Onset Of Neurological Signs Research Articles

Anti-T cell monoclonal antibodies in vivo. II. Modulation of acute and chronic experimental allergic encephalomyelitis (EAE) in guinea pigs.

To determine the effects of anti-T cell monoclonal antibody-induced systemic T cell depletion in neuro-autoimmune disease, we studied the in vivo effects of 8BE6, a mouse anti-guinea pig (GP) pan-T cell monoclonal antibody, on the course and immunopathology of the disease model experimental allergic encephalomyelitis (EAE) in adult Strain 13 GP. Central nervous system (CNS) tissues were studied by routine histology and by an immunoperoxidase staining technique using monoclonal antibodies to T cells, IgM, and macrophages. From 3 days before to 10 days after sensitization with GP spinal cord and complete Freund's adjuvant, the GP were given one or two i.p. doses of 3.4 mg 8BE6 or MOPC 21, the parent mouse myeloma ascites, or normal saline. Eighteen of 18 control-treated GP developed typical acute, paralytic EAE 11 to 21 days after sensitization, whereas acute EAE was prevented in 33 of 49 8BE6-treated GP (67%), and the onset was delayed and disease progression was slowed in the others. Five GP treated with 8BE6 from days 11 to 14 after sensitization, at the onset of neurologic signs, rapidly deteriorated within hours after treatment and had loss of T cell staining, and lymphocytolysis in the CNS. 8BE6-treated GP which did not develop acute EAE were observed daily for up to 700 days (mean = 213 days). Twenty-nine of 39 (74%) had from one to six relapses or fixed neurologic deficits. GP in relapse were additionally treated with 8BE6 (22), MOPC-21 (5), or saline (6) in a cross-over protocol. Clinical scores were improved from days 2 to 12 after treatment (p less than 0.05), and complete recovery within 30 days occurred more frequently (p = 0.046) and more rapidly (p less than 0.01), after 8BE6 as compared with control treatments. Recoveries occurred more often if 8BE6 was given early in the relapse. Multiple treatments led to dose-dependent levels of serum antibodies to mouse immunoglobulin detected by an ELISA. There were no differences between acute and chronic EAE in numbers of inflammatory foci or numbers of macrophages and T cells in CNS infiltrates, but GP with chronic EAE had more extensive demyelination and vascular fibrosis and more numerous IgM+ B cells in parenchymal and meningeal infiltrates than in acute EAE (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Genes and genomes in scrapie

Scrapie in sheep and CreutzfeldtJakob disease (CJD) in man are among a group of at least five degenerative diseases of the CNS which are caused by 'unconventional slow viruses'. Many years can elapse between infection and the onset of neurological signs. Once these appear, the clinical course is relentlessly progressive with an invariably fatal conclusion. At the moment. there are no effective treatments for these diseases and the precise nature of the 'unconventional viruses' that cause them is still in doubt. Experimental models of both scrapie and CJD have been developed in several rodent species and many different scrapie models have been obtained in mice. The routine scrapie models are defined primarily by the strain of agent and the Sinc genotype of mice. The Sinc gene controls scrapie incubation (hence the name) and an equivalent gene is known in sheep 1. Two alleles of the Sinc gene have been identified and the relative incubation periods of scrapie in the three possible Sinc genotypes vary greatly according to the agent strain, including no dominance, partial dominance of either allele, full dominance and over dominance I. The range of interactions between individual scrapie strains and the alleles of the Sinc gene provides one of the methods by which about 20 different scrapie strains have now been identified. Very recently, strong evidence fm the mutation of scrapie strains has been published 2. The evidence comes from studies of the 87A strain of scrapie which has been isolated from six different natural cases involving five breeds of sheep. The properties of 87A always remained constant on serial passage in C57BL mice by injection of low doses (i.e. under conditions of biological cloning) but passage at high doses invariably led, sooner or later, to a dramatic change in properties caused by the appearance and selection of a mutant strain, 7D, which had a much shorter incubation period than 87A. This difference in incubation period excludes the possibility that 87A and 7D were isolated from sheep as a James Hope

The immunopathology of experimental allergic encephalomyelitis. II. Endothelial cell Ia increases prior to inflammatory cell infiltration.

