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1.
J Spinal Disord ; 13(3): 185-99, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10872756

ABSTRACT

From the beginning, the reporting of the results of National Acute Spinal Cord Injury Studies (NASCIS) II and III has been incomplete, leaving clinicians in the spinal cord injury (SCI) community to use or avoid using methylprednisolone in acute SCI on the basis of faith rather than a publicly developed scientific consensus. NASCIS II was initially reported by National Institutes of Health announcements, National Institutes of Health facsimiles to emergency room physicians, and the news media. The subsequent report in the New England Journal of Medicine implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. However, this analysis was in fact negative, and the positive result was found only in a secondary analysis of the subgroup of patients who received treatment within 8 hours. In addition, that subgroup apparently had only 62 patients taking methylprednisolone and 67 receiving placebo. The NASCIS II and III reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or or even explained. These studies show statistical artifacts that call their results into question. In NASCIS II, the placebo group treated before 8 hours did poorly, not only when compared with the methylprednisolone group treated before 8 hours but even when compared with the placebo group treated after 8 hours. Thus, the positive result may have been caused by a weakness in the control group rather than any strength of methylprednisolone. In NASCIS III, a randomization imbalance occurred that allocated a disproportionate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlled for, much of the superiority of the higher dose group seems to disappear. The NASCIS group's decision to admit persons with minor SCIs with minimal or no motor deficit not only enables statistical artifacts it complicates the interpretation of results from the population actually sampled. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thus, we do not know whether the results of these studies reflect the severely injured population to which they have been applied. The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public. The reporting of the NASCIS studies has fallen far short of the guidelines of the ICH/FDA and of the Evidence-based Medicine Group. Despite the lucrative "off label" markets for methylprednisolone in SCI, no Food and Drug Association indication has been obtained. There has been no public process of validation. These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.


Subject(s)
Methylprednisolone/therapeutic use , Randomized Controlled Trials as Topic/standards , Spinal Cord Injuries/drug therapy , Acute Disease , Computer Security , Humans , Publications , Spinal Cord Injuries/diagnosis , United States , United States Food and Drug Administration
2.
Exp Neurol ; 158(2): 279-89, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10415136

ABSTRACT

Muscles innervated from spinal segments close to the site of a human spinal cord injury are often under voluntary control but are weak because they are partially paralyzed and partially denervated. Our objective was to develop an animal model of this clinical condition to evaluate strategies to improve voluntary muscle strength. To do so, we examined the spinal and peripheral innervation of the flexor digitorum superficialis brevis quinti (FDSBQ) muscle of the rat foot, characterized the muscle and motor unit properties, and located the FDSBQ motoneurons. Retrograde labeled motoneurons were in L4 to L6 spinal cord. Unilateral stimulation of L4 to S1 ventral roots and recording of evoked force showed that FDSBQ motor axons exited via two ventral roots (L5 and L6 or L6 and S1) in 38% of rats and via one ventral root in 62% of rats. FDSBQ motor axons traveled via two peripheral nerves, the lateral plantar (76% of axons) and sural nerves (24%). Each ventral root contributed motor axons to each nerve branch. Thus, by combining conduction block of one peripheral nerve to induce partial muscle paralysis and ventral root section to induce partial denervation, it is possible to produce in one rat muscle the consequences of many human cervical spinal cord injuries. FDSBQ muscles and motor units were mainly fast-twitch, fatigable, and composed of fast-type muscle fibers. The narrow range of motor unit forces (1-13 mN), the low mean twitch force (5.1 +/- 0.3 mN), and the large number of motoneurons (31 +/- 4) suggest that rat FDSBQ muscle is a good model of distal human musculature which is frequently influenced by spinal cord injury. We conclude that the FDSBQ muscle and its innervation provide a useful animal model in which to study the consequences of many spinal cord injuries which spare some descending inputs but also induce substantial motoneuron death near the lesion.


Subject(s)
Motor Neurons/physiology , Muscle Contraction/physiology , Muscle, Skeletal/innervation , Paralysis/physiopathology , Spinal Cord Injuries/physiopathology , Spinal Nerve Roots/physiology , Animals , Axons/physiology , Disease Models, Animal , Electric Stimulation , Evoked Potentials , Female , Functional Laterality , Hindlimb , Humans , Muscle, Skeletal/physiology , Muscle, Skeletal/physiopathology , Peripheral Nerves/physiology , Peripheral Nerves/physiopathology , Rats , Rats, Sprague-Dawley , Spinal Nerve Roots/physiopathology , Sural Nerve/physiology , Sural Nerve/physiopathology
3.
J Neurotrauma ; 12(2): 199-208, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7629866

