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A 46-year-old man with a 2-year history of dementia presented with very slow saccades and tongue fasciculations. The diagnosis of amyotrophic lateral sclerosis (ALS) was established by electrophysiologic studies and ultimately on autopsy. Rarely, slowed saccades may be present in ALS, and slow saccades in a relatively young demented patient should prompt consideration of ALS.
The objective of this study was to identify prognostic factors for survival in amyotrophic lateral sclerosis from a large prospective observational study performed in France. The study included a cohort of 2069 patients fulfilling broad entry criteria treated with riluzole. Over 100 demographic, biological, clinical and quality-of-life variables were monitored and assessed for their effect on survival. Patients were randomized post hoc into two groups: one group (two-thirds of the patients) to generate the prognostic models and one group (one-third of the patients) to validate the resulting models. Thirteen variables were found to affect survival independently and were used to construct a survival prediction score, RL401. These included age, disease duration, slow vital capacity, intensity of tiredness (visual analogue scale), number of body levels with spasticity, atrophy and/or fasciculations, cough, distal muscle strength, household income, depression and two biological parameters, plasma creatinine levels and neutrophil counts. A simplified score, RL401S, was constructed, designed to be easy to use and interpret. The predictive powers of the two scores were similar.
Oral administration of malathion (MTH) in sublethal (100 mg/kg) or minimal lethal (125 mg/kg) doses in buffalo calves produced toxicity with an onset within 15-20 min and peak effects including severe tremors and convulsions within 40-60 min. Various antidotal drugs were administered alone or in combination at the time of peak malathion toxicity (within 1 h) and were assessed for their ability to alleviate signs of cholinergic toxicity. Blood cholinesterase and aminotransferases activities were monitored at various times. A combination of atropine sulfate (0.5 mg/kg, 1/4 iv and 3/4 im) and pyridine 2-aldoxime methiodide (2-PAM, 20 mg/kg, iv) reversed the clinical evidence of malathion toxicity within 15 min. The combination of atropine sulfate and diazepam (0.75 mg/kg, iv) prevented death and cholinergic signs of toxicity except for weak muscular fasciculations, which persisted for 30-60 min. Atropine sulfate alone was less effective and also did not reverse malathion-induced biochemical changes. In contrast, administration of either 2-PAM (10-30 mg/kg, iv) or diazepam (0.5-1.0 mg/kg, iv) alone accentuated malathion toxicity. Thus, the combination of atropine sulfate and 2-PAM was the most effective antidotal treatment in acute malathion toxicity.
Pretreatment of rats with the nonspecific esterase inhibitor iso-OMPA (1 mg/kg sc) 1 h prior to carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-methylcarbamate, 0.5 mg/kg sc) administration potentiated carbofuran toxicity by more than threefold. Neither iso-OMPA nor carbofuran in the given doses produced any gross toxic signs. Rats receiving combined treatment, however, showed severe hypercholinergic signs (salivation, tremors, muscle fasciculations, and convulsions) within 5-10 min following carbofuran administration, and the severity was comparatively greater than that observed with an acute dose of carbofuran (1.5 mg/kg sc). Rats pretreated with iso-OMPA (0.5 mg/kg) died within 10-15 min following the acute dose of carbofuran (1.5 mg/kg). Each drug when given alone (1.0 mg/kg iso-OMPA, 0.5 mg/kg carbofuran) caused a significant (p less than .01) inhibition of carboxylesterase (CarbE) activity in brain structures (cortex, stem, striatum, and hippocampus), skeletal muscle (hemidiaphragm), liver, and plasma, whereas acetylcholinesterase (AChE) activity remained significantly (p greater than .01) unchanged. The maximal CarbE inactivation in plasma (less than 14% remaining activity) following either drug indicated a tremendous nonspecific binding to non-AChE serine-containing enzymes. iso-OMPA pretreatment markedly potentiated carbofuran's anticholinesterase activity both in neuronal and in nonneuronal tissues. It can be concluded that iso-OMPA pretreatment potentiates carbofuran toxicity either by preventing nonspecific binding of carbofuran to CarbE and/or possibly by inhibiting its detoxification.