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated neuroimmunologic disease model characterized by meningeal and parenchymal mononuclear cell infiltrates (see preceding companion paper). Here we report enhanced staining for Ia in the central nervous system (CNS) microvasculature endothelium in acute EAE in adult strain 13 guinea pigs (GP) sensitized with GP spinal cord homogenate (SC) or with GP myelin basic protein (MBP) in complete Freund's adjuvant (CFA). Cryostat sections of CNS and other tissues were stained with two monoclonal antibodies, 5S2 and 22C4, to GP Ia determinants, and with polyclonal antibody to factor VIII-related antigen (VIII-RA) as an endothelial cell marker. Morphometric techniques were employed on immunoperoxidase counterstained and coded sections to determine the frequency of Ia+ vessels and cells. Rare (approximately 10% of VIII-RA+) vascular endothelial cells were Ia+ in the CNS of normal and CFA-sensitized controls. SC- or MBP-sensitized strain 13 GP sacrificed on day 7, before the onset of neurologic signs (pre-clinical), had no detectable CNS mononuclear cell infiltrates, but had increased (approximately 30% of VIII-RA+) endothelial cell Ia staining over controls (p less than 0.001). The endothelial Ia staining persisted (approximately 35% of VIII-RA+) in vessels as the animals developed paralysis. There were no differences in endothelial cell Ia between SC- and MBP-induced disease. EAE-resistant strain 2 GP sensitized with SC/CFA had no neurologic signs, and had fewer inflammatory foci than strain 13 GP with EAE, but had similar numbers of Ia+ endothelial cells. No differences in endothelial cell Ia staining were found in non-CNS tissues among any GP groups. In EAE, increased endothelial cell Ia is a pre-inflammatory, target organ-specific alteration that persists during inflammation. The findings suggest that in vivo modulation of endothelial cell Ia may be part of the local immune response. Endothelial cells may play a significant role, in antigen presentation or in promoting T cell migration, in the in situ immune response in the CNS.

Effect of whole body hyperthermia and BCNU on the development of radiation myelitis in the rat.

A radiant heat device was used to study the interaction of 41.8 degrees C whole body hyperthermia (WBH), radiation (40 Gy) and the lipophilic anti-neoplastic agent BCNU in the development of myelitis in the rat spinal cord. The addition of WBH and BCNU neither precipitated myelitis acutely nor shortened the latency before the onset of neurological signs in irradiated animals.

Suppression of experimental allergic neuritis by Cyclosporin-A.

Experimental allergic neuritis (EAN) was induced in guinea pigs and rats and treated with Cyclosporin-A (Cy-A). When Cy-A was given prophylactically for 1 month from the time of induction of the disease, it prevented the development of EAN during the course of its administration. When Cy-A was given therapeutically after the onset of neurological signs, it effectively prevented further deterioration. This effect was more marked after 3 weeks' treatment than after only 1 week's treatment. In both regimens, when dosing with Cy-A ceased there was a latent period before clinical signs of EAN developed. This latent period is similar to that seen in the development of EAN in normal control animals and is probably due to the continued presence of antigen at the injection sites. After primary treatment of EAN with Cy-A, animals that relapsed did not respond to further treatment with Cy-A. Histological examination revealed that the nature of the EAN lesions in both groups of animals given Cy-A were not as severe as those seen in control animals. Despite these observations, there was no statistically significant difference between the maximum clinical grades reached by animals in any one group. These experiments suggest that T-cells are important in the development of EAN and that Cy-A interferes with this process by suppressing T-helper cells. They also show that it is possible to influence favourably the course of immune mediated neurological disease.

Toxicity studies of the toxins isolated from annual ryegrass (Lolium rigidum) infected by Corynebacterium rathayi.

