Scientific Commentaries
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Germinal matrix haemorrhage: destroying
the brain’s building blocks
The most skilled stonemasons cannot construct a cathedral without an ample supply of fine granite blocks. Likewise, the human
brain cannot be built properly if stocks of neuroglial progenitors
(the building blocks of the brain) are depleted by injury during the
critical period of progenitor cell proliferation and migration, as
occurs in germinal matrix haemorrhage in prematurity.
The article by Prof. Marc Del Bigio (2011), representing the
analysis of a career-spanning autopsy cohort of preterm infants
with and without germinal matrix haemorrhage, he addresses a
persistent clinical concern facing paediatric specialists caring for
survivors of prematurity: what are the consequences of germinal
matrix haemorrhage on normal brain development at the microanatomic level, and do they explain observed neurodevelopmental
and neuroimaging outcome data?
As a serious complication of prematurity, germinal matrix haemorrhage and its frequent accompaniment, intraventricular haemorrhage, have been recognized in the medical literature since the
turn of the last century (Corvelaire, 1903). In the period from
1940 to 1970, population studies identified the maternal, obstetric
and neonatal risk factors for development of germinal matrix
haemorrhage, including vaginal delivery, low birth weight, low
Apgar scores, hypoxia and hypercapnea (Bassan, 2009; Ballabh,
2010). Improvements since the 1970s in neonatal intensive care
have reduced the incidence of cardiorespiratory complications and
increased survival following preterm delivery; however, the overall
incidence of intraventricular haemorrhage in very low birth weight
infants has remained static over the last two decades (Jain et al.,
2009). Thus, intraventricular haemorrhage is still a significant
problem affecting 412 000 infants per year in the USA alone
(Guyer et al., 1999). The extent of haemorrhage and ventricular
dilatation, as detected by cranial ultrasound, continue to predict
morbidity and mortality, with ultrasonographic grades III (intraventricular haemorrhage with ventricular dilatation) and IV (intraventricular haemorrhage complicated by periventricular haemorrhagic
infarction) having survival rates of 40 and 67%, respectively; of
those surviving, 50 and 75% ultimately develop definite neurological sequelae (Volpe, 2008). These sequelae are related to progressive post-haemorrhagic hydrocephalus and the need for shunt
placement and maintenance, as well as destruction of projection
and association axons traveling through the periventricular zone
ipsilateral to a periventricular haemorrhagic infarction (Bassan,
2009). In addition, direct cortical injury, periventricular leukomalacia, and secondary impairment of overlying cerebral cortical development may be significant contributors to a complex
constellation of destructive and development-altering influences
in the sick preterm neonate (Volpe, 2009b). Subarachnoid blood
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through administration of soluble Fas receptor improves functional
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Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis
and delayed degeneration after spinal cord injury in rats and monkeys.
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Brain 2011: 134; 1259–1263
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| Brain 2011: 134; 1259–1263
including proinflammatory cytokine expression as detected
in vitro, may play an important role in this phenomenon (Juliet
et al., 2008). In whole animal models, unilateral autologous blood
injection into the periventricular region (from which blood eventually extends into the ventricle) resulted in the suppression of cell
proliferation bilaterally in the germinal matrix 8 h to 1 week
post-injection (Balasubramaniam et al., 2006). Increased cell
death was detected in the ipsilateral striatum and germinal
matrix within 2 days, and astrocytic and microglial reaction
peaked at 2 days and persisted up to 4 weeks. These studies,
led by Prof. Del Bigio, laid the foundation for his current work
published in this issue of Brain.
This article is of landmark significance in our understanding of
the effect of localized haemorrhage on cell proliferation (suppressed), expression of cell cycle arrest transcription factor p53
(increased) and cell lineage marker expression (decreased) during
the critical period in gestation in the human when cell proliferation
in and migration from the germinal matrix zone occurs. While
significantly increased cell death and apoptosis could not be documented by nick-end labelling and caspase-3 immunostaining, respectively, such phenomena cannot be excluded: discrepancies
always exist between animal experiments, in which these techniques can be applied at 8–24 h intervals following the delivered
injury, and post-mortem human studies, which are limited by lack
of control over (or even exact knowledge of) these intervals. The
author also contributes valuable normative data, such as germinal
matrix thickness and cell proliferative indices in the second and
third trimesters of human gestation, as well as the delineation,
using cell lineage markers, of ventral and dorsal segmentation of
the ganglionic evidence (resembling the medial-lateral division
seen in experimental animals, but not fully described before in
the human). The highly proliferative ventral portion of the ganglionic eminence between 15 and 34 weeks gestation, poised to
transition to mature neural and glial cells destined for the cerebral
cortex, basal ganglia and thalamus, represents the quarry of building blocks jeopardized by preterm birth.
