вход по аккаунту


Evidence for a Уdying-backФ gliopathy in demyelinating disease.

код для вставкиСкачать
16. Laterre MEC: Syndrome spinal anterieur par embolies multiples du tissu fibrocartilagineux.
Rev Neurol (Paris) 106:68517. Lvovskiy
i90, 1962AM: Embolism of the spinal vessels by tissues of the
intervertebral discs. 2 Neuropathol Psikhiatr Korsakov
8: 1151-1 157. 1969
18. Naiman JL, Donohue WL, Prichard JS: Fatal nucleus pulposus
embolism of spinal cord after trauma. Neurology (Minneap)
11:83-87, 1961
19. Ogata J, Feigin I: Arteriovenous communications in the
human brain. J Neuropathol Exp Neurol 31:519-525, 1972
20. Pass DA: Posterior paralysis in a sow due to cartilaginous emboli in the spinal cord. Aust Vet J 54100-101, 1978
21. Peiffer J, Wenig CH, M a d e E: Akutes Querschnittssyndrom
durch Embolien von Nucleus-pulposus-Gewebe. Dtsch Med
Wochenschr 101:583-586, 1976
22. Roitzsch E: Die Faserknorpelembolie der Ruckenmarksgefasse-eine seltene Ursache der Myelomalacie. Zentralbl
Allg Pathol 119:lOO-103, 1975
23. Salter RB, Gross AE, Hall JH: Hydrocortisone arthropathy.
An experimental investigation. Can Med Assoc J 97:374-377,
24. Taylor HW, Vandevelde M, Firth EC: Ischemic myelopathy
caused by fibrocartilaginous emboli in a horse. Vet Pathol
14:479-481, 1977
25. Vuia D, AIexianu M: Arteriovenous shunt in the spinal cord
circulation. Acta Neurol Scand 45:216-223, 1969
26. Worthman RP: The longitudinal vertebral venous sinuses of
the dog. I. Anatomy. Am J Vet Res 17:341-348, 1956
27. Zaki FA, Prata RG, Kay WJ: Necrotizing myelopathy in five
great danes. J Am Vet Med Assoc 165:1080-1084, 1974
28. Zaki FA, Prata RG: Necrotizing myelopathy secondary to
embolization of herniated intervertebral disc material in the
dog. J Am Vet Med Assoc 169:222-228, 1976
29. Zaki FA, Prata RG, Werner LL Necrotizing myelopathy in
the cat. J Am Vet Med Assoc 169:228-229, 1976
Evidence for a
“Dying-Back” Gliopathy
in Demyelinating Disease
K. ~ ~ dMB,
~ ~ ic h~ , ,
and Edward S. Johnson, MD#
Recurrent demyelination was produced in mice by
Cuprizone administration. During the second course of
Cuprizone, the animals showed greater resistance to
the toxin and demyelination occurred slowly and was
complete only after prolonged periods. The earliest
changes in oligodendrocytes occurred in the most distal processes, the inner cytoplasmic tongues, which
showed degenerative changes 3 to 4 weeks before degeneration of the oligodendrocyte cell bodies or demyelination occurred. The results show for the first
time that in demyelinating disease, a “dying-back
process similar to that described in axonal disease can
affect the oligodendrocyte.
Ludwin SK, Johnson ES: Evidence for a
“dying-back” gliopathy in demyelinating disease.
A n n Neurol 9:301-305, 1981
A unique feature of cells in the nervous system is the
length of cell processes arising from the perikaryon.
Although this is most noticeable in neurons, where
the axons may extend up to 1 m from the cell body,
oligodendrocyte processes project from the cytoplasm and can myelinate axons at distances far exceeding the diameter of the perikaryon. This capability places an increased metabolic and transport
load on the cells. Of great importance in recent years
has been the definition of the “dying-back’’ neuropathies, or axonopathies-a group of experimental
and clinical conditions characterized by the inability
of the cell to maintain the metabolic processes necessary to support the distal end of the axon [6, 15, 161.
As a consequence, the axon degenerates from the periphery centrally, even though the cell body itself
may remain intact for a long time. The most distal
part of the oligodendrocyte, analogous to the axon
terminal of the neuron, is the inner cell tongue between the myelin sheath and the axon [4, 101. We
From the Department of Pathology (Neuropathology), Queen’s
University, and the Department of Pathology, Kingston General
Hospital, Kingston, Ont, Canada K7L 3N6.
