Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone.

BACKGROUND: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS: Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION: The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

Thermal sensitivity tester. Device for quantitative assessment of thermal sense in diabetic neuropathy.

The Thermal Sensitivity Tester (TST) is a portable device designed to quantify the ability to discriminate small differences in temperature at the distal extremities of the hands and feet. The testing surfaces are two identical nickel-coated copper plates, which can be set and maintained over a wide range of temperature levels. The threshold for detecting the colder surface is determined using a two-alternative, forced-choice algorithm. The mean threshold in the normal population is 0.67 degree C and 1.01 degree C for the index finger and great toe, respectively. The TST is especially useful in diabetic neuropathy and for rapid screening of large populations under field conditions.

Return to alertness after brain-stem hemorrhage. A case with evoked potential and roentgenographic evidence of bilateral tegmental damage.

After a 65-year-old man had received anticoagulation therapy for brain-stem ischemia, a large, bilateral pontomesencephalic hemorrhage developed in the ischemic region. He survived a period of being "locked in" to attain a limited functional recovery. When he first became alert, brain-stem auditory evoked potentials and short-latency somatosensory evoked potentials (SEPs) demonstrated bilateral brain-stem damage; computed tomography revealed a bilateral tegmental hematoma. Results of repeated studies changed little as clinical improvement occurred. Recovery from brain-stem hemorrhage is rare, and return of consciousness with bilateral tegmental involvement is even more rare. The short-latency SEPs are useful in defining the extent of brain-stem damage, but they evaluate structures distinct from those regulating consciousness and cannot predict a return to alertness.

Trimodal evoked potentials compared with magnetic resonance imaging in the diagnosis of multiple sclerosis.

Twenty-three patients with the clinical diagnosis of possible multiple sclerosis (MS) were tested with magnetic resonance imaging (MRI) and trimodal evoked potentials. Fourteen patients showed abnormalities on both MRI scans and at least one evoked potential modality (65%). Four patients had normal MRI scans but at least one abnormality on evoked potential testing (17%). One patient had normal triple evoked potentials with an abnormal MRI result. Four patients had normal results on both MRI and triple evoked potential testing; two of these patients were later found to have immunologic abnormalities in the cerebrospinal fluid consistent with the diagnosis of MS. Combined evoked potential testing was found to have a higher sensitivity than MRI in confirming a diagnosis of MS. Three patients with the clinical diagnosis of definite MS were also tested. All these patients showed abnormalities on evoked potential testing, although one patient had a normal MRI result. Of all 26 patients who were studied, 17 showed abnormal MRI results and 21 showed at least one abnormality on evoked potential testing.

Quantitative sensory testing demonstrates that subclinical sensory neuropathy is prevalent in patients with cancer.

Vibration threshold (VT) determinations were used to assess the function of the large nerve-fiber sensory system in 171 patients with cancer and 58 healthy subjects. Significant differences in VT indicate dysfunction of this sensory system in the cancer group. Twelve percent of the cancer patients had elevated VT compared with 1.7% of control subjects. Elevated VT was not associated with risk factors for neuropathy such as diabetes, renal disease, poor nutrition, or treatment with chemotherapy. Although VT elevation was associated with alcoholism and increasing age, these variables accounted for only a small proportion of the variance in VT. These data suggest that VT determinations are a useful method for quantifying sensory abnormalities in cancer patients. Sensory abnormalities occur in a significant proportion of patients with cancer and seem to be related directly to the neoplasm, rather than to known risk factors for neuropathy.

Rapid screening for peripheral neuropathy: a field study with the Optacon.

The modified Optacon, a simple battery-powered device that measures fingertip vibration sensation, was used by para-professionals to screen 257 acrylamide-exposed individuals. Consistent data were obtained on repeated testing of individuals, and there was an age-related linear decrease in vibration sensitivity within the population. Subclinical peripheral neuropathy was detected in two individuals, one acrylamide-related and the other nutritional-alcoholic. This study establishes the use of the modified Optacon as a screening device for some types of peripheral nerve dysfunction.

Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group.

OBJECTIVE: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN). METHODS: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies. RESULTS: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers. CONCLUSIONS: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.

Prevalence of peripheral neuropathy in injection drug users.

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitors are a critical component of antiretroviral therapy in HIV-infected persons. Several of these medications cause painful, dose-limiting peripheral neuropathy (PN), which may develop earlier and more intensely in persons with preexisting neuropathy. The prevalence of baseline peripheral neuropathy in injection drug users (IDUs), one of the largest populations of HIV-infected persons, has not been described, yet has important implications for the selection of antiretroviral therapy. METHODS: The authors performed a cross-sectional study of PN in 212 HIV-seronegative and HIV-seropositive IDUs using detailed neurologic histories, physical examinations, quantitative electrophysiologic study, and quantitative sensory testing. Data were used to assign patients to one of four positive categories of PN or one of two negative categories. RESULTS: PN was present in 24.5% of HIV-seronegative IDUs, three to four times the reported frequency for HIV-seronegative persons in the general or male homosexual population. PN was present in 32.1% of HIV-seropositive patients. PN was axonal in nature and associated with increased age and alcohol use. PN was asymptomatic in 81% of HIV-seronegative and 71% of HIV-seropositive patients with PN. CONCLUSIONS: There is a high prevalence of PN in HIV-seronegative IDUs. Although these PNs do not seem to predispose HIV-seropositive IDUs to HIV-related PN, they may increase the likelihood of iatrogenic neuropathy. Intravenous drug users may need more diligent monitoring when administered nucleoside analogues than patients in risk groups with lower endemic rates of PN.

2',3'-dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients.

We administered the antiviral agent 2',3'-dideoxycytidine (ddC) to HIV-infected patients with either ARC or AIDS as part of the AIDS Clinical Treatment Group protocol 012 and serially evaluated them with neuropathic symptom questionnaires, neurologic examinations, nerve conduction studies, and quantitative sensory testing (QST). All patients treated with high-dose ddC (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy, with a mean onset of 7.7 weeks, which reached severe intensity over several days. Abnormalities of vibration QST threshold preceded clinical symptoms. Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression. In these patients, the onset of clinical symptoms and QST abnormalities were coincident. Only two of six patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy; in both cases it was very mild and delayed in onset (26 weeks). All patients treated with high-dose ddC reported progression of symptoms (coasting) for 2 to 3 weeks following discontinuation of therapy. This study documents a painful sensory neuropathy resulting from treatment with ddC. With high-dose treatment, only the rapidity of onset and progression differentiated it from the distal, predominantly sensory neuropathy of AIDS.

MRI monitoring of vigabatrin-induced intramyelinic edema in dogs.

Chronic administration of vigabatrin (gamma-vinyl GABA) in dogs produces reversible microvacuolation (intramyelinic edema) in discrete brain regions. Histologic changes are most notable in the columns of the fornix and regions of the hypothalamus, thalamus, optic tract, and hippocampus. In an attempt to image these changes in vivo, we performed high-field MRI on seven treated and four control dogs at baseline and after 15 weeks of dosing with vigabatrin (300 mg/kg/d). All dogs underwent parallel electrophysiologic assessment to determine the effects of vigabatrin on afferent conduction. At 15 weeks, all treated dogs showed increased T2- and decreased T1-weighted signals, with changes from baseline most prominent in the columns of the fornix and to a lesser degree in the surrounding hypothalamus and thalamus. MRIs performed on control dogs were unremarkable. We then perfused a random selection of four treated and two control dogs and imaged their brains ex vivo prior to sectioning. Ex vivo imaging confirmed the in vivo findings and strongly correlated with both electrophysiologic and subsequent histopathologic findings. Imaging was repeated in the surviving dogs 5 and 12 weeks after discontinuation of dosing. Signal abnormalities in the treated dogs progressively diminished during recovery, paralleling the electrophysiologic and histopathologic results. These findings demonstrate that MRI can detect signal changes anatomically congruent with vigabatrin-induced intramyelinic edema and suggest that MRI may provide a useful noninvasive tool for monitoring patients during clinical trials.

