Vertical or asymmetric nystagmus need not imply neurological disease.
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AIM: To indicate that congenital idiopathic nystagmus (CIN) and sensory defect nystagmus (SDN) can be vertical or asymmetric in some children. METHODS: Of 276 children presenting with nystagmus for electrophysiological testing, 14 were identified as having CIN or SDN, yet had a nystagmus which was either vertical (n=11) or horizontal asymmetric (n=3). Flash electroretinograms and flash and pattern visual evoked potentials (VEPs) were recorded in all patients. Eye movement assessment, including horizontal optokinetic nystagmus (OKN) testing, was carried out in 11/14 patients. RESULTS: Eight patients (seven with vertical, one with asymmetric horizontal nystagmus) had congenital cone dysfunction. One patient with vertical and another with asymmetric nystagmus had cone-rod dystrophy. One patient with vertical upbeat had congenital stationary night blindness. Two patients (one downbeat, one upbeat nystagmus) had normal electrophysiological, clinical, and brain magnetic resonance imaging findings and were classified as having CIN. One patient with asymmetric nystagmus showed electrophysiological and clinical findings associated with albinism. Horizontal OKN was present in 80% of patients tested, including the three cases with horizontal asymmetric nystagmus. This is atypical in both CIN and SDN, where the OKN is usually absent. CONCLUSIONS: Vertical and asymmetric nystagmus are most commonly associated with serious intracranial pathology and its presence is an indication for neuroimaging studies. However, such nystagmus can occur in children with retinal disease, albinism, and in cases with CIN. These findings stress the importance of non-invasive VEP/ERG testing in all cases of typical and also atypical nystagmus. (+info)
The cost of Medicaid-covered services provided to disabled adults with neurologic disorders: implications for managed care.
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OBJECTIVES: To estimate the mean annual per capita cost of care provided to disabled adult Medicaid recipients with neurologic conditions and to compare mean annual costs for disabled adult Medicaid recipients with those of nondisabled adult Medicaid recipients. STUDY DESIGN: Medicaid eligibility and claims files for all of calendar year 1993 were obtained from the state of Pennsylvania. Mean annual per capita costs are mean Medicaid expenditures on claims filed for Medicaid-covered services and pharmaceuticals provided in 1993 to full-year eligible Medicaid recipients. PATIENTS AND METHODS: Disabled adults aged 18 to 64 years with one or more of several neurologic conditions were identified from medical diagnoses (International Classification of Diseases, 9th Revision codes) reported on claims. A comparison group of nondisabled adults was chosen from the Medicaid Eligibility File. Annual costs were estimated for a wide range of specific services as well as for 3 broad service categories. RESULTS: There were large differences between disabled and nondisabled adults in mean annual per capita costs of acute care and other medical services ($4142 vs $1451), rehabilitation and support services ($3835 vs $235), and pharmaceuticals ($1116 vs $382). Mean costs also differed significantly among persons with different neurologic conditions. The mean annual per capita cost for all services was $5368 for adults with epilepsy and $19,356 for those with a spinal cord injury. All differences are statistically significant (P < .001). CONCLUSIONS: States may want to separately capitate rehabilitation and support services given the large differences in the magnitude and relative distribution of costs for disabled and nondisabled Medicaid recipients. (+info)
Comparative and correlative neuroanatomy for the toxicologic pathologist.
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Xenobiotic-induced neuroanatomic alterations are always regarded as adverse and are commonly used to define reference doses to manage neurotoxic risk. Thus, the neuropathologist plays an essential role in evaluating potential neurotoxicants. The pathologist must be able to recognize the morphologic differences that exist among species, strains, and ages or between genders (comparative neuroanatomy) and to grasp the impact of structural damage on neural function (correlative neuroanatomy). Brain anatomy and function may be used to group the mammals used in neurotoxicity bioassays into 3 classes: rodent, carnivore, and primate. Neural function may or may not be affected by the structural divergence. Rodents are preferred for neurotoxicity assays because their reduced body size allows optimal perfusion at little cost and their smaller brain size permits screening of multiple regions using few sections. However, care must be exercised when interpreting rodent neuropathology data because the rodent paleocortex does not recapitulate the sophisticated neocortical circuitry and functions of carnivores and primates. Knowledge of the neuroanatomic variations that exist among test species assists the neuropathologist in defining the relevance of structural alterations, the potential clinical sequelae of such findings, and the possible significance of similar changes in humans. (+info)
An integrative approach to neurotoxicology.
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Exposure of human populations to a wide variety of chemicals has generated concern about the potential neurotoxicity of new and existing chemicals. Experimental studies conducted in laboratory animals remain critical to the study of neurotoxicity. An integrative approach using pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral methods is needed to determine whether a chemical is neurotoxic. There are a number of factors that can affect the outcome of a neurotoxicity study, including the choice of animal species, dose and dosage regimen, route of administration, and the intrinsic sensitivity of the nervous system to the test chemical. The neurotoxicity of a chemical can vary at different stages of brain development and maturity. Evidence of neurotoxicity may be highly subjective and species specific and can be complicated by the presence of systemic disease. The aim of this paper is to give an overview of these and other factors involved in the assessment of the neurotoxic potential for chemicals. This article discusses the neurotoxicity of several neurotoxicants (eg, acrylamide, trimethyltin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, manganese, and ivermectin), thereby highlighting a multidisciplinary approach to the assessment of chemically induced neurotoxicity in animals. These model chemicals produce a broad range of effects that includes peripheral axonopathy, selective neuronal damage within the nervous system, and impaired neuronal-glial metabolism. (+info)
Mechanisms of injury in the central nervous system.
