The authors compared clinically based neurotoxicity scales with the Total Neuropathy Scale, with the aim of improving the grading of the severity of chemotherapy-induced peripheral neuropathy (CIPN). The severity of CIPN was evaluated in a series of 60 women treated with cisplatin- and paclitaxel-based chemotherapy. A reduced version of TNS (TNSr) was also compared. The authors concluded that the TNS and TNSr can be used to assess the severity of CIPN effectively, and the results of this evaluation can be reliably correlated with the oncologic grading of sensory peripheral neurotoxicity.

Our study indicates that a precise clinical evaluation of the peripheral nervous system of patients treated with platinum and taxane combination polychemotherapy not only gives reliable information regarding the course of CIPN, but also can be used to predict the final neurological outcome of the treatment.

A 68-year-old man presented with a 4-month history of progressive memory loss and mood disorders. Neurologic examination revealed severe impairment of attention and verbal skills, without motor and sensory deficits. His medical history included mild arterial hypertension, idiopathic partial epilepsy, and obsessive compulsive disorder.Brain MRI showed the presence of bilateral, asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, that partially involved the left frontal cortex (figure). On diffusion-weighted sequences, the white matter abnormalities were consistent with vasogenic edema. No pathologic contrast enhancement was present.Routine blood tests, inflammatory markers, autoantibodies, neoplastic markers, and paraneoplastic antibodies were within normal limits. CSF examination revealed increased level of proteins (152 mg/dL) and cell count (14 leukocyte/L), without intrathecal synthesis of oligoclonal bands. Bacterioscopic and virologic tests (including HIV and JCV) were negative, both on CSF and serum. Search for tumor or infection by total body CT scan was negative.Stereotactic biopsy of the left frontal white matter lesion showed gliosis without signs of infections or neoplasm.After the biopsy, the patient was treated with dexamethasone 24 mg/day IV for 20 days with marked clinical improvement. A control CSF analysis performed 3 months later was within normal limits (Ͻ1 leukocyte/ L, protein 27 mg/dL). Brain MRI demonstrated a reduction in number and extension of the white matter T2-hyperintense lesions (figure). T2*-weighted gradient echo images showed the presence of multiple microhemorrhages scattered over the entire cerebral cortex. No microbleeds were present in basal ganglia, thalami, and posterior fossa (figure).Diagnosis of probable cerebral amyloid angiopathy-related inflammation (CAA-ri) was made upon clinical and MRI findings, supported by the demonstration of APOE ⑀4 homozygosity.A search for A␤ deposits in brain tissue and vessel walls on the biopsy sample was negative; a possible explanation is the deep white matter target, with absence of cortex and leptomeninges in the specimen. The A␤ 1-42 protein in the CSF was reduced both in the first (129 pg/mL) and second (125 pg/mL) lumbar puncture compared to normal values (682-1,063 pg/mL). The A␤ 1-40 protein was also investigated (457 pg/mL in the first CSF; 238 pg/mL in the second); however, due to the large variability of this assay as reported in literature, the meaning of these values is unclear.We hypothesized a spontaneous autoimmune process against CNS A␤ proteins, and assessed the levels of anti-A␤ 1-40 and 1-42 autoantibodies in our patient's CSF, both before and after steroid treatment, compared to 6 age-matched controls (mean age: 63 Ϯ 19 years) and 4 patients with MS (mean age: 45 Ϯ 17 years). We used our ELISA, as described, 1 and detected a marked increase of anti-A␤ 1-40 and 1-42 autoantibodies in the CSF of our CAA-ri patient obtained prior to treatment compared to controls and ...

Background. Taxol is a new anticancer drug that acts as a tubulin polymeration enhancer. Its major toxicities are myelosuppression, hypersensitivity, and mucositis, but it also induces peripheral nerve damage. The use of taxol has recently been proposed for platinum‐resistant cancers, but in these cases there is a possibility of cumulative toxicity in the peripheral nervous system. Methods. Twenty‐two patients affected by a relapse of cisplatin‐treated ovarian cancer were examined clinically and neurophysiologically to determine the evolution of taxol‐induced peripheral somatic and autonomic neurotoxicity and the possible cumulative effect of a combination of taxol and cisplatin. Each patient was examined before, during, and after taxol treatment (using a dose of 135 or 175 mg/m2 in 3 hours every 3 weeks). Results. No patients were excluded from the study because of unacceptable toxicities of any kind. The serial examinations demonstrated that taxol induced onset of (or worsening of preexisting) neuropathic symptoms and signs in almost all the patients. The features were those of a distal, symmetrical, sensory polyneuropathy due to an axonopathy. Motor nerves and the autonomic nervous system were unaffected. Taxol neurotoxicity appeared early in the course of the treatment (i.e., after three courses) and was not severely disabling. In most cases after the early onset of peripheral neuropathy, stabilization of this side effect occurred. Conclusions. Considering the low doses of taxol used in this study, the sensory nerve damage was unexpectedly severe. It appears that a cumulative, but not dose‐limiting, neurotoxic effect occurs using taxol in patients previously treated with cisplatin. Cancer 1995;75:1141–50.

The authors prospectively evaluated the effects of three different schedules of cisplatin (DDP) administration in 60 patients with advanced epithelial ovarian cancer. The individual total dose of DDP was 450 mg/m2 in all three groups, and the anti‐cancer response at the end of treatment was similar for the different regimens. The clinical and neurophysiologic results confirmed that axonal sensory neuropathy occurred after the standard administration of DDP (75 mg/m2 in 3‐week cycles) and probably not only the peripheral, but also the central sensory pathway, was involved. Although the total dose of the drug was identical, the two less conventional schedules were less neurotoxic. These results suggest that not only the total‐dose intensity, but also the single‐dose intensity are relevant in the onset of DDP‐induced sensory neuropathy; therefore, the use of less neurotoxic schedules may prevent or reduce sensory nerve damage.

ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [(3)H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

In recent years several authors have described a close correlation between circulating antineuronal antibodies of different types and the occurrence of paraneoplastic neurological syndromes. Because this has not been widely accepted, we screened 300 serum samples from 181 ovarian cancer patients for the presence of circulating antineuronal antibodies by immunofluorescence. The findings were confirmed by immunoblotting. In 11 patients circulating antineuronal antibodies were detected. In 4 patients they were classified as anti-Yo and in 7 as anti-Ri, titres ranging from 1:400 to 1: 204,800. All the patients underwent thorough neurological and neurophysiological investigations, with special regard to paraneoplastic syndrome. None of them had symptoms pointing to a paraneoplastic neurological syndrome, although patients were followed up to 2 years after the first examination. Thus the frequency of circulating antineuronal antibodies in ovarian cancer patients is higher than the frequency of paraneoplastic syndromes, and antibody positivity does not necessarily lead to the appearance of a neurological paraneoplastic syndrome.

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450-650 mg m-2 were randomized to receive cisplatin 50 mg m-2 weekly +/- 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.