ABSTRACT

Occlusion of the major components of the spinal venous system is usually associated with spinal arteriovenous malformations or systemic thrombophlebitis. Although spinal venous system dysfunction has been implicated in compressive cord syndromes, myelopathies from decompression sickness, and spinal cord trauma, its pathophysiology remains unclear. To characterize disorders associated with spinal venous occlusion, we developed a model in the rat produced by focally coagulating the dorsal spinal vein transdurally at the T7 and T10 vertebral levels. Following such occlusion, venous stasis, sludging and perivascular hemorrhages in the small venous branches were observed. By 1 week postocclusion, animals developed hindlimb paralysis from which they partially recovered over time. Histologic examination in the acute phase disclosed tissue necrosis, edema, and hemorrhages predominantly in the dorsal aspect of the spinal cord. This was gradually replaced by an intense macrophagic infiltration and the partial formation of a cystic cavity by 1 month. These findings indicate that dorsal spinal vein occlusion in the rat causes significant neurologic and pathologic alterations. We conclude that this procedure produces a relevant animal model for the study of the pathophysiology of spinal venous occlusion, and it allows the characterization of its effects on spinal cord blood flow, the blood-spinal cord barrier, and the development of edema independent of cord compression. Our findings in this model provide an insight into one of the mechanisms of injury extension in spinal cord trauma and other disorders associated with spinal venous dysfunction.


Subject(s)
Spinal Cord/blood supply , Vascular Diseases/pathology , Vascular Diseases/physiopathology , Animals , Body Water/metabolism , Constriction, Pathologic , Edema/etiology , Edema/metabolism , Male , Rats , Rats, Sprague-Dawley , Spinal Cord/pathology , Spinal Cord/physiopathology , Spinal Cord Diseases/etiology , Spinal Cord Diseases/metabolism , Time Factors , Vascular Diseases/complications , Veins
4.
AJNR Am J Neuroradiol ; 15(10): 1895-905, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7863939

ABSTRACT

PURPOSE: To determine the MR and CT findings that characterize acute spinal subdural hematoma (ASSH). METHODS: The MR, CT, and clinical findings in three patients with surgically proved ASSH were reviewed and also correlated with the postmortem MR, CT, and cryomicrotome findings in three other patients, two with ASSH and one with an acute spinal epidural hematoma. RESULTS: Imaging findings in ASSH included: (a) hyperdense lesions on plain CT within the dural sac, distinct from the adjacent low-density epidural fat and silhouetted against the lower-density spinal cord and cauda equina, which it compressed; (b) lack of direct continuity with the adjacent osseous structures; (c) clumping, loculation, and streaking of blood within the dural sac on both MR and Ct; and (d) an inhomogeneous and variable signal intensity to the ASSH on all MR pulse sequences, but, nevertheless, a striking low signal intensity on T2-weighted spin-echo or T2-weighted gradient-echo to a major part of the ASSH because of deoxyhemoglobin. Plain CT was most helpful in compartmentalizing the hematoma. CONCLUSION: When MR and plain CT are obtained as complementary studies, they provide characteristic findings that allow the prompt diagnosis of ASSH.


Subject(s)
Hematoma, Subdural/diagnosis , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Adult , Cauda Equina/pathology , Child , Dura Mater/pathology , Female , Hematoma, Subdural/pathology , Hematoma, Subdural/surgery , Humans , Infant , Male , Spinal Cord/pathology , Spinal Cord Compression/diagnosis , Spinal Cord Compression/pathology , Spinal Cord Compression/surgery , Spinal Injuries/diagnosis , Spinal Injuries/pathology , Spinal Injuries/surgery , Spinal Nerve Roots/pathology
5.
J Neurotrauma ; 11(3): 241-54, 1994 Jun.
Article in English | MEDLINE | ID: mdl-7996579

ABSTRACT

Although cavitary lesions of the spinal cord have been recognized for centuries, only recently have effective, noninvasive imaging techniques allowed antemortem diagnosis of this clinical syndrome. Methods of treatment have not been consistently successful in alleviating or reversing the clinical symptoms caused by these cystic lesions. Incomplete understanding of the underlying pathologic basis for the syringes has impeded the development of effective methods of treatment. This review documents historical considerations regarding clinical observations and experimental studies of this entity and the animal models that have been reported for each of the major types of syringomyelia. Recent studies have suggested that development of a relevant animal model of posttraumatic syringomyelia is imminent. Successful development of an experimental model will not only permit definition of the pathogenesis of cyst formation but also provide methods for testing of therapeutic interventions.