*Present address: Department of Pathology, University of Alberta,
Edmonton, Aha, Canada T6G 2G3.
Received June 17, 1980, and in revised form Sept 12. Accepted
for publication Sept 13, 1980.
Address reprint requests to Dr Ludwin, Department of Pathology
(Neuropathology), Queen’s University, Kingston, Ont, Canada
K7L 3N6.
1981 bv the American Neuroloeical
describe for the first time a dying-back phenomenon
in oligodendrocytes using a model of recurrent toxin
administration. This observation may be of importance in understanding the pathogenesis of demyelinating diseases of uncertain cause.
Cuprizone (bis-cyclohexanone oxaldihydrazone) is
a copper-chelating agent known to cause abnormal
dimers of mitochondrial D N A [8] and to decrease
mitochondrial respiration; although it is toxic to liver
cells [17] and other systemic tissues, in the brain only
oligodendrocytes are susceptible [2, 3, 12, 131. Susceptibility of oligodendrocytes is strain specific [5, 7 ,
12, 131, but within these strains only about 20 to
50% of mice were able to resist the systemic toxic
effects and survive to show demyelination [12, 131.
Strains that are totally resistant to systemic toxic effects also fail to show demyelination. Previous experiments [2, 3, 12, 131 demonstrated that mice
subjected to Cuprizone in the diet consistently developed demyelination of the superior cerebellar
peduncles. Necrosis of oligodendrocytes started
shortly after the animals were placed on the diet (2 to
3 weeks) and involved all parts of the cell simultaneously, including the inner tongue. Demyelination
followed this necrosis, occurred relatively acutely ( 4
to 5 weeks), and was usually complete by 6 weeks.
After the mice were returned to normal diets, remyelination of almost all axons by oligodendrocytes
occurred. In the current project the experimental
protocol was manipulated to examine the effects on
the oligodendrocyte of a more chronic toxic state.
Materials and Methods
Weanling male Swiss mice (Biobreeding strain) were
placed o n a diet of 0.6% Cuprizone for 8 weeks to produce
demyelination [12, 131. They were then returned to a normal diet for 9 weeks and remyelination was allowed to proceed. Selected animals were perfused with glutaraldehyde
through the left ventricle, and remyelination in the
superior cerebellar peduncle was checked by electron microscopy as described previously [12, 131. The rest of the
animals with remyelinated peduncles, now 19 or 20 weeks
old, represented 20 to 50% of the original series and comprised those animals that were relatively resistant to systemic toxicity. These mice were subjected to a diet of 1%
Cuprizone, a dose known to cause demyelination in adult
mice (personal observations). At weekly intervals the animals were perfused, their superior cerebellar peduncles
were prepared for electron microscopy [12, 131, and the
process of recurrent demyelination was examined.
The striking finding in this experiment was the decreased tempo of demyelination. Whereas in the
previous studies oligodendrocytes underwent degenerative changes simultaneously in the cell body
and inner tongues as early as 2 weeks, in the present
302 Annals of Neurology Vol 9 No 3 March 1981
experiments on recurrent demyelination, changes
were seen only after 3 or 4 weeks on the diet. The
changes were restricted to the inner cytoplasmic
tongues (Fig 1) and consisted of swelling and enlargment with loss of recognizable cytoplasmic features
such as microtubules. Formation of dense bodies and
vacuoles with debris, degeneration of mitochondria,
and an increase in sequestered axonal profiles within
the inner tongue were common features. At this stage
the myelin sheaths, although thin because of previous
remyelination, were otherwise normal and intact, and
the cell bodies of the oligodendrocytes showed no
evidence of degenerative changes (Fig 2A). After
about 6 weeks on the diet, degenerating oligodendrocytes could be seen. Demyelination started
around the sixth week with the formation of intramyelinic vacuoles and subsequent phagocytosis of
myelin by macrophages. It proceeded slowly, occurred in focal areas, and was not complete until 11
weeks (Fig 2B).
It is unclear why the tempo of demyelination was
decreased in this experiment. In view of the marked
variation in resistance to Cuprizone among species
and individuals, however, it seems reasonable to assume that the animals used for recurrent demyelination may have developed further resistance to Cuprizone, having previously survived an 8-week course.