Estimates of the LD50's of 7 glycolipid toxins (corynetoxins) isolated from toxic annual ryegrass varied in the range 0 . 1-1 . 3 mg/kg in 2-week-old rats. The delay in onset of neurological signs in rats and sheep was independent of dose rate and could be the result of inhibition of protein biosynthesis. In sheep, no influence of the route of administration on the delay in onset of neurological signs was demonstrated. The relationship between the partial structures of the two major corynetoxins and their toxicity is discussed.

The Effects of Fractionated Doses of Fast Neutrons or Photons on the Canine Cervical Spinal Cord

The cervical spinal cords of 36 young adult male beagles were irradiated with fast neutrons with a mean energy of 15 MeV in four fractions/week/5 weeks to total doses of 1167, 1750, 2625, or 3938 rad. Nineteen beagles received 3500, 5250, or 7875 rad of photons in like manner. Sensory evoked responses recorded before and periodically after irradiations remained stable on 22 test and 6 control dogs. The cerebrospinal fluid contained excess protein and erythrocytes often before and always after the onset of neurological symptons. All dogs in the 3938-rad neutron, 6/9 dogs in the 2625-rad neutron, and 4/6 dogs in the 7875-rad photon groups developed cervical muscular spasms, incoordination, and progressive paralysis and were euthanatized. The relative biological effectiveness of fast neutrons as measured by the onset of neurological signs is approximately 3 (7875 photons/ 2625 neutrons) and is less than 4.5 (7875 photons/1750 neutrons). Gross pathological findings included hemorrhages, softening, and poliomyelomalacia, especially of the dorsal horns. Two dogs developed neoplasms in the irradiated field 1065 and 1470 days following neutron irradiation.

Effect of thiamine deficiency on brain serotonin turnover

Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in the medulla-pons, hypothalamus and cerebral cortex. [14C]5-HT levels were normal in all of the brain areas except the cerebral cortex which had an increase of 58%. The ratio of [14C]5-HIAA/[14C]5-HT was significantly increased in every brain region of PT-treated rats except the cerebral cortex. Part of this increase in [14C]5-HIAA was shown to be due to impairment of active transport of this 5-HT metabolite out of the brain. However, increased 5-HT synthesis in the cerebellum, hypothalamus, striatum, hippocampus and cerebral cortex was demonstrated by measurement of 5-HT accumulation after inhibition of brain monoamine oxidase. PT-induced increase in endogenous 5-HIAA in the medulla-pons occurred simultaneously with the onset of neurological signs and both parameters were reversible by thiamine administration. These results suggest that acute thiamine deficiency, induced by PT, both increases brain 5-HT synthesis and impairs 5-HIAA efflux from the brain. There is a close correlation between neurological manifestations and changes in brain 5-HT metabolism in acute thiamine deficiency.

CHRONOLOGICAL STUDY OF ULTRASTRUCTURAL CHANGES IN THE PERIPHERAL NERVES IN MAREK'S DISEASE

A chronological study was made of the ultrastructural changes in peripheral nerves following inoculation of 1-day-old chicks with a neurogenic strain of Marek Disease virus. No virus particles were found in nerves. Cellular infiltration of nerves was detected as early as 5 days after inoculation and by 3 weeks some nerves contained proliferative lesions which possessed many of the ultrastructural features characteristic of normal, reactive lymphoid tissue. About 4 weeks after inoculation, coinciding with the onset of neurological signs, areas of widespread demyelination appeared within these lesions; lymphocytes and macrophages penetrated and destroyed the myelin sheath, but spared Schwann cells and most axons. Later oedematous, sparsely infiltrated B type lesions were observed, some of which contained demyelinated nerve fibres undergoing repair; these were therefore a stage in the regression of the proliferative lesions. Our observations do not favour the hypothesis that cellular infiltration of nerves in Marek's disease is the direct result of auto-sensitization to normal myelin. They are consistent with the hypothesis that demyelination is a secondary feature and that the primary lesions are preferential sites for immune demyelination.

