N-Butyl benzenesulfonamide: a neurotoxic plasticizer inducing a spastic myelopathy in rabbits

Summary N-Butyl benzenesulfonamide (NBBS), a plasticizer used commercially in the polymerization of polyamide compounds, is neurotoxic. Young adult New Zealand white rabbits, inoculated repeatedly with NBBS by the intracisternal or intraperitoneal routes, developed a dose-dependent motor dysfunction characterized by limb splaying, hyperreflexia, hypertonia, gait impairment, and abnormal righting reflexes. Histopathological changes consisted of intramedullary thickening of the ventral horn axons, random neuroaxonal spheroids confined to brain stem nuclei and spinal motor neurons, and swollen dendritic processes of spinal motor neurons. Immunoreactivity to a monoclonal antibody against microtubule-associated protein-2 (MAP-2) was markedly increased in the dendrites of spinal motor neurons following thrice weekly intraperitoneal inoculations of NBBS for 4 months, whereas after 12 monthly intracisternal inoculations. MAP-2 immunoreactivity was absent or strikingly reduced in the same neuronal populations. Ultrastructurally, postsynaptic zones contained vacuoles and multilamellar bodies. These findings raise questions about the safety of NBBS to humans.MJS is a recipient of a research fellowship from the Medical Research Council of Canada. This work has been presented in part at the 42nd Annual Meeting of the American Academy of Neurology, Miami, May 1990     

Aluminum-induced acute cholinergic neurotoxicity in rat

In the present study the acute effect of intravenous aluminum chloride (1 mg/kg) on choline acetyltransferase (ChAT) and acetyl-cholinesterase (AChE) activities of rats was investigated. Aluminum was found to cross the blood-brain barrier (BBB) as indicated by the detection of aluminum in the cerebrospinal fluid (CSF) 30 min after femoral vein injection. Two hours following aluminum injection, ChAT activity in the basal forebrain and hippocampus was significantly reduced by 30% and 22%, respectively, whereas no change was observed in the caudate nuclei. On the other hand, AChE activity was significantly increased by 45% in the caudate nuclei, whereas little change was observed in other brain areas. This report demonstrates that rapid transport of Al across the BBB, and the acute nature of Al neurotoxicity in rats.     

Chronic encephalomyelitis presenting as chronic progressive myelopathy.

Chronic progressive myelopathy is a clinical entity with few neuropathological studies. The most frequent diagnosis in necropsied cases is multiple sclerosis. A case of chronic progressive myelopathy is described with a 16-year course in a woman who was 28 years old at the onset of the disease. At necropsy, there was chronic inflammation in the central nervous system with predominant involvement of the spinal cord with diffuse myelin loss and axonal degeneration.     

Aluminum-induced neurofibrillary changes in axons and dendrites

Summary We examined the chronic effect of aluminum on the rabbit central nervous system (CNS) and documented the occurrence of axonal swellings (spheroids) and dendritic thickening in spinal cord neurons in addition to the accumulation of neurofibrillary material in the perikaryon. The axonal swellings always occurred at the first heminode, and the neurofilaments appeared disorganized, whereas in dendrites the neurofilaments generally retained their longitudinal arrangements. Although neurofibrillary tangles were present in cortical neurons, no axonal swellings were observed. Thickening of segments of apical dendrites proximal to the cell body affected by neurofibrillary changes was present. The axonal swellings resembled those observed in IDPN intoxication, and in amyotrophic lateral sclerosis, and may be useful as a model for studying these diseases.Supported by the Office of Mental Retardation and Developmental Disabilities of the State of New York and the Aluminum Association, Inc.     

Immunoglobulin abnormalities and measles antibody response in chronic myelopathy.

Patients with chronic myelopathy of unknown origin were separated into two groups on the basis of presence or absence of oligoclonal immunoglobulin G (lgG) in cerebrospinal fluid (CSF). Thirty-nine of 48 patients (81%) with oligoclonal lgG in CSF had measles virus antibodies in the CSF and 31 (65%) showed reduced serum/CSF measles virus antibody ratios, in comparison with the corresponding ratios of adenovirus, group-specific, penton hemagglutination-enhancement and poliovirus neutralization-enhancement antibodies. Of 25 patients with myelopathy, but without oligoclonal lgG in their CSF, three had detectable titers of measles CSF antibodies and one of these had a greatly reduced serum/CSF ratio. The conditions of patients with chronic myelopathy of unknown origin and oligoclonal lgG in CSF may be diagnosed as probable multiple sclerosis (MS), in contrast to patients with this disease who lack oligoclonal lgG IN CSF. However, the clinical features of the disease in these two groups do not differ substantially.     

