The mortality rate for low-birth-weight infants with PHH is significantly higher than that for low-birth-weight infants without PHH (16–35% vs. 6.5–13%) (56).
- Temporary zone during last 12 weeks of gestation: During the last 12 weeks of gestation the germinal matrix exists as a temporary zone at the external angles of both the lateral ventricles, just beneath the ependymal lining. It is the source of the future neurons and glial cells of the forebrain. The germinal matrix reaches its maximal size by 23 weeks of gestation, decreases to half its size by 32 weeks, and almost involutes by 36 weeks (18).
- Immature vascularity: The germinal matrix is gelatinous, highly cellular, and vascularized. Because of the temporary nature of this structure, the capillary bed has a minimal collagen basement membrane, no tight junctions, and no glial end-feet, although it receives a disproportionately large amount of cerebral blood flow to uphold the high metabolic demands. Those fragile vessels with the impaired autoregulation are the site of IVH. The blood supply for the germinal matrix is from Heubner’s artery (branch of the anterior cerebral artery), lateral striate arteries (branch of the middle cerebral artery), and the anterior choroidal artery (a branch of the internal carotid or middle cerebral artery) (29).
- Drainage of matrix vascularity imparts resistance: The capillary bed drains into the terminal vein along with medullary, choroidal, and thalamostriate veins. The confluence of these veins drains into the internal cerebral vein. The internal cerebral vein takes a sharp bend that abruptly reverses the direction of blood flow, creating resistance that causes venous intramural stress. It is this condition that contributes to vessel rupture and to further venous congestion. The venous endothelial cell-lined channels are the most common site of rupture compared to the proximal capillary-venule junctions (68).
- Location of hemorrhage age dependent: Macroscopically, the location of the hemorrhage before gestational week 28 is posterior to the body of the caudate nucleus. Later in gestation the location is more anterior, over the head of the caudate nucleus (29).
- Hypoxia injury is ischemic infarct: Infants that are born prematurely with an active germinal matrix are in danger of hemorrhage because the fragile and immature vessels are vulnerable to respiratory and circulatory fluctuations. The major factors associated with germinal matrix are increased cerebral perfusion pressure and hypoxia. Low oxygen delivery at the endothelial cells lining the capillaries makes them vulnerable to infarction and then disruption (99).
- Hypercapnia increases intramural pressure: Hypercapnia additionally dilates the thin-walled vessels.
- Other mechanisms increasing risk of IVH: Other factors that can contribute to IVH are arterial hypertension (especially following systemic hypotension), increased cerebral venous pressure, dehydration followed by resuscitation with rapid infusion of a hyperosmolar solution, and coagulopathies.
- Numerous extraneural risk factors: Many risk factors, environmental and medical, obstetric and neonatal, can result in the aforementioned conditions that cause germinal matrix hemorrhage: rapid volume expansion, seizures, pneumothorax, pulmonary hemorrhage, low gestational age, low birth weight, absence of antenatal steroid exposure, antenatal maternal hemorrhage, maternal chorioamnionitis/infection/inflammation, maternal fertility treatment, neonatal transport, anemia, decreased blood glucose, cyanotic heart disease, respiratory distress syndrome/mechanical ventilation, arterial catheterization, early sepsis, hypotension treatment with pressor agents, severity of illness score, acidosis, maternal cocaine abuse, and prolonged labor (4, 6, 21, 43, 48, 55, 57, 60, 70, 89, 103).
Surrounding brain injury
- Damage by hematoma: Direct damage from the formation of hematoma within the brain tissue is expected after the initial bleeding. Germinal matrix damage theoretically is better tolerated due to the plasticity of the developing brain. Further damage outside the germinal matrix region, superolateral to the head and body of the caudate nucleus, is a more serious insult and results from expansion of the initial bleeding or a periventricular hemorrhagic infarct. Those are separate entities but can also overlap. In a grade IV IVH, the bleeding extension into the parenchyma can be immediate or secondary after several days. During the same period hemorrhagic necrosis of the periventricular white matter is another contributing factor. It is believed that the clot acts as space-occupying lesion that impairs venous drainage of the area due to the sharp bending of the terminal vein. The venous drainage is further impaired when the ventricle expands and the ICP is raised. This problem occurs in 15% of all infants with IVH (25, 90).
- Coalescing PVL leads to porencephaly: PVL is a parenchymal lesion remaining after an arterial ischemic injury. It affects the white matter and presents as multiple cystic foci with coagulation necrosis and loss of cellular architecture. Further progression of these foci results in porencephaly. The location corresponds to the periventricular hemorrhagic infarct areas, and a clear pathogenetic distinction between PVL and periventricular hemorrhagic infarct is difficult. The white matter injury that accompanies IVH is believed to represent the cause of the neurodevelopmental impairment suffered by these neonates (57).
