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Cerebral hypoperfusion in the sudden infant death syndrome brainstem gliosis and vasculature.

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Cerebra1 Hypoperfusion
in the Sudden Infant Death Syndrome?
Brainstem Gliosis and Vasculature
S. Takashima, MD, D. Armstrong, FRCP(C), L. Becker, FRCP(C),
and C. Bryan, FRCP(C)
~~~
Gliosis is increased i n the respiratory control area of the brainstem i n victims of sudden infant death syndrome (SIDS),
as it is i n infants who have d i e d of congenital heart disease. In the latter, the lesions appear to result f r o m hypoxia or
ischemia, and studies of the brainstem microvasculature of SIDS victims indicated a close relationship between the
gliosis and adjacent vasculature. It is postulated that cerebral hypoperfusion may p l a y a role in SIDS.
Takashima S, Armstrong D, Becker L, et al: Cerebral hypoperfusion in the sudden infant death syndrome?
brainstem gliosis and vasculature. Ann Neurol 4:257-262, 1078
Failure of respiratory control m a y be a major factor
i n the pathogenesis of s u d d e n infant death s y n d r o m e
(SIDS). Studies o f SIDS victims have revealed subtle
tissue changes that may reflect reactions to chronic
hypoxia [ 7 , 13-17, 2 2 , 231 a n d physiological respiratory abnormalities such as s l e e p apnea [19, 201.
N a e y e [ 141 reported finding gliosis i n the reticular
formation region of the brainstem in such patients.
We studied the d e v e l o p m e n t and specific distribution of gliosis i n t h e medulla, pons, a n d midbrain in
SIDS victims and in infants w h o died from cyanotic
and noncyanotic congenital heart disease (CHD).
Materials and Methods
Brains of infants less than 12 months old were studied for
gliosis. For SIDS we examined the brains of 46 infants ( 2 3
term and 23 premature). Criteria for selection were a history of sudden and unexpected death and findings at necropsy consistent with a diagnosis of SIDS (groups C and D
in the classification of A1 Barzanji et al [ 11). In addition, the
brains of 24 infants who had died from C H D , cyanotic in
12 cases and noncyanotic in the other 12, were studied. As
controls, we examined the brains of 19 infants of matched
age range who had suffered no intracranial hemorrhage,
infarcts, or anoxic changes. They had died from acute infection, from drowning, or in automobile accidents.
Blocks were taken from formalin-fixed midbrain, pons,
and medulla oblongata and were embedded in paraffin for
sectioning. Sections were stained with hematoxylin and
eosin, Luxol fast blue, Mallory’s phosphotungstic acidhematoxylin (PTAH), and Holzer’s stain.
Astrocytes with astroglial fibers (AAF) observed on sec-
From the Departments of Pathology and Respiratory Physiology,
The Hospital for Sick Children, Research Institute, Toronto, Ont,
Canada.
tions stained with PTAH and Holzer stains were counted
(field, -600 p‘), and astroglial proliferation per field was
graded as: no AAF(-), fewer than 5 (+I, 6 to 10 ( + + I , and
more than 11 AAF ( + + + ). In our examination of the
medulla we included the nucleus ambiguus as part of the
medial reticular nuclei and the nucleus retroambigualis as
part of the lateral reticular nuclear group. For large structures (e.g., the olives), the whole was scanned and a representative field was selected for counting.
T h e observer determining the degree of brainstem
gliosis in control brains was unaware of the age of these
infants.
The brainstem vasculature was also studied to determine
whether gliosis had occurred in border zones. Postmortem
cerebral angiography was performed with a colloidal solution of barium sulfate and gelatine o n 12 brains without
cerebral abnormalities; the infants had ranged in age from
32 weeks’ gestation to 12 months of life. Radiography was
done with soft x-rays. Films were taken of the arterial and
venous microvascular architecture of the brainstem.
Sections of brainstem from 7 SIDS victims were prepared with a metal-impregnation technique [ I01 for study
of the vasculature.
Results
Gliosis
H o l z e r and PTAH staining revealed AAF in m o s t of
the brains (Table). Distribution o f the brainstem
gliosis was consistent in each individual brain.
In control brains, numerous AAF were seen i n t h e
s u b e p e n d y m a l and tegmental midline areas of t h e
brainstem and considerable numbers i n regions of
Address reprint requests to Dr Becker, Department of Pathology,
The Hospital for Sick Children, 555 University Ave, Toronto,
Ont, Canada M5G 1x8.