Finally, work such as this directly in the human brain is essential
to the translation between the bench, where animal models and
tissue culture systems give mechanistic insights, and the bedside,
where strategies for prevention and treatment of germinal matrix
haemorrhage are desperately needed.
Rebecca D. Folkerth1,2,3
Department of Pathology, Brigham and Women’s Hospital,
Boston, MA 02130, USA
2
Department of Pathology, Children’s Hospital Boston, Boston,
MA 02130, USA
3
Department of Pathology, Harvard Medical School, Boston, MA
02130, USA
1
Correspondence to: Rebecca D. Folkerth,
Department of Pathology,
Brigham and Women’s Hospital,
Boston, MA 02130, USA
E-mail: rfolkerth@partners.org
doi:10.1093/brain/awr078
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products are also suspected of causing secondary injury to the
developing cerebellum (Bassan, 2009; Volpe, 2009a). Thus, the
range of neurological deficits in these severely affected children
may include motor, sensory and cognitive functions of a degree
requiring life-long support.
In those survivors without ventricular dilatation and periventricular haemorrhagic infarction, neurological deficits are more
subtle, but may include cognitive and attentional deficits
(Bassan, 2009). These deficits are postulated to be a consequence
of destruction of neuroglial precursors in the germinal zone, before
their differentiation and/or migration to fulfill roles as projection
neurons, interneurons or glia. Of interest is the finding on quantitative neuroimaging of a decrease in cortical thickness in ‘uncomplicated’ germinal matrix haaemorrhage (i.e. without ventricular
dilatation or periventricular hemorrhagic infarction; Vasilieadis
et al., 2004). In that study, infants with overt white matter
injury or grey matter infarcts were excluded in an attempt to
detect the consequence of relatively ‘isolated’ germinal matrix
haemorrhage. Of note, at term equivalent, infants with uncomplicated intraventricular haemorrhage had a statistically significant
16% decrease in cortical grey matter volume compared to those
without intraventricular haemorrhage, leading to speculation regarding the mechanisms of haemorrhage-induced precursor cell
loss (Vasilieadis et al., 2004).
The neuroanatomic and neurophysiological bases of germinal
matrix vulnerability to haemorrhage are currently thought to
relate to: (i) inherent fragility of the germinal matrix vasculature;
(ii) disturbance in cerebral blood flow; and (iii) platelet and coagulation disorders contributing to expansion rather than initiation of
a spontaneous germinal matrix haemorrhage (Ballabh, 2010).
Maternofoetal infection and inflammatory cytokine expression
have also been invoked to play a role in the risk for germinal
matrix haemorrhage (Bassan, 2009). Numerous studies in
humans and experimental animal models have elucidated the
unique characteristics of the germinal matrix zone vasculature: discontinuous glial end-feet of the blood–brain barrier
(El-Khoury et al., 2006), relative lack of pericytes (Braun et al.,
2007), immature basal lamina components (Xu et al., 2008), high
morphometric ratio of diameter to wall thickness (Anstrom et al.,
2005), angiogenic profile with rapid endothelial turnover (Ballabh
et al., 2007) and developmentally regulated expression of vascular
wall molecules such as alkaline phosphatase (Anstrom et al.,
2002). With regard to cerebral blood flow, several key studies in
the intensive care nursery have demonstrated the effect of cerebral pressure-passive circulation on the risk of haemorrhage in at
least a subset of premature infants (Meek et al., 1999; Tsuji et al.,
2000; O’Leary et al., 2009).
Despite the many elegant analyses of the vessels of the germinal
matrix, which explain their vulnerability to the clinically observed
decrease in cerebral blood flow, the fundamental ‘mechanism’ by
which germinal matrix haemorrhage impacts on subsequent neurodevelopment has been the subject of limited study directly in the
human brain. We know that specific blood components, such as
plasma, serum, thrombin and plasmin, have toxic effects on perinatal rat subventricular zone cells, specifically in proliferation, differentiation and migration in oligodendrocyte precursor cell
cultures (Juliet et al., 2009). In addition, microglial response,
Scientific Commentaries
Scientific Commentaries
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