Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial.

OBJECTIVE: The clinical use of cisplatin chemotherapy is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m(2). The present study evaluates the neuroprotective effect of antioxidant supplementation (vitamin E) in patients treated with cisplatin chemotherapy. METHODS: A total of 108 patients treated with cisplatin chemotherapy were randomly assigned to receive vitamin E supplementation (alpha-tocopherol 400 mg/day) or placebo. Treatment was started orally before chemotherapy and continued for 3 months after the suspension of cisplatin. RESULTS: Of 108 randomized patients, 68 received at least one clinical and neurophysiologic examination after cisplatin CT; 41 patients received a cumulative dose of cisplatin higher than 300 mg/m(2) and were eligible for statistical analysis: 17 in the vitamin E group (group 1) and 24 in the placebo group (group 2). The incidence of neurotoxicity was significantly lower in group 1 (5.9%) than in group 2 (41.7%) (p < 0.01). The severity of neurotoxicity, measured with a validated neurotoxicity score (Total Neuropathy Score [TNS]), was significantly lower in patients receiving vitamin E than those receiving placebo (mean TNS 1.4 vs 4.1; p < 0.01). CONCLUSIONS: This phase III study confirms the neuroprotective role of vitamin E against cisplatin peripheral neurotoxicity. Vitamin E supplementation should be adopted in patients receiving cisplatin-based chemotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02-1.00, p < 0.05).

Luminance and chromatic visual evoked potentials in type I and type II diabetes: relationships with peripheral neuropathy.

The objective of the study was to investigate the subclinical visual deficit in type I and II diabetes, and its relationship with peripheral neuropathy. Thirty-two healthy volunteers, 20 patients with type I diabetes and 30 patients with type II diabetes were studied in a clinical neurophysiology setting. Luminance (VEPs) and chromatic visual evoked potentials (CVEPs) were recorded, with white-black, grey-black, red-green and blue-yellow sinusoidal gratings. The peak latencies of the VEP positive wave and CVEP negative wave were recorded. Ten patients with type I and 8 with type II diabetes had peripheral neuropathy. VEPs were slower in patients with type II diabetes and CVEPs were slower in patients with type I and type II diabetes than in controls. Blue-yellow CVEPs were slower in type II than in type I diabetes. VEPs and red-green CVEPs were slower in patients with diabetes with neuropathy than in those without. In conclusion, we found that visual system impairment differs in diabetes with and without peripheral neuropathy.

Cerebellar atrophy and monoclonal gammopathy of undetermined significance: a possible correlation?

Central Nervous System involvement in Monoclonal gammopathies of undetermined significance has seldomly been reported and in all the cases a demyelinating disease was found. We report the case of a young man who had been suffering for five years of progressive cerebellar syndrome. MRI showed marked cerebellar vermis atrophy. An IgG lambda monoclonal gammopathy was revealed in the serum. Cerebrospinal fluid examination showed oligoclonal bands and elevated Link-Index. Serologic research for HBV, HCV, HIV, Lues, Rubella, Measles was negative, as also genetic analysis for SCA1, SCA2, SCA3, SCA7 and Friederich's ataxia. Nerve conduction studies were normal. Plasmatic vit.E was low, but treatment with high doses of tocopherol was ineffective. i.v. immunoglobulins and steroids obtained only transient clinical benefits. In conclusion, we hypothesize a pathogenetic role of the IgG in this cerebellar atrophy.

Surface electromyography and mechanomyography recording: a new differential composite probe.

The objective of the study was to develop a new surface probe for differential mechanomyographic (MMG) and electromyographic (EMG) recording. Differential amplification is commonly used in electromyography to improve the signal-to-noise ratio. A new composite probe was developed with two electrodes (EMG) and two identical piezo-electric membranes (MMG) to be positioned on muscle. The probe had two built-in fixed-gain differential amplifiers: one to amplify the electric signal and the other to amplify the vibration signal. A similar non-differential MMG probe was used for comparisons. Burst muscular activity was recorded using the non-differential and differential probes and was used to test the performance of the two probes in suppressing artifacts of non-muscular origin. Power spectrum analysis of signals from the two probes showed that differential amplification significantly improved the signal-to-noise ratio in MMG recordings and significantly suppressed artifacts (power difference > 90%). The composite probe allowed simultaneous differential recording of MMG and EMG signals from the same muscular site. It recorded muscular activity more efficiently than the non-differential probe and could therefore be useful in studying fatigue and neuromuscular diseases.

Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response.

BACKGROUND: The optimal treatment for low-grade glioma (LGG) is still controversial. Recent data indicate a potential influence of chemotherapy on the natural evolution of these tumors, allowing for the deferral of more aggressive therapies. PATIENTS AND METHODS: Forty-three patients affected with LGG (29 astrocytoma, four oligodendroglioma and 10 mixed oligo-astrocytoma) were treated with temozolomide (TMZ) at the time of documented clinical and radiological progression. McDonald's response criteria were utilized to evaluate TMZ activity. Thirty patients (69.7%) had previously received radiotherapy; 16 (37.2%) had received prior chemotherapy. Clinical benefit was evaluated measuring seizure control, reduction in steroid dose and modification of Karnofsky performance status and Barthel index. Quality of life was assessed with the QLQ-C30 questionnaire. RESULTS: We observed a complete response in four patients, 16 partial responses, 17 stable disease (with four minor response) and six progressive disease. Median duration of response was 10 months [95% confidence interval (CI) 8-12], with a 76% rate of progression free survival (PFS) at 6 months, and a 39% rate of PFS at 12 months. A relevant clinical benefit was observed particularly in patients presenting epilepsy. CONCLUSIONS: The high response rate of 47% (95% CI 31% to 61%) confirms that TMZ chemotherapy is a valid option in the treatment of progressive LGG. The present preliminary results seem interesting and warrant further evaluation of TMZ clinical activity in a larger series of progressive LGG.

