close

Вход

Забыли?

вход по аккаунту

?

Cerebellar degeneration in the rat following rapid correction of hyponatremia.

код для вставкиСкачать
Cerebellar Degeneration in the Rat Following
Rapid Correction of Hyponatremia
B. K. Kleinschmidt-DeMasters, MD, and Michael D . Norenberg, M D
Degenerative lesions in the superior vermis of the cerebellum were produced in 8 of 14 rats that were first made
hyponatremic for three days with vasopressin and water and then given hypertonic saline. Within the superior
vermis, lesions were predominantly localized to the crests of the folia. These lesions were characterized by demyelination of folial white matter and necrosis of granule cells at the junction with the white matter. In severe degeneration, the entire width of the granule cell layer was involved and Purkinje cell necrosis was found as well. Hyponatremia alone or administration of hypertonic saline to normonatremic rats did not result in lesions. Because of the
topographical and histopathological similarity of these lesions to those of alcoholic cerebellar degeneration, our
findings raise the possibility of a contribution of electrolyte-induced injury to the pathogenesis of alcoholic cerebellar degeneration.
Kleinschmidt-DeMasters BK, Norenberg MD: Cerebellar degeneration in the rat
following rapid correction of hyponatremia. Ann Neurol 10:561-565, 1981
Alcoholic cerebellar degeneration (ACD) is characterized by degeneration of the superior vermis and
adjacent folia of the cerebellar hemispheres, with essentially all neuronal elements of the cerebellar cortex involved. Crests rather than depths of the folia
seem predominantly affected [ 11. Clinically, ACD is
manifested by ataxia of gait and incoordination of the
lower extremities evolving over a varying period of
time and is often followed by years of stability. The
cause of ACD is unknown although nutritional factors, particularly thiamine deficiency [ 1, 26, 271, and
the direct effects of alcohol [2, 5, 7, 8, 131 have generally been implicated.
A recent analysis of a group of patients with central
pontine myelinolysis, a condition also most commonly seen in the alcoholic patient, disclosed that a
rapid rise in serum sodium from a hyponatremic
baseline preceded the clinical expression of the disorder [ 151. To test the view that a rapid rise in serum
sodium may be causal in central pontine myelinolysis,
rats were made hyponatremic and then hypertonic
saline was administered. The rats displayed symmetrical, predominantly demyelinative lesions in the
cerebral cortex, hippocampus and its fimbria, corpus striatum, external capsule, anterior commissure, thalamus, and brainstem tegmentum [ 141.
Noteworthy was the presence of cerebellar lesions,
chiefly confined to the superior vermis. This report
details the morphological findings in the cerebellum
of these animals and raises the possibility of a con-
tribution of electrolyte-induced
pathogenesis of ACD.
injury
to the
From the Laboratory of Neuropathology, Veterans Administration
Medical Center, and the Department of Pathology, University of
Colorado Health Sciences Center, Denver, CO.
Received Feb 13, 1981. Accepted for publication Apr 11, 1981.
Materials and Methods
Details of the methodology and controls have been published elsewhere [ 141. Briefly, experiments were performed on 14 adult male Sprague-Dawley rats. Hyponatremia was induced by subcutaneous injection of 0.5 unit
of vasopressin tannate (Parke-Davis) per 100 gm of body
weight, followed by an intraperitoneal injection of 2.5%
dextrose in water equal to 5% of the body weight [9].Vasopressin and 2.5% dextrose in water were given twice daily
on days 1 and 3 and once o n day 2. O n days 4 and 5, animals received 2 ml per 100 gm of body weight of hypertonic saline (1 M) as a single intraperitoneal injection.
Laboratory chow and water were restricted until day 6.
Animals that survived the experiment were killed by overexposure to ether on days 8 to 10. Control animals consisted
of 6 rats made hyponatremic for 8 days, 6 rats given only
the same amount of hypertonic saline intraperitoneally for
2 days and killed on day 5 , and 6 normal untreated rats.
Brains were fixed in 10% formalin and processed routinely
for light microscopy. Paraffin sections were stained with
hematoxylin and eosin, Nissl, Lux01 fast bludperiodic
acid-Schiff, and the Bodian method.