New developments in the diagnosis of diabetic neuropathy.

The development of new treatments to slow or arrest the progression of diabetic polyneuropathy (DPN) has increased the importance of the early and accurate identification of this complication. It is likely that effective intervention will be possible only during the subclinical or early phase of dysfunction. Accurate diagnosis of DPN is a formidable task because of the diversity of presentations, involvement of different nerve fiber types, and the common dissociation of symptoms from objective measures of neural function. Several diagnostic tools are available or in development, each with strengths and limitations. Electrophysiology is a sensitive, objective, and targeted measure of DPN, but it reflects, almost exclusively, the activity of large-caliber, myelinated axons. Newly refined skin-punch biopsy procedures use morphometric and immunohistochemical methods to examine thinly myelinated and unmyelinated nerve fibers. The integrity, density, and distribution of these fibers may provide a sensitive index of small-fiber distal axonopathy. Improvements in quantitative sensory testing include better control of stimulation characteristics and the use of computer-assisted testing algorithms (e.g., CASE IV), as well as the ability to examine a distal to proximal gradient of sensation (Physitemp NTE-2a). Composite scales, which combine the assessment of signs, symptoms, electrophysiology, and specific quantitative sensory measures, have also been proposed and, in some cases, validated. The existing diagnostic tools and newly emerging methods provide a battery of tests that can be used to assess multiple aspects of neural function and increase sensitivity to detect the onset and progression of DPN.

Preliminary studies of cytokine-induced functional effects on the visual pathways in the rabbit.

Epidural visual evoked potentials (VEP) were used to study the role of cytokines in the induction of pathophysiologic changes associated with inflammation in the central nervous system (CNS) of the rabbit. In normal rabbits, intraocular injection of human recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) increased the peak latency of the cortical VEP by more than 2 ms within 3 h of injection; equal volume injections of control substances had no effect. Alterations in conduction induced by IFN-gamma and TNF reversed within 24 h and could be reinduced by reinjection. Intraocular injection of recombinant human interleukin-1 beta (IL-1) induced a more progressive delay in conduction that peaked 24 h after intraocular challenge and reversed over the ensuing 48 h. Pathologic examination of the tissues indicated that the primary effect of these cytokines is on the vasculature and induces changes associated with inflammation. The results suggest that the acute reversible effects of cytokines on CNS function are associated with vascular events; further they support the sensitivity of the 'rabbit eye model' for studies on the pathophysiologic effect of inflammatory mediators on the CNS in vivo.

Monitoring potential neurotoxic effects of hazardous waste disposal.

This report reviews neurotoxicological principles relevant to situations of hazardous waste disposal. Some of the diagnostic techniques currently used for field assessment of nervous system dysfunction are critically evaluated. These include nerve conduction velocity, evoked potentials, neuropsychological testing and use of the Optacon.

Structure and function of the somatosensory system: a neurotoxicological perspective.

The somatosensory system comprises those elements of the peripheral nervous system (PNS) and the central nervous system (CNS) subserving the modalities of touch, vibration, temperature, pain and kinesthesia. Specific modalities can be associated with unique peripheral receptors, peripheral axons of stereotyped diameter and specific central projection pathways. Several features of the somatosensory system render regions of it vulnerable to a wide variety of toxicants. The present report highlights these features and , furthermore, suggests that analysis of these regions is invaluable in studying the three most common varieties of toxic neuropathy: toxic distal axonopathy, toxic myelinopathy and toxic sensory neuronopathy.

Effects of a frontal lesion on the cortical potentials associated with voluntary movement in the awake monkey.