Antiviral Chemotherapy and Neonatal Herpes Simplex Virus Infection: A Pilot Study—Experience With Adenine Arabinoside (ARA-A)

Among 13 neonates with herpes simplex virus (HSV) infection, eight had disseminated disease, one localized CNS disease, and in four the infection was confined to the skin and eyes. Ara-A, a purine nucleoside with anti-viral activity against DNA-viruses, was given (10 to 20 mg/kg/ day) by a continuous 12-hour intravenous drip for 10 to 15 days. In all, ara-A administration was begun within three to eight days after the appearance of skin vesicles which represented the hallmark of the disease. Both diagnosis and ara-A treatment were much delayed in one infant without skin vesicles and four infants whose skin vesicles appeared late, long after the occurrence of CNS damage. In this group of infants with disseminated disease, four died and one infant was left with severe neurological deficits. Eight infants (four with disseminated and four with localized skin disease) with skin vesicles as the earliest sign of infection received ara-A early, within three days after the onset of neurologic signs. All survived with no neurologic deficit at 6 months to 1 year of age. There was no apparent toxicity of ara-A to the bone marrow, liver, or kidney.

Acute polyneuropathy complicating chronic renal failure.

This is a case report of a 43-year-old housewife who developed acute polyneuritis as a terminal complication of chronic pyelonephritis. Death occurred from respiratory failure 18 days after the onset of neurological signs. The principal clinical findings were uraemia and a profound symmetrical weakness of the proximal muscles of the upper and lower limbs. There was also a moderate symmetrical weakness of the distal muscles of the upper and lower limbs. Limb reflexes, apart from the biceps jerks, were absent. There were no sensory abnormalities. Post mortem examination revealed chronic pyelonephritis with secondary hyperparathyroidism and osteitis fibrosa. At all levels of the spinal cord many motor neurones showed chromatolysis. There was degeneration of the terminal arborisations of the intramuscular nerves in distal limb muscles. There were no histological abnormalities in the spinal nerve roots and dorsal root ganglia nor in the extramuscular regions of the peripheral nerves. There was no histological evidence of a myopathy. It is suggested that the abnormalities in the intramuscular nerve fibres are due to a dying-back process of the spinal motor neurones, rather than to changes in the Schwann cells. The nature of the primary defect in the spinal motor neurones responsible for the dying-back phenomenon of the intramuscular nerve fibres is not known.

Acute Spinal Epidural Abscess.

1. Two cases of acute spinal epidural abscess are reported. 2. Complete recovery followed early drainage in one case. 3. Late diagnosis in the second case was attended by a poor result. 4. The development of severe pain in the back with signs of infection may merge almost imperceptibly with the onset of neurological signs and symptoms.

Herpes simplex encephalitis

Herpes simplex encephalitis (HSE) is a severe disease with high mortality and morbidity. As effective antiviral therapy improves the outcome of younger patients, the early diagnosis of the disease has become important, especially in children. The annual incidence of HSE in Japan among children is estimated to be about 100-200 cases, and the mortality is 10-20%. Instead of brain biopsy, we applied the polymerase chain reaction (PCR) assay to the early diagnosis. The DNA of herpes simplex virus was detectable in CSF of all HSE patients in the acute phase. Serial quantitation of viral genome by PCR also revealed that the amount of DNA decreased gradually corresponding to antiviral therapy, and it turned to be negative 3 to 18 days after the onset of neurological signs and symptoms (mean 10.1 days). These results show the PCR assay is a useful diagnostic tool for the early and non-invasive diagnosis of HSE.

Acute lumbar epidural abscess; report of a case.

THE diagnosis of an acute abscess of the spinal epidural space is rarely made before onset of neurologic signs, in spite of the fact that the severe back pain generally causes the patient to consult a physician before irreversible neurologic disabilities develop. A case is reported below to re-emphasize the importance of the syndrome of severe back pain, with local spinous tenderness, fever and leukocytosis. Early surgical intervention, combined with antibiotics, makes the prognosis of this disease less serious.Case ReportA 26-year-old sergeant entered the United States Army Hospital, Camp Gordon, Georgia, on September 24, 1952, because of chills, . . .