Male Sprague-Dawley rats administered with a sublethal acute dose of carbofuran (1.5 mg/kg, sc) developed the observable toxic signs of anticholinesterase nature within 5-7 min. The toxic signs with increasing propensity to maximal severity including tremors, generalized muscle fasciculations, and convulsions were evident during 15 min to 1 h and lasted for 2 h. Thereafter, signs were seen up to 3 h with reduced intensity. By the end of 3.5 h toxic signs were completely subsided. Maximal acetylcholinesterase (AChE) inactivation occurred at 1 h in discrete brain regions (cortex, stem, striatum, and hippocampus) and hemidiaphragm muscle when most severe signs of toxicity were also evident. A single sc dose of memantine HCl (MEM, 18 mg/kg) and atropine sulfate (ATS, 16 mg/kg) 60 and 15 min, respectively, prior to carbofuran administration completely prevented the expected gross toxic signs and significantly (p less than .01) attenuated the carbofuran-induced inhibition of AChE activity. When given therapeutically, this combined treatment completely reversed the clinical evidence of carbofuran toxicity within 15 min and also markedly reduced AChE inactivation. Memantine or atropine when given alone was less effective compared to their combined administration. The results of this study suggested that, in addition to cholinolytic effects of atropine, memantine may prevent and antagonize the acute toxicity of carbofuran by (a) protection of AChE activity and its rapid reactivation from inhibition and (b) rapid elimination of carbofuran.
A case in which SPECT brain imaging was used in the diagnosis and treatment of chronic effects from acute acetylcholinesterase inhibitor poisoning is presented. The patient was exposed to an insecticide mixture containing phosphorothiate, pyrethrin, piperonyl butoxide, and petroleum distillates, which produced symptoms consistent with acute acetylcholinesterase inhibitor poisoning as well as an upper respiratory tract irritant. Delayed sequelae of gross neurologic symptoms followed, that is, coarse tremor, intermittent hemiballistic movements of the right arm and leg, flaccid muscular tone, fasciculations of muscle groups, muscle cramps, and sensory disturbances. A brain single-photon emission computerized tomography (SPECT) scan was performed 34 mo postexposure, revealing significantly decreased blood flow to the left temporal lobe and to the right and left basal ganglia. The patient's paresthesias were treated with phenytoin, which resulted in worsening of her movement disorder. A trial of amantadine and selegiline (Deprenyl) resulted in a dramatic reduction in dysfunctional movements and ataxia. Post amantadine and selegiline therapy, brain SPECT images revealed significantly improved blood flow with minimally decreased blood flow to the right and left basal ganglia. The use of SPECT scan techniques helped to elucidate objective chronic central nervous system effects subsequent to an acute insecticide exposure and also assisted in the evaluation of the effectiveness of therapeutic intervention.
The objective of this investigation was to determine the distribution of cholinergic (acetyl-cholinesterase, AChE) and noncholinergic markers in slow-, fast-, and mixed-fiber containing muscles (soleus, SOL; extensor digitorum longus, EDL; and diaphragm, DIA, respectively). Noncholinergic markers included high-energy phosphates (adenosine triphosphate, ATP; phosphocreatine, PCr; and their metabolites), and the activity of creatine kinase (CK) and lactate dehydrogenase (LDH) and their isoenzymes and subforms. All three types of muscles had only one CK isoenzyme, CK-MM, which totally consisted of MM3 subform. Levels of these determinants were highest in EDL followed by DIA and least in SOL. Another objective was to determine alterations of these markers under the influence of acute carbofuran (1.5 mg/kg) or methyl parathion (MPTH, 5 mg/kg) toxicity. Rats receiving either insecticide showed cholinergic signs with maximal severity including muscle fasciculations and convulsions within 15-30 min that lasted for about 2 h. At 1 h postinsecticide injection, when AChE was maximally inhibited (81-96%), significant depletion of ATP and PCr was evident in muscles (DIA > SOL > EDL), and activities of CK-MM and LDH were elevated in muscles and consequently in serum. Serum CK-MM3 activity was markedly reduced with sequential increase in MM2 and MM1 subforms, probably due to induced higher carboxypeptidase activity. These findings suggested that (1) the differences in levels of biochemical constituents in muscles depend upon the fiber type, (2) anticholinesterase insecticide-induced increased muscle activity produces characteristic changes in CK and LDH isoenzymes patterns, and (3) leakage of these enzymes/isoenzymes into serum is due to depletion of ATP and PCr, which are required to maintain the cell membrane permeability.