An accidental, punctate lesion to a medial portion of the frontal lobe, including supplementary motor cortex and anterior commissure, produced a change in the cortical potentials preceding voluntary movement in a cynomolgus monkey. At the time of the lesion, the animal was highly trained in a repetitive voluntary movement task, and baseline mapping of specific movement-related potentials (MRPs) was complete. Prelesion MRPs were characterized by a well-defined N2 response, which began approximately 100 msec before the onset of movement. This response was centered over the contralateral precentral gyrus and believed to reflect the phasic portion of the corticospinal discharge. After the lesion, the animal fully recovered the ability to perform the movement task. However, the amplitude of N2 on the side ipsilateral to the lesion was significantly reduced. This decrease was not associated with any deficit in movement execution. EMG measurements did not exhibit any diminished or abnormal patterns of activity. These data suggest that portions of the frontal lobe not directly involved in the genesis of MRPs may still provide a supportive role in organizing the sequence and pattern of neuroelectric activity associated with movement. Furthermore, the findings document the sensitivity of MRPs for detecting subtle changes in the pattern of efferent electrical activity associated with a lesion within the brain, even in the absence of overt movement disorders.

Preventing the spread of vancomycin-resistant enterococci in a long-term care facility.

OBJECTIVES: To test the hypothesis that infection control practices can prevent the spread of vancomycin-resistant enterococci (VRE) to residents of a long-term care facility (LCF) from an affiliated acute care facility with a high endemic rate of colonization. DESIGN: Point prevalence study of the rate of rectal colonization. SETTING: A state-supported veterans nursing home and an acute care veterans hospital. PARTICIPANTS: Residents in a state veterans home. INTERVENTIONS: Identification of patients with rectal colonization by VRE before transfer to the state veterans home, contact isolation for colonized veterans, use of oral bacitracin to eliminate colonization. MEASUREMENTS: Rectal swab and culture for VRE, review of clinical records and recording of presumptive risk factors for VRE colonization. The risk factors were age, gender, length of stay at nursing home, treatment with vancomycin or oral antibiotics, prior hospitalization at the acute care facility during the prior year, use of indwelling urethral catheters, presence of diarrhea, and fecal or urinary incontinence. RESULTS: Sixty-nine of 200 residents were cultured in the first study (1996) and 130 of 230 residents were cultured in the second study (1998). Residents who consented to culture differed from those who did not only with regards to gender (2 vs 7, P = .012). In neither study were any residents found to be colonized with VRE who had not already been identified as positive on admission. CONCLUSIONS: Adherence to infection control practices by the patient care staff of the LTCF was associated with the absence of transmission of VRE colonization among its residents. The presence of rectal colonization with VRE in an acute care patient should not be a barrier to acceptance in a nursing home.

Averaged multiple unit activity as an estimate of phasic changes in local neuronal activity: effects of volume-conducted potentials.

A technique for the derivation of digitally-averaged multiple unit activity (MUA) is described. The use of signal averaging instead of analog integration improves the temporal resolution and thus provides a clearer picture of the instantaneous MUA level. MUA recordings have been used in the identification of regions active in the generation of event-related potentials, based in part on the limited volume within which a semi-microelectrode 'sees' action potentials. However, averaged MUA waveforms may be affected by time-locked activity volume-conducted to the electrode site. A theoretical analysis of the magnitude of this effect is presented, along with experimental data in support of its assumptions and predictions. The most important factor is not the absolute size of the volume-conducted potentials, but their magnitude relative to that of the locally-generated MUA. When full-wave rectification is used, volume-conducted activity which is a considerable fraction of the MUA level will not significantly affect the averaged MUA waveform. Half-wave rectification should not be used, as it leads to a much larger effect from small far-field potentials.

Cation binding at the node of Ranvier: II. Redistribution of binding sites during electrical stimulation.