- Cascading pathways with accumulating risks for injury: Common molecular pathways are involved in the initiation of the hemorrhage and the secondary white matter damage. The cyclooxygenase 2 (COX-2) system is induced by hypoxia, growth factors [transforming growth factor (TGF)-β)], and inflammatory modulators [interleukin (ΙL)-6, IL-1β, tumor necrosis factor (TNF)-α)]. The resultant prostanoids mediate the production and release of vascular endothelial growth factor (VEGF). Cytokines, nitric oxide (NO), and VEGF mediate a cascade leading to the disruption of tight junctions, increased blood-brain barrier permeability, and microglial activation in the developing periventricular white matter. Microglial activation releases reactive oxygen species (ROS), which result in direct endothelial damage, alter hemostasis, and increase anaerobic metabolism (3, 11, 73).
Clinical Results of IVH
- Timing of IVH: The time from birth seems to affect neurodevelopmental outcome. Infants who develop hemorrhage during the first 6 hours of life have a greater chance of suffering from cerebral palsy and lower IQ scores (96).
- Mortality rate varies with grade of IVH: The severity of IVH, as determined by its grade, is an important factor for the mortality rate (56, 66). The mortality rate for grade I is 5%; grade II, 10%; grade III, 20%; and grade IV, 50%.
- Spasticity and colpocephaly: Neurological disabilities are primarily influenced by the presence and extent of the parenchymal injury. Spasticity and intellectual deficits result from posthemorrhagic infarction, while PVL is mainly responsible for spastic diplegia, typically more severe in the lower than in the upper limbs. Mental retardation, seizures, and cerebral palsy are the most frequent disabilities.
- Obstruction of foramina by large clots: Large clots can directly obstruct the intraventricular CSF pathways (foramen of Monro, aqueduct, foramina of Magendie and Luschka) or cause reactive gliosis.
- Obstruction of transependymal channels: The very likely presence of small transependymal channels provides another site for CSF reabsorption through small blood vessels within the parenchyma. Multiple clots can block those channels as well.
- Obstruction of subarachnoidal space and arachnoidal villi: The rheological properties of CSF are altered as well, and that impedes the circulation in the subarachnoid space and the reabsorption through the arachnoid villi. At this point some ventricular dilation may occur and can be reversible if blood clots resolve quickly (12).
- Induction of arachnoiditis and gliosis: High concentrations of TGF-β1 have been found in the CSF of infants who have suffered IVH, especially in the PHH group. In the CSF of normal infants, TGF-β1 is undetectable. TGF-β1 is involved in the upregulation of genes for extracellular matrix protein synthesis such as fibronectin and laminin. It is linked also to wound healing, scar formation, and fibrotic diseases (e.g., cirrhosis). TGF-β1 in the CSF could originate from the platelets or from the choroid plexus. In addition, high levels of C-propeptide of precollagen I have been found in CSF samples of preterm infants (very low birth weight) with PHH. These data suggest that IVH induces the production of extracellular matrix proteins and local collagen synthesis that promote fibrosing obliterative arachnoiditis, meningeal fibrosis, and subependymal gliosis. This occurs 2–6 weeks after the initial bleed in the germinal matrix, and there is a tendency for more resistant ventricular dilation. Extracellular matrix protein deposits are more prominent in the posterior fossa and can block the fourth ventricular outflow by the resultant adhesive arachnoiditis. The small diameter channels of transependymal reabsorption and the arachnoid villi are also vulnerable to blockage by fibrosis (33, 67, 106, 113).
- Injury resulting from ventriculomegaly: Besides the parenchymal injury from the initial bleeding and the following periventricular posthemorrhagic ischemia, further brain damage is anticipated by the ventriculomegaly. A typical mechanism describes fiber stretch and vessel compression, venous and arterial, with subsequent hypoxia due to increased ICP. Further oxidative stress is caused by free radicals and the inflammatory impact through a number of cytokines [(TNF-α, IL-1β, IL-6, IL-8, interferon (IFN-8)]. The neuropathological consequences affect neurons (swelling, impaired synaptogenesis), fibers (stretching, disruption, defective myelination), and neurotransmitters (lower levels of catecholamines, deficient synthesis) (17, 51, 56, 72, 81, 84).
- Genes associated with IVH: There may be a genetic relationship to the incidence and severity of brain damage due to IVH. As seen in adult intracerebral hemorrhage where there is a high incidence of the allele for the apolipoprotein E4 or E2, the proposed candidate genes associated with infantile IVH include IL-6 (174 CC and 572 C alleles), TNF-α, Factor V (Leiden), prothrombin (G20210A), and collagen type IVa1 (22, 23, 24, 31, 48, 57).