INTRODUCTION: Chlorophenoxy herbicides are used widely for the control of broad-leaved weeds. They exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation, and disruption of acetylcoenzyme A metabolism. Between January 1962 and January 1999, 66 cases of chlorophenoxy herbicide poisoning following ingestion were reported in the literature. FEATURES FOLLOWING INGESTION: Adjuvants in the formulations may have contributed to some of the features observed. Vomiting, abdominal pain, diarrhea, and, occasionally, gastrointestinal hemorrhage were early effects. When present, hypotension was predominantly due to intravascular volume loss, although vasodilation and direct myocardial toxicity may have contributed in some cases. Neurotoxic features included coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation, and paralysis. Hypoventilation occurred not infrequently, usually in association with central nervous system depression, but respiratory muscle weakness was a factor in the development of respiratory failure in some patients. Myopathic symptoms including limb muscle weakness, loss of tendon reflexes, and myotonia were observed and increased creatine kinase activity was noted in some cases. Other clinical features reported included metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia, and hyperventilation. Twenty-two of 66 patients died. FEATURES FOLLOWING DERMAL AND INHALATIONAL EXPOSURE: Substantial dermal or inhalational 2,4-dichlorophenoxyacetic acid exposure has occasionally led to systemic features but no such reports have been published in the last 20 years and no fatalities have been reported at any time. Substantial dermal exposure has been reported to cause mild gastrointestinal irritation after a latent period followed by progressive mixed sensory-motor peripheral neuropathy. Mild, transient gastrointestinal and peripheral neuromuscular symptoms have also occurred after occupational inhalation exposure, with or without dermal exposure. MANAGEMENT: In addition to supportive care, alkaline diuresis to enhance herbicide elimination should be considered in all seriously poisoned patients. Limited clinical data suggest that hemodialysis produces similar herbicide clearance to alkaline diuresis without the need for urine pH manipulation and the administration of substantial amounts of intravenous fluid in an already compromised patient. CONCLUSIONS: While chlorophenoxy herbicide poisoning is uncommon, ingestion of a chlorophenoxy herbicide can result in serious and sometimes fatal sequelae. In severe cases of poisoning, alkaline diuresis or hemodialysis to increase herbicide elimination should be considered.
BACKGROUND: Dendrotoxin is a highly potent blocker of KV1.1, KV1.2, and KV1.6 potassium channels that is derived from the venom of the green mamba (Dendroaspis angusticeps). It is commonly used to inhibit the function of whole nerve preparations in vitro. Despite the widespread use and potency of this compound, neurotoxicity in humans has not been described from refined toxin. We report a case of dendrotoxin toxicity from dermal exposure. CASE REPORT: A healthy 40-year-old female neurobiochemist presented with complaints of progressive numbness of the left malar region and lateral orbit that progressed to include the medial orbit and tongue. One hour prior to presentation she used her bare hands to remove residual petroleum jelly from a dish that had previously contained 500 nanoliters of 500 nanomolar dendrotoxin. She recalled rubbing her left eye prior to the onset of symptoms. Before touching the dish, she had washed it with running water and then 70% ethanol while using latex gloves. Physical examination was remarkable only for weakness to superior gaze and some mild tongue fasciculations. Within 12 hours of exposure, she was completely asymptomatic. CONCLUSION: Dendrotoxin is a highly potent neurotoxin that can cause localized impairment of nerve function after mucous membrane exposure.