The results clearly demonstrate for the first time
that the oligodendrocyte can undergo a dying-back
process, with degeneration starting in the inner-cell
most distal part-and
eventually progressing proximally to involve the perikaryon, with resulting demyelination. A clear metabolic derangement caused by the Cuprizone affects the mitochondria and is analogous to the types of metabolic
changes involved in the production of dying-back
neuropathies [6, 15, 161. In the peripheral nerve in
the model of hind limb paralysis affecting the Syrian
hamster [9], inner tongues of Schwann cells have
been shown to be affected first before the myelin
breaks down, and a similar mechanism has been
postulated to be present in this situation.
The relevance of this finding to clinical disease is
speculative at this stage, but the process could operate in certain human demyelinating conditions. In
experimental vitamin BI2deficiency [ 11, demyelination occurs following the metabolic abnormality,
before axonal changes start, and in the absence of
recognizable changes in the oligodendrocytes. It is
tempting to postulate that a dying-back process may
be occurring in the oligodendrocytes.
In clinical subacute combined deficiency, Pant et a1
[ 141 were unable to determine whether the primary
pathological process affected myelin or axons. How-
Fig 1. (A)Dense bodies, vacuoles, and debris are present in an
expanded granular inner cytoplasmic tongue from an animal
on a recurrent course of Cuprizone for 4 weeks. Note Previously
remyelinated thin myelin sheaths, which ure otherwise normal.
(X28,500 before 25 % reduction.) (B) Expanded inner tongue
containing dense bodies, vacuoles with granular material, and
increased sequestration of axonal profiles, from another animal
on a recurrent 4-week course of Cuprizone. Thin myelin
25% reduction.}
sheaths are again seen. ( ~ 1 8 , 3 0 before
Brief Communication: Ludwin and Johnson: “Dying-Back” Gliopathy
ever, they found that myelin seemed to be affected
more than the axons, and they postulated that the
disease might be caused by an abnormality of the
oligodendrocyte s.
In this respect, the recent report by Itoyama et a1
[ 111 is of great interest. During examination of multiple sclerosis plaques they found that myelinassociated glycoprotein (MAG) was lost to a much
greater extent than myelin or myelin basic protein.
Since MAG in adults is restricted to the adaxonal
space and inner tongue, this finding may imply that
oligodendrocyte changes in the inner tongue precede
304 Annals of Neurology
Vol 9 No 3
March 1981
F i g 2. (A) Normal oligodendrocytes,showing no degenerative
changes,from another animal on a recurrent 4-week course of
Cuprizone. Note the inner tongue changes in the axon seen i n
the lower l e f t . { x 10,300 before 25 % reduction.) ( B ) Demyelination of the superior cerebellar peduncle after 11 weeks on a
second course of Cuprizone. ( x 10,500 before 25 5% reduction.)
myelin loss in multiple sclerosis. Further clinical and
experimental studies are needed to determine the
importance of dying-back gliopathy in nervous system disease.
Supported by Grant MA 5818 from the Medical Research Council
of Canada.
The authors thank M. Chiong and P. Scilley for excellent assistance.