Subject(s)
Syringomyelia , Animals , Arachnoiditis/complications , Dogs , Humans , Spinal Cord Injuries/complications , Spinal Cord Neoplasms/complications , Syringomyelia/congenital , Syringomyelia/etiology , Syringomyelia/pathology
6.
J Neurotrauma ; 10(4): 445-56, 1993.
Article in English | MEDLINE | ID: mdl-8145267

ABSTRACT

Microinjections of quisqualic acid were made in the spinal cord to evaluate the excitotoxic effects of this excitatory amino acid agonist on spinal neurons in the rat. Animals were divided into four groups based on post injection survival times of 7-49 days. Injections ranging from 0.3 to 2.0 microL of 8.3, 83, and 125 mM quisqualic acid or normal saline were made in the lower thoracic and upper lumbar spinal cord. At all survival times evaluated unilateral injections of quisqualic acid produced unilateral or bilateral cell death and a prominent inflammatory reaction. In 23/25 animals spinal cavities were also observed. Spinal cord segments at or near quisqualate injection sites contained darkly stained, hypertrophied neuronal profiles, and increased staining for glial fibrillary acidic factor. Immunostaining for glial fibrillary acidic factor was especially intense in areas of neuronal degeneration and in border areas of spinal cavities. The results of this study suggest that the intraspinal injection of quisqualic acid may be an effective method to study the mechanisms of excitatory amino acid neurotoxicity, and the pathogenesis of spinal cavitation following neuronal injury.


Subject(s)
Nerve Degeneration/drug effects , Neurons/drug effects , Quisqualic Acid/toxicity , Spinal Cord/drug effects , Animals , Behavior, Animal/drug effects , Glial Fibrillary Acidic Protein/immunology , Glial Fibrillary Acidic Protein/metabolism , Grooming/drug effects , Male , Microinjections , Rats , Spinal Cord/cytology , Spinal Cord/metabolism
7.
J Auton Nerv Syst ; 19(3): 199-209, 1987 Jun.
Article in English | MEDLINE | ID: mdl-3040847

ABSTRACT

The effects of 3 phosphodiesterase inhibitors, aminophylline, isobutylmethylxanthine (IBMX), and RO 20-1724, were tested on descending intraspinal and spinal reflex transmission to sympathetic preganglionic neurons in unanesthetized spinal cats. Sympathetic discharges, recorded from upper thoracic preganglionic white rami, were evoked by stimulation (0.1 Hz) of descending excitatory pathways in the cervical dorsolateral funiculus (intraspinal) or of adjacent intercostal nerves (spinal reflex). Each phosphodiesterase rapidly and markedly enhanced transmission through intraspinal pathways but only slowly and modestly enhanced transmission through spinal reflex pathways. Pretreatment with a methyltyrosine-reserpine combination, chlorpromazine, or prazosin markedly restricted the enhancement of intraspinal transmission by IBMX to levels typically produced on spinal reflex pathways. Clonidine markedly depressed transmission through both pathways and prevented enhancement by the phosphodiesterase inhibitors. Yohimbine or tolazoline antagonized the depressant effects of clonidine and restored the ability of the phosphodiesterase inhibitors to enhance transmission. Somatic spinal reflexes were not affected by the phosphodiesterase inhibitors. The results suggest that descending norepinephrine pathways to sympathetic preganglionic neurons activate adenylate cyclase to generate cyclic AMP which increases neuronal excitability, possibly by phosphorylating membrane proteins. Clonidine appears to depress neuronal excitability by inhibiting adenylate cyclase through activation of alpha 2-adrenergic receptors.


Subject(s)
Clonidine/pharmacology , Neurons/physiology , Phosphodiesterase Inhibitors/pharmacology , Spinal Cord/physiology , Sympathetic Nervous System/physiology , Synaptic Transmission/drug effects , Animals , Catecholamines/antagonists & inhibitors , Catecholamines/metabolism , Cats , Decerebrate State , Female , Ganglia/cytology , Ganglia/physiology , Male , Reflex/drug effects , Sympathetic Nervous System/cytology
8.
Eur J Pharmacol ; 78(1): 53-9, 1982 Feb 19.
Article in English | MEDLINE | ID: mdl-7075664

ABSTRACT

The dose-response effects of clonidine HCl (2.5-200 micrograms/kg i.v.) on transmission through somatospinal reflex, viscerospinal reflex, intraspinal, and spinal-bulbospinal reflex pathways were determined in spinal or chloralose-anesthetized cats to assess principle sites of drug action. Evoked sympathetic discharges were recorded from upper thoracic preganglionic rami. Clonidine rapidly produced parallel, dose-dependent depression of transmission through each pathway which was rapidly antagonized by tolazoline or yohimbine. The two spinal reflex pathways were least sensitive to depression which was identical and was limited to 60%. In contrast, both descending pathways could be depressed completely. Although the spinal-bulbospinal reflex pathway was more sensitive to depression than its efferent, descending intraspinal pathway alone, analysis of the relative depression of transmission at spinal and at brainstem levels indicates that the spinal site is more sensitive to clonidine that it is generally considered to be.


