ORIGINAL ARTICLE
Folia Neuropathol.
Vol. 41, No. 4, pp. 209–215
Copyright © 2003 Via Medica
ISSN 1641–4640
Morphology of pineal glands in human foetuses
and infants with brain lesions
Milena Laure-Kamionowska1, Danuta Maślińska1, Krzysztof Deręgowski2,
Elżbieta Czichos3, Barbara Raczkowska1
1Department
of Developmental Neuropathology, Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland
of Reproductive Pathology, Princess Anna Mazowiecka’s University Hospital, Warszawa, Poland
3Department of Clinical Pathomorphology, Institute of Polish Mother Health Centre, Łódź, Poland
2Department
The pineal gland is an organ involved in regulation of homeostasis and body rhythms. It plays an important
role in the growth foetuses and adaptation of newborns to new environmental conditions. The requirements of foetuses and newborns progressively change during development. The purpose of the study was
to evaluate morphological changes of pineal glands in foetuses and infants with brain lesions. The results
of our study showed that parenchyma of developing pineal glands was susceptible to injury in most autopsied foetal and infantile cases. Morphological changes in pineal glands were found in 90% of autopsied
brains but 100% of the cases had infections. The lesions in the pineal included mainly haemorrhagic,
necrotic and cystic changes. In our autopsied foetuses and children, morphological changes in pineal
glands were concomitant with various lesions of brain parenchyma. All results of our study lead to the
conclusion that the pineal gland during its development is very susceptible to injury. The failure of normal
pineal gland development and subsequent impaired production of melatonin decrease resistance of newborns and children to various environmental harmful agents.
key words: pineal gland, morphological changes, foetus, childhood
INTRODUCTION
The pineal gland plays a role of interface between
the cyclic environmental and rhythmic functions of the
vertebrate body. The pineal is considered as one of the
most important components of the vertebrate circadian system because of its rhythmic production of melatonin. Melatonin is a hormone synthesised from tryptophan, and its characteristic circadian rhythm is controlled by light through the regulation of two limiting
Address for correspondence: Milena Laure-Kamionowska, MD
Department of Developmental Neuropathology
Medical Research Centre, Polish Academy of Sciences
ul. Pawińskiego 5, 02–106 Warszawa, Poland
tel: (+48 22) 668 54 34, fax: (+48 22) 668 55 32
e-mail: [email protected]
enzymes N-acetyl-transferase and hydroxyindole-O-methyl-transferase [5, 10]. In addition to the above-mentioned function, the pineal is a prominent secretory organ, which synthesises and secretes a number of exocrine and endocrine substances, such as indoles,
peptides, various enzymes, amino acids and their derivatives, lipids, carbohydrates, and inorganic constituents. The pineal also influences thermoregulation, electrolyte metabolism, haemopoiesis and immune system
function [17]. Melatonin seems to be an integral part of
the immune system, by exerting direct and/or indirect
stimulatory effects on both cellular and humoral immunities [1, 6]. An alteration of pineal gland functions leads
to the inability of the body to adapt to the environmental
variables, including the capacity for proper thermoregulation or resistance to bacterial or viral agents [14].
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The literature shows that the pineal gland is an important neurohormone organ involved in the regulation
of homeostasis and body rhythms. However, still little is
known about the role of pineal gland in human foetuses
and children. The evidence gathered during the past decade indicates that the circadian timing system develops prenatally and the suprachiasmatic nuclei, the site
of a circadian clock, is present by midgestation. After birth,
there is progressive maturation of the circadian system
outputs, with rhythms in sleep-wake and hormone secretion generally developing after 2 months of age [15].
Maternal melatonin crosses the placenta and enters the foetal circulation. Melatonin receptors are widespread in the human foetus and occur from early in foetal development [20]. The foetal pineal gland is capable of a limited melatonin synthesis from the 26th week
of gestation with decreasing value reaching its lowest
level around term. After birth, full term neonates actively secrete melatonin. The highest values were reached
between 4 and 7 years of age with a steady decline
thereafter [3].