Results
Vasopressin and 2.5% dextrose in water induced a
step-wise decrement in serum sodium to 106.3 -+
11.6 mEq per liter (mean f SD) at the end of 3 days
(normal, 139.2 k 2.6). During this phase, occasional
animals showed mild lethargy, while most remained
Address reprint requests to Dr Norenberg, Laboratory of
Neuropathology, Veterans Administration Medical Center, 1055
Clermont St, Denver, C O 80220.
561
F i g 1 . Midsagittal section of rat cerebellum. In the superior
vermis, degeneration i.r indicated by pallor nf the granule cell
layer. Note tendency of the lesion t o inadtie crests nf folia.
(Ni.rsI: x l S before 10%)reduction.)
clinically normal. After the hypertonic saline injection on day 4,most animals began to show decreased
activity. By days 5 and 6 they developed an ataxic
gait, paresis of hind limbs, adduction of forelimbs, and
ruffled fur. Animals displayed little spontaneous activity, although bursts of hyperactivity and hyperirritability were occasionally noted with handling. Four
rats remained almost clinically normal throughout
the experiment. Five animals died between days 5
and 7. The serum sodium value at sacrifice for animals that survived to days 8 through 10 was 15 1.8 +
5.0 mEq per liter.
Eight of 14 rats had lesions in the superior vermis
of the cerebellum. These lesions consisted of a combination of necrosis and demyelination predominantly at the crests of the folia (Fig 1). The white
Fig 2. (A)Superior t8ermi.r shows demyelination offolial white
matter and macrophage injiltratiow (large arrow). Normal
deep white matter (WM)for comparison is seen below. The
molecular luyer i.r spongy (small arrows). (Luxnlfast bluet
periodic uiid-Scbijjf; x75 .) ( B ) Adjment section demonstrates
relatif'eprrserz'ation of axons in deniyelinated area (arrow).
(Bndian; ~ 7 5 . 1
562 Annals of Neurology
Vol 10 No 6 December 1981
F i g 3 . Granule cell necrosis (large arrows) is seen at the junction with the macrophage-laden white matter (WM). Note
that where the full width of the granule cell layer is pyknotic
(on the right), adjacent Purkinje cells show early necrosis
(small arrows). ( H 6 E ; ~ 6 4 . )
matter of the folia demonstrated a loss of myelin,
infiltration by foamy macrophages (Fig 2A), and relative preservation of axons (Fig 2B). Granule cells,
especially those at the junction with the white matter,
were marked by nuclear pyknosis (Fig 3). In severe
degeneration the entire width of the granule cell
layer was necrotic (Fig 3). Purkinje cells were well
preserved in milder cases but were frequently necrotic (eosinophilic change) in lesions in which the entire
width of the granule cell layer was involved (Fig 3).
The molecular layer showed pallor, spongy change
(Fig 2A), and occasional infiltration by macrophages.
Three rats that died early had additional lesions in
adjacent cerebellar folia. No lesions were found in
hyponatremic control rats or in normal rats given the
same amount of saline solutions as the experimental
rats.
Discussion
The cause of ACD is unknown. In their original report on the disorder in 1959, Victor et al [26] concluded that nearly all their patients were malnourished or might have been malnourished during
the period preceding the onset of symptoms. Since
then, nutritional factors, especially thiamine deficiency, have been widely accepted as the cause of
ACD. Corroboration of this view comes from the
frequent association of ACD with Wernicke’s disease, a disorder caused by thiamine deficiency. In the
monograph by Victor et a1 [25], 4 of 11 patients
with ACD were reported to have Wernicke’s disease,
while 25 of 63 patients with Wernicke’s disease had
ACD.
Despite assertions that nutritional factors are
causative in ACD, surprisingly few cases have been
published in which malnutrition was present without
concomitant alcoholism. A case frequently cited as
proof of a nutritional cause for ACD was reported by
Mancall and McEntee [17]. The patient was an 18year-old, nonalcoholic man with protracted vomiting
secondary to congenital duodenal bands who developed ataxia of gait, nystagmus, and internuclear
ophthalmoplegia. At autopsy, lesions of Wernicke’s
Kleinschmidt-DeMasters and Norenberg: Cerebellar Degeneration and Serum Sodium
563
disease were found as well as a softened, hemorrhagic
superior vermis and anterior cerebellar hemispheres.
This case, however, is unusual inasmuch as lesions of
the caudate and putamen were also described, areas
seldom, if ever, affected in Wernicke’s disease [2 1,
221. One wonders if an additional disease process
may have been present that could account for the patient’s striatal and cerebellar lesions.
