will be revised and their features will be critically examined, with a special focus on their reliability and reproducibility across examiners and, when available, through direct comparison. © 2009 Elsevier Ltd. All rights reserved.

We investigated a series of bortezomib-treated patients and correlated the course of bortezomib-induced peripheral neurotoxicity with the presence or absence of peripheral neuropathy at baseline. Forty-eight patients were examined with the total neuropathy score reduced version (TNSr), visual analogue score (VAS) for pain, and nerve conduction studies at baseline and after two and four cycles of chemotherapy. Twenty-three patients had a baseline TNSr = 0–2, and 25 patients had a baseline TNSr >2 (median = 6, range 3–13). The course of bortezomib-induced peripheral neurotoxicity was generally more severe in those patients with the highest baseline TNSr. However, among those subjects with a normal baseline TNSr, two patients developed a clinically relevant peripheral neuropathy with a marked increase in TNSr as early as after two cycles of bortezomib treatment (TNSr = 10 and 15, respectively), while after four cycles, three other patients with normal baseline TNSr had a TNSr of 11, 12, and 13. VAS reporting confirmed that painful neuropathy is frequent after bortezomib administration. Our results indicate that the course of bortezomib-induced peripheral neurotoxicity can be severe in subjects with normal neurological examination at baseline, and therefore, careful monitoring during treatment is suggested in these patients.

Objective: Cerebral amyloid angiopathy (CAA) is characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries of cerebral cortex and leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. A subgroup of CAA patients develop perivascular inflammation linked to the Aβ laden vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline, leading to a condition known as CAA-related inflammation (CAA-ri). This syndrome has parallels with what observed in about 10% of patients affected by Alzheimer's disease (AD) who developed reversible VE after immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of therapeutic protocols. Recent MRI data have also shown that up to 17% of the treated patients have signs of VE directly related to the drug dose, even if in the absence of clinical correlates. Methods: thanks to a novel technique for the ultra sensitive evaluation (patent application pending), we followed the concentration of anti-Aβ antibodies in the CSF of 10 CAA-ri patient during the acute phase (acCAA-ri) and after the remission phase (rpCAA-ri), compared to 8 non-inflammatory CAA, 10 AD, 10 MS and 20 healthy control subjects. Results: we demonstrated that the concentration of anti-Aβ antibodies is specifically increased in the CSF of acCAA-ri patients, followed by a progressive reduction of their concentration after steroid treatment, accordingly to clinical-radiological improvements. Moreover, we observed a spontaneous decrease of these autoantibodies in rpCAA-ri patients without any immunosuppressant treatment, finally proving that the event is not secondary to an unspecific effect of treatment, but strictly related to disease progression. Conclusions: our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction against Aβ, directly mediated by anti-Aβ autoantibodies. Since an invasive procedure such as brain biopsy is still needed for a definite diagnosis of CAA-ri, the outcomes implied by anti-Aβ dosage in CSF may be proposed to support future targets for early diagnosis and follow-up, in association with clinical and radiological features, and as a surrogate biomarker for clinical trials of disease modifying therapies