Accepted for publication Mar 6 , 1978.
0364-5134/78/0004-0311$01.25 @ 1978 by S. Takashima
257
Comparison of Brainstem Gliosis (Astrocytes w i t h Astroglial Fibers)
i n ControL Brains, Sudden Infant Death Syndrome, and Congenital Heart Disease
Control
-
Sire
(N = 19)
+
++ +++
4
14
15
10
2
1
2
-
+
++ +++
CHD (N = 24)
SIDS (Premature)
SIDS (Term)
(N)
-
+
++ +++
(N) -
+
++ +++
~
Medulla oblongata
Midline
Paramedian r.n.
Magnocellular r.n.
Lateral r.n.
Solitary n.
Dorsal n. of vagus
Inferior olive n.
Pons
Midline
Middle r.n.
Lateral r.n.
Midbrain
Midline
N. of Darkshevich
Mesencephalic r.n.
Superior colliculus
3
3
7
8
7
3
5
11
10
6
10
2
5
5
13
1
2
3
6
9
4
12
7
2
6
11
3
7
11
2
3
12
6
1
C
21=
15a
14=
9"
1
loa
12"
6
Sa
9"
3"
ISa
20"
(21)
(23)
(23)
(23)
(23)
(23)
(23)
11"
7"
21a
5
2
(21)
(23)
(23)
7
14
12
"Significantly different from controls ( p
Sa
3
3
2
2
3
2
4
6
4
Sn
9"
7'
8"
88
12'
8a
1
3
3
4
4a
28
2
3
2
2
12
14
4
4
7
4
15
(19)
2
2
12
7"
1
(22)
2
13
7
(22)
6
14
1
(21)
1
5
17
2
12a
18"
(23)
(23)
(23)
(20)
(20)
(23)
(22)
(23)
5"
17
5
2
3
10
(15)
(17)
(17)
(16)
6
7
Ya
7
3
1
1
1
3=
21a
12a
9a
4
4
6
6
5
5
5
7
6
1
4
8n
Ila
4
4
16=
2
22
9
9
1
11
5
4
19
8
3
7
1
9
12
4
1"
8
14
2
(23)
(23)
1
2
5
8
4
9"
12'
3
0.01).
SIDS = sudden infant death syndrome; CHD = congenital heart disease; n.
the pontine and inferior olivary nuclei. Only a few
(+) were seen in the reticular formation, the nucleus
solitarius, and the dorsal motor nucleus of the vagus.
The AAF were most dense in the subependymal and
midline areas of the medulla. There appeared to be
no age-related changes in the number of AAF, but
the number of fibers per AAF increased with age.
Gliosis (+) was seen in the subependymal and midline areas in 1 brain (36 weeks' gestation).
Astrocytes with astroglial fibers in the reticular
formation of the medulla and pons, nucleus solitarius, and dorsal motor nucleus of the vagus (Fig 1)
were more dense in SIDS brains than in controls (Fig
2) and were most prominent in the medulla (see the
Table). Diffuse AAF were present in several areas of
the' brainstem, but in sites with slight gliosis they
were recognized chiefly around the vessels. The degree and distribution of AAF did not differ in the
brains of term and prematurely born infants.
In CHD brains, AAF were present in the reticular
formation, nucleus solitarius, and dorsal motor nucleus of the vagus. The degree and distribution of
AAF were n o different in patients with cyanotic or
noncyanotic disease. Astrogliosis was distributed in
the same pattern as in SIDS but was less severe (see
the Table).
Vasculature
Arteriograms of the medulla showed three main
groups of perforating arteries and a few short
branches from the leptomeninges (Fig 3 ) . T h e
paramedian arteries supplied the medial parts of the
medulla, the lateral or short circumferential arteries
258 Annals of Neurology Vol 4
No 3
=
nucleus; r.n.
=
reticular nucleus.
the middle parts of the tegmentum and the lateral
parts of the olivary nuclei and medulla. The posterior
perforating o r long circumferential arteries supplied
the gracile and cuneiform nuclei in the inferior part
of the medulla. In the pons there were two main
groups of perforating arteries and some branches
from the leptomeninges. The paramedian arteries
supplied the medial parts of the pons, and the lateral
perforating or short circumferential arteries supplied
the lateral parts of the tegmentum. The floor of the
fourth ventricle, the nuclei of the tegmentum, the
olivary nuclei, and the pontine nuclei were at
watershed- or end-zones of the perforating arteries.