Thus, the evidence for thiamine deficiency causing
ACD remains circumstantial. The relationship between Wernicke’s disease and ACD may simply be
fortuitous, with some other common factor possibly
playing a more important etiological role. Several
authors have specifically stated that they thought nutrition had been adequate in their patients with ACD
[3, 181. Additionally, the histopathology of Wernicke’s disease differs from that of ACD. Unlike the
lesions of Wernicke’s disease, the cerebellar lesions
of ACD do not consist of endothelial and microglial
proliferation with relative preservation of neurons.
Instead, the changes are of a chronic, nonspecific degenerative type in which neurons are particularly affected [26]. While the different histopathology in the
two sites may be caused by temporal factors [17],
acute and subacute phases of ACD are seldom recognized pathologically and the evolution of the disease
is not understood.
Experimental attempts to produce convincing
cerebellar degeneration by thiamine deficiency have
been unsuccessful [ l , 10, 281. Early studies by Swank
and Prados [23] on the production of cerebellar lesions in pigeons showed subtle axonal changes with
the use of metallic-impregnation methods which are
difficult to interpret. More recent work by Collins
and Converse [6] showed no cerebellar alterations at
the light microscopic level but did demonstrate
minor degenerative changes in dendrites and glycogen accumulation in cerebellar astrocytes by electron
microscopy. Studies comparing the cerebellar vermis
to the rest of the cerebellum in this regard were not
undertaken, and the importance of these findings
remains uncertain.
The direct effect of alcohol as a causative agent in
ACD has been considered by some [8, 13, 19, 241.
Except for the case of Mancall and McEntee [ 171 and
possibly one other, reported by Podacar (referred to
by Adams [l]),no further examples of unequivocal
AC D in nonalcoholic patients have been published to
our knowledge. Experimental work attempting to
produce histopathological lesions similar to A C D in
animals fed alcohol has thus far been unsuccessful [ 1,
10, 16, 281.
Besides excessive ethanol consumption and malnutrition, serum electrolyte derangements are frequent in patients with alcoholic liver disease [4, 11,
12, 20, 29, 301. Interestingly, even in the one nonalcoholic patient with cerebellar degeneration reported
by Mancall and McEntee, electrolyte derangements
may have been present, as their patient had protracted vomiting. Unfortunately, their report did not
include serum electrolyte values. The unusual similarity between the topography of the abnormalities in
our experimental animals and that seen in ACD
raises the possibility that rapid serum electrolyte
fluctuations may be involved in the pathogenesis of
ACD. How electrolyte shifts bring about these morphological changes, especially their localization to the
superior vermis, is not known.
Supported by the Research Service of the Veterans Administration.
The technical ssistance of Katherine P. Bell and Martin Wallace
and the photography by Martin Kondreck are gratefully acknowledged.
References
1. Adams RD: Nutritional cerebellar degeneration. In Vinken
PJ, Bruyn GW (eds): Handbook of Clinical Neurology.
Amsterdam, North-Holland, 1976, vol 28, pp 271-283
2. Allsop J, Turner B: Cerebellar degeneration associated with
chronic alcoholism. J Neurol Sci 3:238-258, 1966
3. Ames F: Six cases of cerebellar degeneration associated with
chronic alcoholism. S Afr Med J 35:152-154, 1961
4. Beard JD, Knott DH: The effect of alcohol on fluid and electrolyte merabolism. In Kissin B, Begleicer H (eds): The Biology of Alcoholism. New York, Plenum, 1971, vol 1, pp
353-376
5. Chodoff P, Auth T, Toupin H: Parenchymatous cortical cerebellar atrophy. J Nerv Ment Dis 123:376-381, 1956
6. Collins GH, Converse WK: Cerebellar degeneration in