The pineal gland has to play an important role in
foetuses with their requirements progressively changing during development and in adaptation of newborns
after birth to new environmental conditions. The developing circadian rhythmically influences human physiology and illness.
The purpose of the study was to evaluate the morphological picture of the pineal lesions appearing in the
routinely neuropathologically diagnosed foetal and infantile injured brains.
MATERIAL AND METHODS
Post-mortem examinations were carried in the Department of Developmental Neuropathology from
1998–2002. The routinely examined foetal and infantile brains were analysed histologically for presence of
changes in the pineal gland. The Department of Reproductive Pathology (Princess Anna Mazowiecka’s University Hospital, Warszawa) and the Department of Clinical Pathomorphology (Institute of Polish Mother Health
Centre, Łódź) supplied the brains and pineal glands. The
study was done on 170 autoptical cases. All brains and
pineal glands were fixed in formalin and embedded in
paraffin. The representative cerebral and pineal slides
were stained with hematoxilin-eosin and cresyl violet,
while the selected pineal gland sections were immunohistochemically stained for glial fibrillary acidic protein
anti GFAP (1:1000) and for vessel visualisation Ulex
Europaeous (UEA 1:100).
RESULTS
Neuropathological examination revealed morphological changes in 90% of the autopsied brains and pineal
glands (Table 1).
In some foetuses (mainly up to 25th week of gestation), morphological pathological changes in the brain
and pineal gland were not found.
The lesions in the pineal glands included mainly
haemorrhagic, necrotic and cystic changes. In the group
of younger cases, haemorrhages and foci of necroses
were predominantly observed. Cystic changes predominated in older newborns and infants.
Table 1. Clinico-pathological data
Age
Pathological changes
in the pineal gland
Pathological changes
in the cerebrum
Clinical data
12–24 GW
Foci of rarefacted and disintegrated tissue,
small perivascular cavities,
haemosiderin granules
Subarachnoideal and
intraventricular haemorrhages
Spontaneous abortions
28–40 GW
Old and recent haemorrhages, foci
of disintegratedtissue surrounded
by haemosiderin granules, parenchymal
necrotic foci, cavities with macrophages,
haemosiderin at the margin of the gland
Anoxic neonatal encephalopathy-cortical and white matter lesions,
periventricular and subarachnoideal
haemorrhages
Maternal placental
abruption and infection,
perinatal asphyxia,
neonatal sepsis, neonatal
hyaline membrane disease,
neonatal heart failure
6–14 mo
Old parenchymal haemorrhages, foci
of parenchymal necrosis, dispersed small
cavities with macrophages,
medium cavities with liquid
Anoxic neonatal encephalopathy-ulegyria and white matter atrophy,
Foci of necrosis in the periventricular
white matter, old haemorrhage
subarachnoideal
Heart failures, pneumonia,
infection-sepsis
2–11 yrs
Large cavities with liquid and macrophages,
foci of parenchymal necrotic tissue,
calcifications
Malformation-defect of migration,
anoxic encephalopathy, petechial
haemorrhages
Persistent pulmonary
hypertension, bone marrow
aplasia, sepsis
GW — gestational weeks; mo — months; yrs — years
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Milena Laure-Kamionowska et al., Foetal and infantile pineal glands
Haemorrhagic changes were found in the parenchyma of the central part of the gland and in the subcapsular region. At the margin of the gland, haemosiderin
granules were present in the leptomeninges and in the
underlying parenchyma. They were observed in cases
with a history of proven subarachnoid haemorrhage.
Recent and old haemorrhages were seen in the central
pineal parenchyma. The haemorrhages were small, petechial “per diapedesim”, as well as, in some cases, multiple massive haemorrhagic foci with haematoidin and
haemosiderin were found (Fig. 1). A dark-yellow pigment
was present in the tissue adjacent to haemorrhages,
mainly in the perivascular spaces. Most of the granules
were localised in the endothelial cells of vessels and in
the perivascular extracellular spaces, but some were
taken up by the cytoplasm of the pineal cells. Haemosiderin granules lined small cavities in a few cases. The
residual stages of haemorrhages were the foci of disintegrated tissue surrounded by dispersed haemosiderin
granules. The haemorrhagic lesions in the pineal parenchyma coexisted with haemorrhagic cerebral lesions.