The nodal and paranodal areas of mature myelinated axons are known to bind cations. To examine whether the cation binding substance may play a role in saltatory conduction, a combined electrophysiological and histochemical study was undertaken. The sciatic nerve of anesthetized or unanesthetized adult C57B1 mice was exposed and not stimulated (control) or stimulated with constant square-wave pulses at one of the following rates: 10/sec, 30/sec, 100/sec or 500/sec. Phosphate-buffered 2.5% glutaraldehyde was either dropped onto the nerve during stimulation until cessation of the compound action potential or the nerve was fixed after discontinuing stimulation. The nerve was excised and processed for the histochemical reaction of copper sulfate/potassium ferrocyanide (which forms an electron dense precipitate at areas of cation binding), dehydrated and infiltrated with SpurrR epoxy resin. Individual nerve fibers were microdissected and counts made of the numbers of paranodal and nodal areas exhibiting the reaction product. The percentage of nodes stained, with respect to the total numbers of nodes and paranodes stained, was calculated. There was no significant difference in percent of nodes stained between the simultaneously fixed, non-stimulated, anesthetized (43.1%), the non-stimulated unanesthetized (45.3%), the animals stimulated at 10/sec (45.9%) and the animals stimulated at 30/sec (50.2%) and 100/sec(46.0%), and fixed post-stimulation. However, all values at the higher frequencies and fixed during stimulation were significantly different both from the control and from each other (30/sec-59.3%; 100/sec-70.5%; and 500/sec-76.4%). The location of cation binding appears to change in response to electrical stimulation and correlates with the increased frequency of the inward movement of sodium ions.

Phase-locked cortical responses to a human speech sound and low-frequency tones in the monkey.

Concurrent recordings of average evoked potentials (AEP) and multiple unit activity (MUA) in monkey primary cortex to the syllable/da/, low-frequency tones, and clicks were performed. The AEP in response to the syllable consisted of a periodic alternation superimposed upon slower phasic deflections. All components inverted across the superior temporal plane, indicating their auditory cortical origin. The periodic activity was phase-locked to the syllable's fundamental frequency at a latency of approximately 11 msec. MUA displayed a similar pattern of periodic activity, but with a shorter interval between stimulus and response peaks. This phase-locked MUA occurred only at regions of AEP polarity inversion. Phase-locked activity was also observed in the cortical AEP to 100 and 250 Hz, but not to 500 Hz tonal stimulation. MUA phase-locked to the stimulus frequency only occurred at 100 Hz. Both the periodic and slow components of the AEP were volume-conducted to the dorsal cortical surface. This finding suggests the possibility that similar cortical responses to speech sounds can be recorded from the human scalp.

Speech evoked activity in the auditory radiations and cortex of the awake monkey.

To determine whether phonetic features of human speech are reflected in activity patterns of the auditory cortex and its thalamic afferents, concurrent recordings of multiple unit activity (MUA) and averaged evoked potentials (AEP) to 3 synthetic syllables: /da/,/ba/ and /ta/, were performed in awake monkeys. Using clicks, responses from thalamocortical axons and cortical cells were differentiated on the basis of their response latency, spatial distribution, and relationships to AEP components. Voice onset time was reflected in MUA time-locked to consonant release and voicing onset, and phase-locked to the syllables' fundamental frequency. Place of articulation was reflected in discriminative 'on' and phase-locked responses occurring to the formant transitions of the syllables. Duration of the voiced formant transitions was represented by an accentuation of the phase-locked responses occurring to this period. Activity of thalamocortical fibers and cortical cells differed. Thalamocortical fibers were more responsive to speech sounds, as well as responding more frequently with a phase-locked response pattern. Cortical cells responded with sustained activity to a greater degree. Responses to identical portions of the vowels were biased by the preceding consonant. The spatial extent and timing of the responses demonstrate that speech sounds are processed along parallel, but not synchronous, channels. Relevance to human psychoacoustical phenomena is discussed.