OBJECTIVES: In Taiwan, the widespread use of organophosphates (OPs) in agricultural and household environments results in numerous OP poisoning. To better understand the clinical significance of associated parameters on respiratory failure and patient outcome, we evaluate patients admitted to the Nephrology ward in our hospital with OP intoxication. PATIENTS AND METHODS: Over a period of 2 years, a total of 42 consecutive patients with OP poisoning admitted to the nephrology ward or the Intensive Care Unit of Chang-Gung Memorial Hospital were the subjects in the study. The diagnosis of poisoning was based on history of ingestion and characteristic clinical features of anticholinesterase agent poisoning. Prior to treatment, all symptoms recorded at emergency room and blood samples for blood chemistry including plasma amylase and plasma acetyl-cholinesterase were collected from each patient immediately after the admission. RESULTS: As clinical manifestations of OP show, nausea and vomiting and salivation were the leading manifestations, 45.2% and 33.3%, respectively. Patients who developed respiratory failure were older than those who did not (54.3+/-6.9 vs. 43.1+/-5.6, p<0.05). The dosage of atropine administered for treatment was significantly higher in the patient group with respiratory failure compared to those without respiratory failure (29.7+/-14.5 vs. 9.1+/-10.2, p<0.05). Plasma amylase level of the patient group with respiratory failure was significantly higher than those without respiratory failure (436.1+/-87.1 vs. 181.3+/-29.6, p<0.01). Of course, mean days of hospitalization in the respiratory failure group are significantly longer than the other group (12.1+/-2.1 vs. 5.4+/-1.9, p<0.05). Based on univariant analysis, bradycardia, hypotension, fasciculation and coma were significant factors associated with respiratory failure. The dose of atropine administered for treatment was significantly higher in the oral exposure group compared to nonoral exposure group (23.6+/-12.6 vs. 10.6+/-6.4, p<0.05). The same is true for the pralidoxime treatment (9.6+/-1.9 vs. 5.3+/-1.4, p<0.05). As for mean days of hospitalization (11.6+/-3.9 vs. 6.4+/-2.1, p<0.05) and fatality (2 vs. 0, p<0.05), those of oral exposure patients were significantly longer and higher than those with nonoral exposure. CONCLUSIONS: We demonstrate that elevated plasma amylase concentration was related to the development of respiratory failure in OP intoxication. It also provided us various important risk factors to identify those patients with OP poisoning who would ultimately require ventilatory support.
A phage endoneuraminidase that specifically cleaves alpha-2, 8-linked polysialic acid has been found to be a useful probe for examining the biological role of this sugar moiety on the neural cell adhesion molecule (NCAM). The enzyme caused a 3.3-fold increase in the rate of NCAM-dependent aggregation of membrane vesicles from chicken embryonic brain, without the nonspecific effects previously encountered with the use of exoneuraminidases. The enhancement of aggregation was closely correlated with removal of sialic acid as assessed by electrophoretic mobility. Extension of this analysis to cultures of spinal ganglia indicated that removal of sialic acid by the endoneuraminidase results in an increase in the thickness of neurite bundles. This enhancement of fasciculation was reversed by addition of anti-NCAM Fab, suggesting that the enzyme treatment was not toxic and did not produce nonspecific effects on adhesion. Injection of the enzyme into the eyes of 3.5-d chicken embryos consistently produced a striking array of abnormalities in those parts of the neural retina that contained the highest concentrations of NCAM at the time of injection. These perturbations included a dramatic thickening of the neural epithelium in the posterior eye, a failure of cells in this region to elongate radially, formation of an ectopic optic fiber layer, and an incomplete association of the presumptive pigmented epithelium with the neural retina. These results provide the first direct evidence that the polysialic acid on NCAM has a regulatory effect on adhesion between living cells, and that the amount of this carbohydrate is critical for the normal morphogenesis of nerve tissue.
The neuron-glia cell adhesion molecule (Ng-CAM) has been identified in mammalian brain tissue and PC12 pheochromocytoma cells as Mr 200,000 and Mr 230,000 species, respectively. When PC12 cells were treated with nerve growth factor (NGF), the amount of Ng-CAM at the cell surface was increased approximately threefold, whereas the amount of the neural cell adhesion molecule (N-CAM) remained unchanged. An NGF-inducible large external glycoprotein (NILE) has been previously identified by its enhanced expression in NGF-treated PC12 cells. Ng-CAM and NILE are similar in molecular weight, expression during development, and responsiveness to NGF in PC12 cells, suggesting that the two molecules are related. In addition, antibodies to Ng-CAM and NILE cross-reacted and the molecules had similar peptide maps after limited proteolysis. Moreover, antibodies to Ng-CAM inhibited fasciculation of neurites, a functional property shared with NILE. The results show that cell adhesion molecules can respond selectively to growth factors and suggest that NILE is, in fact, mammalian Ng-CAM.