Necrotic changes found in pineal parenchyma
showed mainly cavity formation. The cavities were variable in distributions and sizes. A disintegrated tissue,
resulting in parenchymal necrotic foci (Fig. 2) and next
in smooth-walled cysts (Fig. 3), was observed in the
central part of the gland. Destroyed macrophages were
enclosed (Fig. 4) inside the minute, often grouped in
clusters cavities. The macrophages linearly settled
along cysts’ walls (Fig. 3), or scattered inside these
cysts (Fig. 5, 6).
Small cavities, occurring mainly at the margin of the
gland in the subcapsular region, were mostly found
along borders of the minute blood vessels. Some of the
cavities were filled with liquid (Fig. 3, 7, 8). The cavities
with liquid had variable sizes from medium to large. The
medium liquid cavities were localised in the central
parenchyma (Fig. 7). The large liquid cavities distinctly
or indistinctly demarcated from the surrounding occupied wide areas of the pineal glands (Fig. 8). The parenchymal border of cysts was normal (Fig. 7) or narrow
(Fig. 8). In a few cases, large cavities were empty, without liquid and macrophages. They were surrounded by
the normal pineal parenchyma, or were localised in the
unstructural “plaques” (Fig. 9).
Variable number of GFAP positive glial fibrils was
observed at the margin of the gland and in the vicinity
of cavities.
Necrotic disorganisation of pineal parenchyma was
seen mainly in the cases with clinical signs of infec-
Figure 1. The haemorrhage in the pineal parenchyma. Cresyl
violet, ¥ 40.
Figure 2. Parenchymal necrotic focus. Cresyl violet, ¥ 60.
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Figure 6. The numerous macrophages scattered inside the
cyst. Hematoxilin-eosin, ¥ 100.
Figure 3. The smooth walled cavity filled with liquid. Cresyl
violet, ¥ 100.
Figure 7. The large liquid cavity occupying a wide area of the
pineal gland. Cresyl violet, ¥ 40.
Figure 4. The cluster of macrophages grouped inside the
minute cavity. Hematoxilin-eosin, ¥ 100.
tion and hypoxia. The necrotic and cystic lesions in the
pineal gland were concomitant with the picture of anoxic encephalopathy in the cerebral and cerebellar
structures.
UEA-positive vessels penetrating pineal parenchyma
from the capsular blood network were stated in the
youngest foetuses, 12–14 gestational weeks old. With
increase in age, the number of capillaries increased
forming an interlobular network.
Small calcifications were detected in the perivascular space in a few infantile cases.
DISCUSSION
Figure 5. Macrophages linearly settled along cyst walls. Hematoxilin-eosin, ¥ 100.
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The results of our study show that parenchyma of
developing pineal gland is susceptible to injury in most
autopsied foetuses and infants. Morphological changes
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Milena Laure-Kamionowska et al., Foetal and infantile pineal glands
Figure 8. The large liquid cavity with narrow parenchymal border. Cresyl violet, ¥ 40.
Figure 9. The empty cyst localised in the unstructural “plaque”.
Cresyl violet, ¥ 40.
were observed in 90% of the brains and pineal glands.
The lesions in the pineal gland included mainly haemorrhagic, necrotic and cystic changes.
The pineal gland is one of the first glands that develops in the body and is clearly distinguishable already at 5–7 gestational weeks and consists of cords
of closely packed, dark, nucleated cells [18]. It is infiltrated by blood vessels in the middle of the third month
of gestation. During this time, the intrapineal vascular
architecture with specific features of the central part
of the gland highly vascularised by large sinusoid capillaries is formed [4]. At that period of development,
we found ischaemic necroses and haemorrhagic foci
in the pineal parenchyma. During gestational development, the human pineal glands undergo a remarkable morphologic evolution. Besides closely packed
dark cells, loosely arranged clear cells appear [11].