thiamine-deficient rats. Am J Pathol 58:219-233, 1970
7. Decker JB, Wells CE, McDowell F Cerebellar dysfunction
associated with chronic alcoholism. Neurology (Minneap)
9:361-366, 1959
8. Deitrich RA: Plasmalogen content of cerebellum samples
from alcoholic and non-alcoholic humans. Alcoholism
1~57-59, 1977
9. Dila CJ, Pappius HM: Cerebral water and electrolytes. An experimental model of inappropriate secretion of anti-diuretic
hormone. Arch Neurol 26:85-90, 1972
10. Dreyfus PM: Diseases of the nervous system in chronic alcoholics. In Kissin B, Begleiter H (eds): The Biology of Alcoholism. New York, Plenum, 1974, vol 3, pp 272-277
11. Epstein M: Deranged sodium homeostasis in cirrhosis. Gastroenterology 76:622-63 5, 1979
12. Hilden T , Svendsen TL: Electrolyte disturbances in beer drinkers. Lancet 2:245-246, 1975
13. Kiessling KH: The occurrence of acetaldehyde in various
parts of rat brain after alcohol injection, and its effect on
pyruvate oxidation. Exp Cell Res 27:367-368, 1962
14. Kleinschmidt-DeMasters BK, Norenberg MD: Rapid correction of hyponatremia causes demyelination: relation to central
pontine myelinolysis. Science 21 1:1068-1070, 1981
15. Leslie KO, Robertson AS, Norenberg MD: Central pontine
myelinolysis: an osmotic gradient pathogenesis. J Neuropathol Exp Neurol 39:370, 1980
564 Annals of Neurology Vol 10 No 6 December 1981
16. Lhermitte J, Ajuriaguerra J, Garnier L Les lesions du syst6me
nerveux dans I’intoxication alcoolique exp6rimentale. C R SOC
Biol (Paris) 128:386-388, 1938
17. Mancall EL, McEntee WJ: Alterations of the cerebellar cortex
in nutritional encephalopathy. Neurology (Minneap) 15:
303-313, 1965
18. Martin EA: Alcoholic cerebellar degeneration: a report of 3
cases. J Ir Med Assoc 56:172-175, 1965
19. Mello NK, Mendelson JH: Alcohol and human behavior. In
lversen LL, Iversen SD, Snyder SH (eds): Handbook of
Psychopharmacology. New York, Plenum, 1978, vol 12, pp
235-317
20. Reynolds TB: Water, electrolyte, and acid-base disorders in
liver disease. In Maxwell MH, Kleeman CR (eds): Clinical
Disorders of Fluid and Electrolyte Metabolism. New York,
McGraw-Hill, 1972, pp 1251-1265
21. Riggs HE, Boles RS: Wernicke’s disease: a clinical and
pathological study of 42 cases. Q J Stud Alcohol 5:361-370,
1944
22. Rinehart JF, Friedman M, Greenberg LD: Effect of experimental thiamine deficiency in the nervous system of the
Rhesus monkey. Arch Pathol 48:129-139, 1949
23. Swank RL, Prados M: Avian thiamine deficiency. 11.
24.
25.
26.
27.
28.
29.
30.
Pathological changes in the brain and cranial nerves and their
relation to clinical behavior. Arch Neurol Psychiatry 47:
97-131, 1942
Truitt EB Jr, Walsh MG: The role of acetaldehyde in the actions of alcohol. In Kissin B, Begleiter H (eds): The Biology
of Alcoholism. New York, Plenum, 1971, vol 1, pp 161-195
Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff
Syndrome. Philadelphia, Davis, 1971, pp 95, 140-141
Victor M, Adams RD, Mancall E L A restricted form of cerebellar cortical degeneration occurring in alcoholic patients.
AMA Arch Neurol 1:579-688, 1959
Victor M, Ferrendelli JA: The nutritional and metabolic diseases of the cerebellum. Clinical and pathological aspects. In
Fields WS, Willis WD (eds): The Cerebellum in Health and
Disease. St Louis, Warren H . Green, 1970, chap XVI, pp
4 12-449
Wallgren H , Barry H 111: Actions of Alcohol. Amsterdam,
Elsevier, 1970, pp 479-618
Warren SE, Mitas JA 111, Swerdlin AHR: Hypernatremia in
hepatic failure. JAMA 243:1257-1260, 1980
Wilkinson SP, Blendis LM, Williams R: Frequency and type of
renal and electrolyte disorders in fulminant hepatic failure. Br
Med J 1:186-189, 1974
Kleinschmidt-DeMasters and N o r e n b e r g : Cerebellar Degeneration and Serum Sodium
565
Документ
Категория
Без категории
Просмотров
0
Размер файла
571 Кб
Теги
rapid, corrections, hyponatremia, cerebellar, degeneration, following, rat
1/--страниц
Пожаловаться на содержимое документа