Multiple specificities of antibrain antibodies in multiple sclerosis and chronic myelopathy

The presence of complement-fixing antibodies against brain antigens was tested in paired serum and cerebrospinal fluid (CSF) samples from 60 multiple sclerosis (MS) patients, 15 patients with chronic myelopathy of undetermined cause (CM) and 60 control patients. Six MS sera, 34 MS CSF, 4 CM sera, 3 CM CSF, 4 control sera and 1 control CSF gave positive reactions either with a lipid extract or a saline extract of normal human brain. The proportion of anticomplementary CSF was significantly higher in the MS group than in the control group (15% vs 0%, P < 0.01). The reactivity of a large number of individual positive samples was further investigated. Seven antibody specificities were discerned in the MS samples. Most samples reacted with nonlipid antigens, the dominating being a heat-labile, nonlipid component associated with CNS myelin. Antibodies to cerebroside and sulfatide were detected in a few patients. A number of samples reacted with cholesterol in combination with a variety of lipids. Positive samples from the CM patients exhibited a similar heterogeneity. In the control group positive reactions were seen in one patient with systemic lupus erythematosus (SLE), two patients with rheumatoid arthritis (RA), and one with a spinal meningioma. The reaction patterns of these patients were different from those commonly seen in MS patients. The complement-fixing antibrain antibodies in MS CSF are usually of IgG class (Ryberg 1976). This applies also to the positive MS sera in this study. The distribution of the antibodies between serum and CSF indicated, in several cases, an intrathecal synthesis. All of a number of human brains, including one MS brain, contained all 6 antigens (haptens) reactive in saline extracts. Antibodies to tissues outside the CNS were rarely detected in MS patients. The varied humoral autoimmune response in MS might reflect a heterogeneity in the MS patients, the disease itself or its causative agent.     

Delayed myelopathy induced by chronic compression in the rat spinal cord

Cervical myelopathy is a common cause of neurological disability among the elderly; however, the exact mechanism for the insidious and progressive deterioration remains to be elucidated. To study the pathophysiology, we developed a simple experimental model reproducing the course. In rats, a thin sheet of expanding polymer was implanted microsurgically underneath the C5-C6 laminae. In the control group, the polymer sheet was removed immediately. Changes in motor functions were monitored for 25 weeks after the operation, with voluntary exercise activity measured by odometer attached to revolving cages, and forced running capability measured by duration of exercise on a rotating treadmill. Motor neurons were counted stereologically in continuous sections. In the compression group, the forced running capability deteriorated after a latent period of 17 weeks and progressively thereafter. In the control group, it stayed unchanged throughout 25 weeks. Course of the voluntary exercise was comparable between the groups. Motor neuron density in the compression group decreased significantly in 9 weeks (-20.3%) and 25 weeks (-35.5%), but not in 1 or 3 weeks. This practical model properly reproduces characteristic features of the clinical cervical myelopathy, with progressive motor disturbance after a latency and insidious neuronal loss preceding the symptoms.     

HTLV-I associated myelopathy (HAM) complicated with chronic polymyositis

The patient was a 49-year-old woman. Since her age of 42, she noticed a proximal weakness of both legs. She also experienced pedal paresthesia and urinary frequency. Physical examination disclosed a diffuse goiter and bilateral Babinski sign. Results of EMG and muscle pathology were compatible with the diagnosis of polymyositis. Treatment with prednisolone improved muscle weakness, urinary difficulties and struma. 7 years later, HTLV-I antibody happened to be strongly positive both in serum and CSF. Then most of her neurological problems were attributed to HAM. However, recent studies of re-biopsy muscle specimens disclosed scattered necrotic fibers, phagocytosis and endomysial or perivascular infiltration of inflammatory cells. These infiltrating cells were classed mostly as helper/inducer T cells. These observations suggested the coexistence of polymyositis in the present case as well. So far, the combination of HAM and polymyositis has not been reported. It seems important to decide if HTLV-I could induce chronic polymyositis as in the case of HIV infections.     

Management of chronic myelopathy symptoms and activities of daily living

Many disorders can injure the spinal cord resulting in long-term chronic myelopathy. Spinal cord dysfunction influences the homeostasis of multiple organ systems ranging from the heart or lung to the integument, thus presenting a wide variety of challenges for medical management. Although most of our knowledge about the consequences of myelopathies derives from the study of traumatic spinal cord injuries, similar complications occur in myelopathies of all etiologies. The authors survey some of the important clinical issues that the general neurologist needs to consider in caring for patients with chronic spinal cord disease.     

Spinal neurenteric cyst presenting in infancy with chronic fever and acute myelopathy

The authors describe the clinical, radiologic, and pathologic features of a neonatal spinal neurenteric cyst (NC) presenting with long-lasting fever and acute myelopathy, and compare this observation with other infants reported in the literature. This observation shows that NC must be considered in the differential diagnosis of acute myelopathy with persistent fever in infancy. Fever is attributed to degenerative changes in the NC, triggering inflammatory cell infiltration and tumor necrosis factor alpha secretion.     

A case of chronic progressive radiation myelopathy successfully treated with corticosteroid

One patient who underwent radiation therapy for laryngeal cancer two years earlier developed chronic progressive radiation myelopathy and exhibited localized swelling of the cervical spinal cord at the C4 level and resultant blocking of the subarachnoid space on myelography and CT myelography. The condition responded markedly to the administration of corticosteroid except for persisting mild spasticity and sensory disturbances. On myelography and CT myelography half a year later, the cervical spinal cord showed no swelling. The corticosteroid therapy is considered to be useful for radiation myelopathy.     