Subject(s)
Clonidine/pharmacology , Sympathetic Nervous System/drug effects , Animals , Cats , Depression, Chemical , Evoked Potentials/drug effects , Neural Pathways/drug effects , Spinal Cord/drug effects
9.
Neurosci Lett ; 28(2): 211-6, 1982 Feb 12.
Article in English | MEDLINE | ID: mdl-6175928

ABSTRACT

Preganglionic sympathetic discharges, evoked by cervical stimulation in spinal cats, were rapidly and markedly enhanced for 1-2 h by aminophylline or isobutylmethylxanthine. Clonidine depressed intraspinal transmission and prevented enhancement by the xanthines; alpha 2-receptor antagonists blocked the effect of clonidine and not only restored but also markedly prolonged the enhancement by the xanthines. The results suggest that the excitability of sympathetic preganglionic neurons is regulated by cyclic AMP through activation of different subtypes of adrenergic receptors that are either positively or negatively coupled to adenylate cyclase.


Subject(s)
Adrenergic Fibers/drug effects , Autonomic Fibers, Preganglionic/drug effects , Clonidine/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Synaptic Transmission/drug effects , 1-Methyl-3-isobutylxanthine/pharmacology , Adenylyl Cyclases/metabolism , Adrenergic alpha-Antagonists/pharmacology , Aminophylline/pharmacology , Animals , Cats , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Neurons/drug effects
10.
Clin Exp Hypertens A ; 4(4-5): 543-62, 1982.
Article in English | MEDLINE | ID: mdl-6286173

ABSTRACT

Despite considerable progress in mapping the central monoaminergic pathways to sympathetic preganglionic neurons in the spinal cord, the respective functional roles of these pathways have not been resolved. Evidence for both excitation and inhibition has been advanced for each of the three monoamines, serotonin, norepinephrine, and epinephrine. Our previous studies on spinal sympathetic pathways to sympathetic preganglionic neurons support the prevailing opinion that serotonin pathways are inhibitory but did not satisfactorily resolve the functional role of the norepinephrine pathways. However, more recent studies showing that intraspinally evoked sympathetic discharges were rapidly and markedly enhanced by phosphodiesterase inhibitors and that this effect was prevented by clonidine have led to formulation of a coherent hypothesis which accommodates much of the conflicting evidence regarding norepinephrine. In addition, evidence for the role of the epinephrine pathways has been obtained by using a selective inhibitor of epinephrine synthesis. The results of these recent studies complement our previous results and suggest that the excitability of sympathetic preganglionic neurons is regulated by excitatory norepinephrine pathways and inhibitory epinephrine pathways that activate or suppress adenylate cyclase to control intraneuronal levels of cyclic AMP.


Subject(s)
Catecholamines/physiology , Cyclic AMP/physiology , Ganglia, Sympathetic/physiology , Spinal Cord/physiology , Animals , Cats , Clonidine/pharmacology , Epinephrine/physiology , Neurons/physiology , Norepinephrine/physiology , Serotonin/physiology , Synaptic Transmission/drug effects
11.
Clin Exp Hypertens (1978) ; 3(6): 1151-63, 1981.
Article in English | MEDLINE | ID: mdl-6977434

ABSTRACT

The effects of clonidine HCI were compared with those of 5-HTP on transmission through two spinal sympathetic pathways, segmental spinal reflex pathways and descending intraspinal excitatory pathways, in unanesthetized spinal cats. Evoked sympathetic discharges were recorded from upper thoracic preganglionic rami. Clonidine (5-50 microgram/kg) produced a parallel, dose-dependent depression of transmission through each pathway. The intraspinal pathway was five time more sensitive than the spinal reflex pathway (ED50's, 6 and 30 microgram/kg), and the spinal reflex pathway could not be depressed by more than 60% even by higher doses. In contrast, 5-HTP was more effective in depressing the spinal reflex than the intraspinal pathway (ED50's 32 and 44 mg/kg), and both pathways could be depressed completely. Small doses of tolazoline or yohimbine rapidly antagonized the effects of clonidine but not 5-HTP. Clonidine and 5-HTP appear to depress the excitability of sympathetic preganglionic neurons by activating alpha2- and 5-HT receptors, respectively. Each mechanism may contribute independently to regulation of the sympathetic outflow.


Subject(s)
5-Hydroxytryptophan/pharmacology , Clonidine/pharmacology , Spinal Cord/drug effects , Sympathetic Nervous System/drug effects , Animals , Cats , Dose-Response Relationship, Drug , Neural Pathways/drug effects , Receptors, Adrenergic/drug effects , Spinal Cord/physiology
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