To determine whether specific asparagine-linked (N-linked) oligosaccharides present in cell surface glycoproteins are required for cell-cell interactions within the peripheral nervous system, we have used castanospermine to inhibit maturation of N-linked sugars in cell cultures of neurons or neurons plus Schwann cells. Maximally 10-15% of the N-linked oligosaccharides on neuronal proteins have normal structure when cells are cultured in the presence of 250 micrograms/ml castanospermine; the remaining oligosaccharides are present as immature carbohydrate chains not normally found in these glycoproteins. Although cultures were treated for 2 wk with castanospermine, cells always remained viable and appeared healthy. We have analyzed several biological responses of embryonic dorsal root ganglion neurons, with or without added purified populations of Schwann cells, in the presence of castanospermine. We have observed that a normal complement of mature, N-linked sugars are not required for neurite outgrowth, neuron-Schwann cell adhesion, neuron-induced Schwann cell proliferation, or ensheathment of neurites by Schwann cells. Treatment of neuronal cultures with castanospermine increases the propensity of neurites to fasciculate. Extracellular matrix deposition by Schwann cells and myelination of neurons by Schwann cells are greatly diminished in the presence of castanospermine as assayed by electron microscopy and immunocytochemistry, suggesting that specific N-linked oligosaccharides are required for the expression of these cellular functions.
The cellular and subcellular localization of the neural cell adhesion molecules L1 and N-CAM was studied by pre- and postembedding immunoelectron microscopic labeling procedures in the developing mouse cerebellar cortex. The salient features of the study are: L1 displays a previously unrecognized restricted expression by particular neuronal cell types (i.e., it is expressed by granule cells but not by stellate and basket cells) and by particular subcellular compartments (i.e., it is expressed on axons but not on dendrites or cell bodies of Purkinje cells). L1 is always expressed on fasciculating axons and on postmitotic, premigratory, and migrating granule cells at sites of neuron-neuron contact, but never at contact sites between neuron and glia, thus strengthening the view that L1 is not involved in granule cell migration as a neuron-glia adhesion molecule. While N-CAM antibodies reacting with the three major components of N-CAM (180, 140, and 120 kD) show a rather uniform labeling of all cell types, antibodies to the 180-kD component (N-CAM180) stain only the postmigratory granule cell bodies supporting the notion that N-CAM180, the N-CAM component with the longest cytoplasmic domain, is not expressed before stable cell contacts are formed. Furthermore, N-CAM180 is only transiently expressed on Purkinje cell dendrites. N-CAM is present in synapses on both pre- and post-synaptic membranes. L1 is expressed only preterminally and not in the subsynaptic membranes. These observations indicate an exquisite degree of fine tuning in adhesion molecule expression during neural development and suggest a rich combinatorial repertoire in the specification of cell surface contacts.
The patterns of deposition of thrombospondin (TSP), a trimeric extracellular matrix glycoprotein, were determined during the initial establishment of the external granule cell layer and the subsequent inward migration of granule cells forming the molecular and (internal) granule cell layers. The early homogeneous deposition of TSP became restricted to the rhombic lip in the region of granule cell exit from the neuroepithelium, and was present between migrating granule cells. During the later inward migration of granule cells, little TSP was associated with dividing granule cells; it was enriched in premigratory granule cells. With the cessation of migration, TSP was lost except in association with fasciculating axons in the molecular layer where staining persisted briefly. At the EM level, TSP was associated with the leading process of granule cells as they associated with Bergmann glial cells and migrated through the molecular layer. TSP was present within granule cell axons; Purkinje cells and their dendrites, as well as Bergmann glial fibers and endfeet were negative for TSP. When anti-TSP antibodies were added to explant cultures of cerebellar cortex during active granule cell migration, a dose-dependent inhibition of migration was observed. In control cultures, granule cells migrated into the (internal) granule cell layer, while granule cells exposed to anti-TSP antibodies were arrested within the external granule cell layer. These results suggest that TSP plays an important role in the histogenesis of the cerebellar cortex by influencing granule cell migration.