Aluminum-induced neurotoxicity: alterations in membrane function at the blood-brain barrier

Aluminum is established as a neurotoxin, although the basis for its toxicity is unknown. It recently has been shown to alter the function of the blood-brain barrier (BBB), which regulates exchanges between the central nervous system (CNS) and peripheral circulation. The BBB owes its unique properties to the integrity of the cell membranes that comprise it. Aluminum affects some of the membrane-like functions of the BBB. It increases the rate of transmembrane diffusion and selectively changes saturable transport systems without disrupting the integrity of the membranes or altering CNS hemodynamics. Such alterations in the access to the brain of nutrients, hormones, toxins, and drugs could be the basis of CNS dysfunction. Aluminum is capable of altering membrane function at the BBB; many of its effects on the CNS as well as peripheral tissues can be explained by its actions as a membrane toxin.     

Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis

It is hypothesized that in MS and HTLV-1, chemokine and chemokine receptor expression are important mechanisms by which T cells migrate to sites of inflammation. Preliminary evidence supports the roles of several chemokines, including MIP 1beta, in mediating the enhanced migration capacity of MS derived PBLs. In addition, the ligand CCR-5 seems to be up regulated on PBLs from some MS patients. Analysis of T cell clones does not reveal a definite correlation between cytokine phenotype and chemokine receptor profile. The chemokines and chemokine receptor family are likely to be important molecules in chronic progressive neurological diseases, in which immune cells invade the central nervous system.     

Thoracic myelopathy revealing a chronic ossificans arachnoiditis of the thoraco-lumbar spinal cord

We report a case of chronic spinal, ossificans, thoraco-lumbar arachnoiditis, associated with an arachnoidal cyst at the level of TH7, and revealed by a rapidly progressive thoracic myelopathy. Two years ago, he had presented with a spinal intrathecal haemorrhage of unknown etiology. There was no evidence of spinal traumatism, arterial hypertension or coagulation disorder. The finding of several small cysts and angiomas in the liver of this patient lead us to suspect an associated spinal vascular malformation, not detected on the spinal magnetic resonance imaging. A partial neurologic improvement was observed after laminectomy and cysto-peritoneal derivation.     

Aluminum-induced apoptosis in cultured astrocytes and its effect on calcium homeostasis

Aluminum exposure and apoptotic cell death has been implicated in several neurodegenerative conditions including Alzheimer's disease. In this study, we use cultured astrocytes to investigate the ability of aluminum to induce the apoptosis of astrocytes. The proportion of apoptotic cells and cell cycle distribution were determined by flow cytometric analysis. Our results showed that exposure to aluminum at low levels (100 and 200 microM) for up to 6 days did not result in the apoptosis of astrocytes, and a dramatic blockage of apoptotic cells was found at 200 microM aluminum. However, at 400 microM, aluminum markedly induced the apoptosis of astrocytes, which was associated with a significant change in cell cycle distribution characterized by increase of G2/M phase cells (128%). Measurements of intracellular Ca(2+) concentration using the fluorescent calcium indicator dye Fluo-3 demonstrated a significant increase in the levels of intracellular calcium after aluminum treatment. However, no differences were observed among aluminum-treated groups. These findings suggest that aluminum induce and block selectively the apoptosis of astrocytes, which depend upon the concentrations of aluminum. Increased intracellular Ca(2+) may not be the primary mechanism of aluminum-mediated apoptotic cell death.     

Aluminum-induced neurofilamentous changes in cultured rat dorsal root ganglia explants.

Intrathecal administration of aluminum (AI) salts to susceptible species causes prominent accumulations of neurofilaments (NFs) in neurons of the CNS. Involved nerve cells display abnormal phosphorylation of perikaryal NFs, impaired axonal transport of NFs, and reduced levels of mRNA for NF proteins. Further understanding of the pathogenesis of AI toxicity has been limited by difficulties inherent in the available in vivo systems. For this reason, we have developed a model to study the effects of AI on cultured sensory neurons. Explant cultures of rat dorsal root ganglia (DRG) were exposed to 1 mM aluminum lactate for 1 d, 3 d, or 7 d and then examined morphologically. Accumulations of NFs were noted as early as 1 d after exposure, and prominent masses of NFs were seen at 3 and 7 d. Northern analysis of mRNA extracted from the cultured ganglia showed that high, medium, and low molecular weight NF protein mRNA levels were markedly reduced compared to control values by 1 d of exposure. Class II beta-tubulin mRNA was also moderately decreased. Reversibility of toxicity was assessed by removing the aluminum lactate from the medium after a 3 d exposure and examining the cultures 1 week later. The perikaryal masses of NFs dispersed and the levels of mRNA coding for the NF proteins and class II beta-tubulin increased. The neurotoxic effects of AI on cultured DRG recapitulates the effects of intrathecal administration of AI on animals; this model produces similar changes in neuronal morphology with neurofilamentous masses and similar modifications of NF gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)