About 32 weeks of gestation, well-formed astrocytes
and weakly staining network of their processes appeared in differentiated areas of the pineal gland. Both
astrocytes and their interstitial network of processes
became more prominent with increase in age. Astrocytic endfeet formed a limiting lamina at the periphery
of the gland, and a barrier between perivascular spaces and the pineal parenchyma [13].
In newborns and infants, pineal cysts of various
numbers and sizes were mainly found in our materials suggesting that many of the cysts evolved from
necrotic and haemorrhagic changes. GFAP positive
glial fibres were seen in the vicinity of cavities. Astrocytes play a pivotal role in repairing processes occurring in the injured central nervous system. They provide a structural framework and metabolic support
for the network of other parenchymal cells. Following
injury, astrocytes undergo changes in their motility,
function and production of biological active substances. Their new functions, after transformation, involve
astrogliosis, formation of demarcating glial barrier
around necrotic tissue and finally scaring. In the pineal gland, the inflammatory response to injury characterised by resolution and evacuation of necrotic debris by macrophages is concomitant with small reaction of pineal astrocytes leading to the formation of
cavities. In our study, numerous macrophages were
present in the necrotic foci and inside the cavities of
the destroyed pineal parenchyma. The macrophages/microglia cells in the pineal gland were described
by Jiang-Shieh [8] in adult rats. The author observed
prominent aggregations of these cells around the larger blood vessels. Sato [16] showed that such cells
express MHC class II (Ia) antigen and their numbers
significantly increase in the pineal gland of intoxicated rats.
Lesion of the foetal pineal gland leads to failure of
normal pineal development and subsequent impairment
of production of melatonin. Since melatonin plays an
important role in communication processes between the
neuroendocrine and the immune systems, disturbed
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pineal function may increase the susceptibility of injured
neonates to infections. This can also decrease the adaptive ability of an organism to environmental challenges.
Moreover, melatonin as an antioxidant substance that
protects organisms against free radicals, which are generated under a variety of harmful conditions, including
ischaemia-hypoxia injury.
In our autopsied foetuses and children, morphological changes in pineal glands were concomitant with
brain lesions caused by perinatal asphyxia.
The functional relationship of the pineal gland with
the central nervous system has been well documented
[12]. A properly functioning pineal gland requires intact
efferent and afferent innervating systems. Recent studies have shown that the amount of foetal melatonin
excreted is determined by the development of neural
connections to the pineal gland [2] that can be destroyed
both by pineal and brain lesions. Lesions in some areas
of the nervous system before, during or soon after birth
could lead to a malfunctioning pineal gland.
Melatonin plays a role in the early growth and development of the human brain. Melatonin may act on the
human foetus via the melatonin receptor at a number
of discrete brain sites. The melatonin receptors in the
human foetal brain are localised in the leptomeninges,
cerebellum, thalamus, hypothalamus and brain stem.
In the hypothalamus, specific binding is present in the
suprachiasmatic nuclei as well as in the arcuate, ventromedial and mammillary nuclei. In the brain stem,
specific binding was present in the cranial nerve nuclei
including the oculomotor, trochlear, facial, cochlear
motor and sensory trigeminal nuclei [21].
The pineal gland has a weak regenerative system
due to its neuronal derivation [7]. The number of pinealocytes is genetically determined, and the new cells in
later postnatal life cannot replace the ones that have
been destroyed. The reduced number of pinealocytes
may cause a state of pineal failure especially important
in children affected by different diseases.
Low melatonin excretion in the first weeks of life
correlates with delayed psychomotor achievements at
3 and 6 months of age. This association suggests
a causal or predictive link between melatonin and neurodevelopment in infants [19].
Intrauterine growth retardation or foetal distress in
human infants is associated with a pronounced reduction in melatonin secretion during the first 3 months of
life. These associations persist beyond infancy [9].
All our results lead to the conclusion that the pineal gland during its development is very susceptible to
injury. Injured pineal glands were found in most au-
214
topsied foetuses and infants with brain lesions, suggesting that the insults (ischaemic, toxic or infections)
harmful to the often affect pineal brain parenchyma
as well.
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