1. Agamanolis DP, Victor M, Harris JW, et al: An ultrastructural
study of subacute combined degeneration in the spinal cord in
vitamin B 12-deficient rhesus monkeys. J Neuropathol Exp
Neurol 37:273-299, 1978
2. Blakemore WF: Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in
Cuprizone intoxication in mice. J Neurocytol 1:413-426,
3. Blakemore WF: Demyelination of the superior cerebellar
peduncle in the mouse induced by Cuprizone. J Neurol Sci
20~63-72, 1973
4. Bunge RP: Glial cells and the central rnyelin sheath. Physiol
Rev 48:194-251, 1968
5. Carlton WW: Spongiform encephalopathy induced in rats and
guinea pigs by Cuprizone. Exp Mol Pathol 10:274-287, 1969
6. Cavanagh JB: The “dying-back” process. A common denominator in many naturally occurring and toxic neuropathies. Arch Pathol Lab Med 103:657-664, 1979
7. Elsworth S, McHowell J: Variation in the response of mice to
Cuprizone. Res Vet Sci 14385-387, 1973
8. Guerineau M, Guerineau S, Gosse C: Abnormal rnitochondrial DNA molecules in megamitochondria from Cuprizone-treated rats. Eur J Biochem 47:313-319, 1974
7. Hirano A: A possible mechanism of demyelination in the Syrian hamster with hindleg paralysis. Lab Invest 38:115-121,
10. Hirano A, Dernbitzer HM: A structural analysis of the myelin
sheath in the central nervous system. J Cell Biol 34:555-567,
11. Itoyama Y ,Sternberger N H , Webster HdeF, et al: Immunocytochemical observations on the distribution of
myelin-associated glycoprotein and myelin basic protein in
multiple sclerosis lesions. Ann Neurol 7: 167-177, 1980
12. Ludwin SK: Central nervous system demyelination and remyelination in the mouse. An ultrastructural study of Cuprizone toxicity. Lab Invest 39:597-612, 1978
13. Ludwin SK: An autoradiographic study of cellular proliferation in remyelination of the central nervous system. Am J
Pathol 75:683-690, 1979
14. Pant SS, Asbury AK, Richardson EP: The myelopathy of pernicious anemia. Acta Neurol Scand 44:suppl 35:7-36, 1968
15. Prineas J: The pathogenesis of dying back polyneuropathies:
11. An ultrastructural study of experimental acrylamide intoxication in the cat. J Neuropathol Exp Neurol 28:598-62 1,
16. Spencer PS, Schaumburg H H : Central-peripheral distal
axonopathy-the pathology of dying-back polyneuropathies.
In Zimmerman H M (ed): Progress in Neuropathology. New
York, Grune & Stratton, 1776, vol 3, pp 253-295
17. Suzuki K, KikkiwaY: Status spongiosus of C.N.S. and hepatic
changes induced by Cuprizone (biscyclohexanone oxaldihydrozone). Am J Pathol 54:307-321, 1969
Usefulness of
Electroph ysiological
Studies in the Diagnosis of
Lumbosacral Root Disease
Richard F. Tonzola, MD, Albert A. Ackil, MD,
Bhagwan T. Shahani, MD, and Robert R . Young,
Clinical, electrophysiological, and myelographic findings were correlated in 57 patients with the clinical
diagnosis of lumbosacral root disease. Conventional
motor and sensory (including sural nerve) conduction
studies were normal in all patients. Electromyography,
late response studies in different muscles of the lower
extremity, the myelogram, or combinations of these
tests were abnormal in 44 patients (77%). Of 36 patients (63%) with abnormal myelograms, 14 had normal electrophysiological studies. Twenty-nine (5 1%)
had an abnormal electrophysiological finding; although 8 patients in this group had a normal myelogram, 2 had an abnormal discogram and 1 an abnormal
epidurogram. Electrophysiological or myelographic
findings, in some cases both, correlated well with clinical signs and symptoms in 41 patients (72%). H-reflex
and F response studies, when abnormal, helped in localizing a lesion in the appropriate root distribution.
Tonzola RF, Ackil AA, Shahani BT, Y o u n g R R :
Usefulness of electrophysiological studies i n t h e
diagnosis of lumbosacral root disease.
A n n Neurol 9:305-308, 1981
Lumbosacral disc-root disease causing pain, weakness, sensory disturbances, or sphincter dsyfunction
is a common and costly medical problem. Accurate
diagnosis is not always possible. A prospective study
was undertaken to correlate clinical, electrophysiological, and myelographic findings in patients
who presented with a suspected clinical diagnosis
of lumbosacral root disease [8]. The purpose of the
study was to assess our diagnostic accuracy and to see
if newer electrophysiological techniques (H-reflex
and F responses) aided our other laboratory studies.
Thus, both the clinical evaluation and the electrophysiological studies provided information on
anatomical abnormalities.
From the Clinical Neurophysiology Laboratories, Massachusetts
General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 021 14.
Received Aug 11, 1980, and in revised form Oct 3. Accepted for
publication Oct 4 , 1780.
Address reprint requests to Dr Shahani.
0364-5 134/81/030305-04$01.25 @ 1980 by t h e American Neurological Association
Без категории
Размер файла
774 Кб
уdying, gliopathy, evidence, disease, demyelination, back
Пожаловаться на содержимое документа