A method for clamping cytosolic free Ca2+ ([Ca2+]i) in cultures of rat sympathetic neurons at or below resting levels for several days was devised to determine whether Ca2+ signals are required for neurite outgrowth from neurons that depend on Nerve Growth Factor (NGF) for their growth and survival. To control [Ca2+]i, normal Ca2+ influx was eliminated by titration of extracellular Ca2+ with EGTA and reinstated through voltage-sensitive Ca2+ channels. The rate of neurite outgrowth and the number of neurites thus became dependent on the extent of depolarization by KCl, and withdrawal of KCl caused an immediate cessation of growth. Neurite outgrowth was completely blocked by the L type Ca2+ channel antagonists nifedipine, nitrendipine, D600, or diltiazem at sub- or micromolar concentrations. Measurement of [Ca2+]i in cell bodies using the fluorescent Ca2+ indicator fura-2 established that optimal growth, similar to that seen in normal medium, was obtained when [Ca2+]i was clamped at resting levels. These levels of [Ca2+]i were set by serum, which elevated [Ca2+]i by integral of 30 nM, whereas the addition of NGF had no effect on [Ca2+]i. The reduction of [Ca2+]o prevented neurite fasciculation but this had no effect on the rate of neurite elongation or on the number of extending neurites. These results show that neurite outgrowth from NGF-dependent neurons occurs over long periods in the complete absence of Ca2+ signals, suggesting that Ca2+ signals are not necessary for operating the basic machinery of neurite outgrowth.
Fasciclin I is a membrane-associated glycoprotein that is regionally expressed on a subset of fasciculating axons during neuronal development in insects; it is expressed on apposing cell surfaces, suggesting a role in specific cell adhesion. In this paper we show that Drosophila fasciclin I is a novel homophilic cell adhesion molecule. When the nonadhesive Drosophila S2 cells are transfected with the fasciclin I cDNA, they form aggregates that are blocked by antisera against fasciclin I. When cells expressing fasciclin I are mixed with cells expressing fasciclin III, another Drosophila homophilic adhesion molecule, the mixture sorts into aggregates homogeneous for either fasciclin I- or fasciclin III-expressing cells. The ability of these two novel adhesion molecules to mediate cell sorting in vitro suggests that they might play a similar role during neuronal development.
Axonin-1 is a neuronal glycoprotein occurring both as a membrane-bound and a secreted form. Membrane-bound axonin-1 is predominantly located in membranes of developing nerve fiber tracts and has recently been characterized as a cell adhesion molecule; the soluble form is secreted from axons and accumulates in the cerebrospinal fluid and the vitreous fluid of the eye. In the present study, we addressed the question as to whether secreted axonin-1 was released in a functionally competent form and we found that it strongly promotes neurite outgrowth when presented to neurons as an immobilized substratum. Neurite lengths elaborated by embryonic dorsal root ganglia neurons on axonin-1 were similar to those on the established neurite-promoting substrata L1 and laminin. Fab fragments of axonin-1 antibodies completely inhibited neurite growth on axonin-1, but not on other substrata. In soluble form, axonin-1 had an anti-adhesive effect, as revealed by perturbation of neurite fasciculation. In view of their structural similarity, we conclude that secreted and membrane-bound axonin-1 interact with the same growth-promoting neuritic receptor. The fact that secreted axonin-1 is functionally active, together with our previous findings that it is secreted from an internal cellular pool, suggests a functional dualism between membrane-bound and secreted axonin-1 at the site of secretion, which is most likely the growth cone. The secretion of adhesion molecules could represent a powerful and rapidly acting regulatory element of growth cone-neurite interactions in the control of neurite elongation, pathway selection, and possibly target recognition.