Demyelinating disease in monoclonal gammopathy of undetermined significance.

We describe herein the case of a 57 year old man who, over the last five years, has presented ataxic and spastic gait on the right side, a reduction in fine motor movement of the fingers mainly on the right side, superficial right side brachiocrural hypoesthesia and a marked dysarthria associated with internuclear ophthalmoplegia. The neurological picture, after an initial progressive worsening which lasted some months, remained relatively stable over the years. Repeated magnetic resonance imaging (MRI) of the brain and spinal cord documented the presence of demyelinating plaques spread in the white matter of the periventricular region and the semioval centres, and a right side paramedian plaque at the C4-C5 level, none of which were in the active phase. Oligoclonal bands were revealed in the cerebrospinal fluid (CSF). Monoclonal IgM/lambda gammopathy with anti-myelin and anti-nucleo reactivity, found with serum immunofixation, were confirmed several times in successive annual controls, not associated to myeloproliferative pathology. The lack of progression in the clinical picture would seem to contradict the diagnosis of late Multiple Sclerosis. The presence of antibody activity against the myelin might support the hypothesis of a pathogenetic role of the immunoglobulins at the onset of the demyelinating disease in this patient. However, in the end, there is the possibility of casual association with a poorly functioning immune system connected to age.

Masseteric silent period and reflex before and after dentomaxillofacial surgery.

The aim of this study was to evaluate massetteric silent period and reflex in patients affected by progenia, before and after maxillofacial surgery, in order to determine their clinical utility. The electrophysiological changes generated by malocclusion secondary to prognatism have been evaluated before and after maxillofacial corrective surgery in 14 patients aged between 18 and 36 years. The masseteric reflex and the silent period (SP) of the masseteric muscles elicited by stimulation of the mental nerve were recorded. A correspondence between the neurophysiological and clinical findings was present in 12 of 14 patients, in particular concerning the latency of SP2. This study demonstrates that the masseteric silent period may be used as a diagnostic and prognostic support, before and after surgery for malocclusion.

A new color vep procedure discloses asymptomatic visual impairments in optic neuritis and glaucoma suspects.

OBJECTIVE: To evaluate the reliability of visual evoked potentials obtained with a set of multiple chromatic and achromatic patterns (C-VEPs) in differentiating asymptomatic perifoveal retinal impairment from central conduction impairment. METHODS: We propose a set of colored pattern stimuli that allows relatively differential activation of the magnocellular and parvocellular pathways. The system runs on a standard Pentium PC with peripherals that present stimuli and collect, analyze and print data. P1 latencies of C-VEPs obtained with achromatic (black/white) and chromatic (blue/black and red/black isocontrast) checkerboards were evaluated in normal subjects and patients with subclinical retinal impairment (glaucoma suspects) or mild neural conduction impairment (optic neuritis), none of whom had subjective visual defects. RESULTS: The procedure evoked robust cortical signals and statistically distinguished the 3 groups of subjects. The achromatic and chromatic stimuli used distinguished controls from glaucoma suspects and patients with optic neuritis. Glaucoma suspects had greater impairment of C-VEPs to blue/black checkerboards whereas patients with optic neuritis had greater impairment of responses to red/black stimuli. CONCLUSIONS: Our data suggest that chromatic patterns (color/ black, red and blue), that may activate the parvocellular and magnocellular systems differentially but not selectively, can distinguish between mild perifoveal or foveal conduction impairment. They have the additional advantage of evoking large, stable responses across all the subjects.

Comparison of myocardial imaging with iodine-123-iodophenyl-9-methyl pentadecanoic acid and thallium-201-chloride for assessment of patients with exercise-induced myocardial ischemia.

Iodine-123-iodophenyl-9-methyl-pentadecanoic acid [( 123I]MPDA) and thallium-201 (201Tl) were sequentially injected in 11 patients during exercise-induced myocardial ischemia. Simultaneous dual-energy planar images were obtained at 5 min, 3 and 5 hr. All studies were concordantly either positive (8/11) or negative (3/11) by both radionuclides. Exact agreement for segmental uptake was 93%, 94% and 94% for 5-min, 3- and 5-hr images, respectively. Exact agreement for defect reversibility by 3 and 5 hr were 95% and 92%. The initial defect contrasts and myocardial-to-lung ratios were similar by both agents but myocardial-to-liver ratio was lower by [123I]MPDA at 5 min, which became similar to 201Tl at 5 hr. Normal percent myocardial clearances of both agents were comparable and significantly higher than those in defect zones. Thus [123I]MPDA is suitable for myocardial imaging and correlates closely with 201Tl for initial postexercise myocardial uptake and defect reversibility. Defect reversibility appears to result from differential myocardial clearance from normal and ischemic regions.