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Neurotoxicants with similar structural features or common mechanisms of chemical action frequently produce widely divergent neuropathologic outcomes. Methylmercury (MeHg) produces marked cerebellar dysmorphogenesis during critical periods of development. The pathologic picture is characterized by complete architectural disruption of neuronal elements within the cerebellum. MeHg binds strongly to protein and soluble sulphydryl groups. Binding to microtubular -SH groups results in catastrophic depolymerization of immature tyrosinated microtubules. However, more mature acetylated microtubules are resistant to MeHg-induced depolymerization. In contrast to MeHg, the structurally similar organotin trimethyltin (TMT) elicits specific apoptotic destruction of pyramidal neurons in the CA3 region of the hippocampus and in other limbic structures. Expression of the phylogenetically conserved protein stannin is required for development of TMT-induced lesions. Inhibition of expression using antisense oligonucleotides against stannin protects neurons from the effects of TMT, suggesting that this protein is required for expression of neurotoxicity. However, expression of stannin alone is insufficient for induction of apoptotic pathways in neuronal populations. The aromatic nitrocompound 1,3-dinitrobenzene (DNB) has 2 independent nitro groups that can redox cycle in the presence of molecular oxygen. Despite its ability to deplete neural glutathione stores, DNB produces edematous gliovascular lesions in the brain stem of rats. Glial cells are susceptible despite high concentrations of reduced glutathione compared with neuronal somata in the central nervous system (CNS). The severity of lesions produced by DNB is modulated by the activity of neurons in the affected pathways. The inherent discrepancy between susceptibility of neuronal and glial cell populations is likely mediated by differential control of the mitochondrial permeability transition in astrocytes and neurons. Lessons learned in the mechanistic investigation of neurotoxicants suggest caution in the evaluation and interpretation of structure-activity relationships, eg, TMT, MeHg, and DNB all induce oxidative stress, whereas TMT and triethyltin produce neuronal damage and myelin edema, respectively. The precise CNS molecular targets of cell-specific lipophilic neurotoxicants remain to be determined. (+info)
Virtual neuropathology: three-dimensional visualization of lesions due to toxic insult.
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A first-pass approach incorporating high-field magnetic resonance imaging (MRI) was used for rapid detection of neuropathologic lesions in fixed rat brains. This inherently 3-dimensional and nondestructive technique provides high-resolution, high-contrast images of fixed neuronal tissue in the absence of sectioning or staining. This technique, magnetic resonance microscopy (MRM), was used to identify diverse lesions in 2 well-established rat neurotoxicity models. The intrinsic contrast in the images delineated lesions that were identified using a battery of histologic stains, some of which would not be used in routine screening. Furthermore, the MRM images provided the locations of lesions, which were verified upon subsequent sectioning and staining of the same samples. The inherent contrast generated by water properties is exploited in MRM by choosing suitable pulse sequences, or proton stains. This approach provides the potential for a comprehensive initial MRM screen for neurotoxicity in preclinical models with the capability for extrapolation to clinical analyses using classical MRI. (+info)
Characterization of carbon disulfide neurotoxicity in C57BL6 mice: behavioral, morphologic, and molecular effects.
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Female C57BL6 mice were exposed to 0 or 800 ppm carbon disulfide (CS2), 6 h/d, 5 d/wk for 20 weeks. The neurologic function of all mice was assessed once at the end of exposures using a functional observational battery. General health effects included a decrease in body weight gain, piloerection, hunched body posture, and ptosis. Treatment-related effects included altered gait (uncoordinated placement of hind limbs and ataxia) and impaired function on an inverted screen test. In addition, rearing and locomotor movement were decreased in treated mice. Focal to multifocal axonal swelling was seen predominantly in the muscular branch of the posterior tibial nerve, and occasionally giant axonal swelling was detected in the lumbar segment of the spinal cord. Electron microscopic examination revealed swollen axons with massive accumulation of neurofilament proteins within the axoplasm. Covalent cross-linking of erythrocyte spectrin (surrogate protein to neurofilament protein) was demonstrated in mice exposed to CS2 but not in mice receiving filtered air. These data provide supportive evidence that covalent cross-linking of neurofilament proteins is a significant feature of the axonal swellings in mice produced by inhalation exposure to CS2. (+info)
The role of developmental neurotoxicology studies in risk assessment.
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A number of questions have been raised about the use of the US Environmental Protection Agency's Developmental Neurotoxicity Testing Guideline (DNTG) in the hazard identification of chemicals. The applicability and sensitivity of animal tests in the DNTG relative to human developmental neurotoxicity have recently been questioned. In a workshop held in 1989, participants compared the effects of several known developmental neurotoxicants in humans and animal models and concluded that the DNTG would have detected known human developmental neurotoxicants. They also concluded that although procedural differences may differ in the testing of humans and animals, the neurobiologic functions (ie, autonomic, sensory, motor, and cognitive) affected by chemical exposure were similar. In cases where the DNTG has been compared with other measures of reproductive and developmental toxicity, the DNTG has been relatively sensitive and specific. To date, DNTGs have been required 12 times, for 9 pesticides and 3 solvents. The sensitivity of the measures in the DNTG relative to other measures of developmental and adult toxicity supports the continued use of the DNTG in risk assessment. (+info)