Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer.

CONTEXT: Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. OBJECTIVE: The objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. METHODS: Chemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510-520 mg/m2 (T1) and 1020-1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. RESULTS: Latent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. CONCLUSION: We identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.

Evidence for a separate mechanism of toxicity for the Type I and the Type II pyrethroid insecticides.

Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. Of the alpha-cyano pyrethroids, deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six alpha-cyano pyrethroids (lambda-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of lambda-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups.

Neuroimaging of toxic and metabolic disorders.

Imaging of the brain, magnetic resonance imaging (MRI) in particular, is a key adjunctive tool in the diagnosis and management of toxic-metabolic disorders such as alcoholism, mitochondrial encephalopathies, disorders of iron or copper metabolism, exposure to carbon monoxide, radiotherapy, immunosuppressive agents, toluene, and recreational drugs. In this article, we review the neuroimaging findings of common toxic and metabolic disorders focusing on the role of conventional MRI. We also consider advanced imaging methods, such as magnetic resonance spectroscopy, diffusion MRI, and positron emission tomography. We hope this article will prove useful to trainees and practitioners in the clinical and imaging fields of the neurosciences.

Diffusion-weighted MRI in cyclosporin A neurotoxicity for the classification of cerebral edema.

Cyclosporin A, an immunosuppressive agent, is known to have neurotoxic effects, but until now, there has not been agreement on the underlying mechanism. Our report suggests, by using diffusion-weighted MRI, that the brain lesions caused by cyclosporin A, are probably related to vasogenic edema. This may explain the complete recovery of the lesions on imaging when cyclosporine therapy is stopped.