Venograms of the medulla and pons showed almost the same patterns being produced by the perforating veins as by the perforating arteries. The
upper part of the pons contained a periventricular
vein unaccompanied by an artery.
Vascular stains of medulla and pons showed a fairly
fine network of vessels in the subependymal area.
T h e vascular architecture in this area differed from
that of the tegmentum in that the nuclei appeared to
be at vascular end-zones. The midline of the pons and
medulla near the fourth ventricle was relatively avascular (Fig 4 ) .
Discussion
Fibrillary gliosis in the floor of the fourth ventricle
and the median raphe has been reported in patients
with chronic prolonged hypoxia [4] and cyanotic
CHD [ 3 , 181. It is also seen in brains with no apparent abnormalities [S, 6, 111, as in our controls.
Naeye [ 141 reported brainstem gliosis in infants
September 1978
Fig 1. Brain specimens from SIDS victims. (A) Infant aged2
months. Gliosis is seen in the subependymaland midline areas,
inferior oliaiary nuclei, reticularformation, and other nuclei, including the solitary nuclei anddorsal nuclei of the vagus.
(Holzer; x I O before25 % reduction.)(B) Infant aged 3 months.
Proliferation of astroglia with glialj2e.r ( + +-) i n the dorsal
0
25 9%reduction.)
nuclei of the vagus. (PTAH; ~ 4 0 before
+
Takashima et al: Brainstem Gliosis in SIDS
259
Fig 2. Control brain. The infant had diedfrom acute enterocolitisat age 6 months. No gliosis is apparent in the reticular formation or other nuclei, including the solitary nuclei and
dorsal nuclei of the vagus, but there is gliosis ( + +- +) in the
subependymal area, midline areas, and inferior olivary
nuclei. (Holzer; X 8 0 before 25% reduction.)
Fig 3. Arteriogram of the medulla showing three main groups of
perf rating arteries. (V =fourth ventricle.)
who died of SIDS but did not study its distribution.
In our study, the gliosis was notably increased in
areas crucial to respiratory control-the nucleus of
the solitary tract, the dorsal nucleus of the vagus, the
nuclei ambiguus and retroambigualis, and the reticular formation. These areas are recognized as the primary sites for generation of the respiratory rhythm
[ 121.
Involvement of these specific nuclei raises important questions. Are lesions of the respiratory nuclei
the cause of SIDS? Does astrogliosis of the respiratory nuclei result in chronic hypoxia? Whatever the
mechanism, why does the astrogliosis occur in these
regions?
The finding of similar lesions in infants who have
died of CHD suggests that the brainstem gliosis results from hypoxia o r ischemia. An interaction may
develop in which hypoxia o r ischemia further damages the respiratory nuclei, resulting in greater
hypoxia. O n e can postulate that an unrecognized episode of perinatal asphyxia might disrupt the respiratory control centers, setting up a form of “Ondine’s
curse.” Respiration while awake is largely determined by behavioral demands. During sleep, respiration is dominated by metabolic control [8,91; Baker
260 Annals of Neurology Vol 4 No 3 September 1978
F i g 4. i\.lirvovascukurpatterw in the tegmentum ofthe medulh.
(V=fourth zuntrirle.)
and McGinty [2] showed that it is particularly vulnerable during non-REM sleep. Their suggestion that
the intense reticular activity in REM sleep is akin to
the behavioral input during the awake state accords
with observations by Shannon et a1 [19] that in Ondine's curse, respiration is most depressed during
n o n - E M sleep.
The specificity of the sites of astrogliosis in the
medullary regions may reflect their relationship to
the brainstem microvasculature. The midline gliosis
was in an area with very few, very small vessels. In all
the brains, the subependymal gliosis was found in an
area that contained a network of vessels, probably
dilated capillaries. All other areas of gliosis were at
the arterial end or in border zones, consistent with
our finding of subcortical leukomalacia in vascular
watershed areas of the subcortical white matter of
SIDS victims [2 1, 221. This relationship to the vasculature may indicate that the gliosis is caused by
hypoperfusion rather than by hypoxemia per se. Such
hypoperfusion might occur during the bradycardia
that accompanies apnea.
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