KEY POINTS
- 1.
Very-low-birthweight infants are at risk of spontaneous germinal matrix–intraventricular hemorrhages (GM-IVHs).
- 2.
GM-IVHs usually originate within the subependymal germinal matrix lining the ventricles and progress outwards into the ventricles. IVH occurs most frequently during the first 72 hours after birth.
- 3.
A subset of infants with IVH develop periventricular hemorrhagic infarction, posthemorrhagic ventricular dilatation, and posthemorrhagic hydrocephalus (PHH).
- 4.
Posthemorrhagic ventricular dilatation is noted in 30% to 50% of infants with IVH of grade III or IV and can damage the surrounding white matter due to increased pressure. One-third of these infants recover, but others require intervention.
- 5.
The definitive treatment of PHH is usually the placement of a ventriculoperitoneal shunt, where the catheter has a proximal end in the ventricular system of the brain that is connected to a valve underneath the skin to control cerebrospinal fluid flow. Several other treatment modalities are being investigated.
Introduction
Premature infants with a birth weight <1500 g (very low birth weight infants) are at risk of spontaneous germinal matrix–intraventricular hemorrhages (GM-IVHs). These hemorrhages usually originate within the subependymal germinal matrix lining the ventricles, , a highly vascularized region rich in neuronal-glial precursor cells in the periventricular regions in the developing brain, and can progress outward. The etiology of IVH is multifactorial, but as currently understood, it can be ascribed primarily to frequent, accentuated fluctuations in the cerebral blood flow and the fragile vasculature of the germinal matrix. A subset of infants with IVH develop periventricular hemorrhagic infarction and posthemorrhagic ventricular dilatation (PHVD). , The ventricular dilatation may reflect hydrocephalus ex vacuo from encephalomalacia in some and symptomatic progressive posthemorrhagic hydrocephalus (PHH) with increased intracranial pressure in others. , Despite all the improvement in the frequency of neonatal morbidities and mortality in the past 2 decades, the incidence if IVH has not changed. GM-IVH is associated with increased mortality and abnormal neurodevelopmental outcomes in the form of posthemorrhagic hydrocephalus, cerebral palsy, epilepsy, severe cognitive impairment, and visual and hearing impairment.
In this chapter, we review the pathophysiology of IVH and PHVD, outline the medical and surgical management, and discuss interventions for prevention of IVH. In addition to data from our own unpublished quality-improvement/outcome-monitoring studies, this chapter includes information from an extensive literature review of the PubMed, EMBASE, and Scopus databases. To avoid bias in identifying studies, keywords were short-listed a priori from anecdotal experience and PubMed’s Medical Subject Heading (MeSH) thesaurus.
Incidence and Timing of GM-IVH
GM-IVH is seen most frequently in premature infants, and both the incidence and severity of hemorrhage are inversely related to birth weight and gestational age. The incidence of IVH is highest is extremely low birth weight infants, although this varies by center and ranges between 5% to 52% of grades 3 to 4 and 5% to 19% of grade 2, respectively. Overall, the incidence of some of form of IVH in very low birth weight infants ranges from 20% to 25%. IVH occurs most frequently during the first 72 days after birth; nearly 50% of all IVHs occur within the first 24 hours, 25% on the 2nd day, and 15% on the 3rd day.
Neuropathology
Normal Cerebrospinal Fluid Pathways
Cerebrospinal fluid (CSF) is normally produced in the ependyma and choroid plexus. It flows from the lateral ventricles and passes through the foramina of Monro and then into the third ventricle. From there, it travels down the aqueduct of Sylvius and into the fourth ventricle. It then leaves the ventricular system through the foramina of Luschka and Magendie, entering the subarachnoid space of the basal cisterns. The flow continues up over the cerebral convexities to the arachnoid granulations, where it is resorbed into the venous system by a pressure-dependent mechanism. These details are shown in Fig. 52.1 .
Germinal Matrix-Intraventricular Hemorrhage
In GM-IVH, the bleeding originates in the germinal matrix, the region of the brain located just outside ependymal lining of the ventricles. The groove between the head of the caudate nucleus and the thalamus is the most frequently involved site , ; this region is a rich source of neuroblasts that migrate outwards from developing fetal brain ( Fig. 52.2 ). , The germinal matrix is largest during midgestation at 23 to 24 weeks’ gestation and then gradually involutes by 36 weeks. The capillary bed in the germinal matrix is highly vascular and is composed of relatively large, irregular endothelial-lined vessels. The high propensity for hemorrhage in the germinal matrix is due to characteristic features including exuberant angiogenesis, which could possibly be related to the high vascular endothelial growth factor and angiopoietin levels, discontinuous glial end-feet of the blood-brain barrier, paucity of pericytes, immaturity of the basal lamina, and developmentally regulated vascular wall characteristics such as a high morphometric ratio of diameter to wall thickness. In most cases of germinal matrix hemorrhage, the blood enters the lateral ventricles and spreads throughout the ventricular system (see Fig. 52.1 ). This blood may trigger obliterative arachnoiditis over the next few days and may hamper CSF dynamics, leading to obstruction of CSF flow. , Neuropathological consequences of IVH include germinal matrix destruction, cerebral white matter injury/dysmaturation, cerebral gray matter dysmaturation, cerebellar dysmaturation, periventricular hemorrhagic infarction, and posthemorrhagic hydrocephalus.
The pathogenesis of GM-IVH is multifactorial and it is primarily related to intravascular factors (related to regulation of blood flow), vascular factors (related to fragility of germinal matrix vasculature), and extravascular factors (related to platelet and coagulation disturbances; Table 52.1 ). The risk of hemorrhage can be partially explained on the basis of vascular anatomic features ( Fig. 52.4 ). However, because all premature neonates do not develop IVH, additional factors are likely involved.
| Major Pathogenetic Mechanism | Probable Mechanism | Risk Factors |
|---|---|---|
| Intravascular factors (dysregulation of cerebral blood flow) | Fluctuation in cerebral blood flow/altered autoregulation | Hypercarbia Hypoxia Asynchrony on mechanical ventilation Suctioning PDA Agitation Hypovolemia |
| Pressure-passive circulation | Hypertension Hypotension Rapid volume expansion Hypercarbia Decreased hematocrit Decreased blood glucose | |
| Increase in cerebral venous pressure/altered autoregulation | Labor and vaginal delivery Asphyxia Respiratory disturbances Pneumothorax | |
| Vascular factors (fragility of germinal matrix) | Maturational changes/structural weakness of capillaries (involuting and remodeling capillary bed, deficient vascular lining, large surface area of the vascular lumen) | Prematurity |
| Vulnerability of GM to hypoxic, ischemic injury (vascular border zones, high metabolism) | Prematurity Hypoxic ischemic insult Sepsis | |
| Extravascular factors (platelet dysfunction, immature coagulation) | Immature vascular structure Abnormal fibrinolytic activity | Prematurity Thrombocytopenia Disseminated intravascular coagulation |
The increased risk of IVH in premature infants can be ascribed to multiple pathophysiological factors (see Fig. 52.3 ).
- 1.
Anatomic and developmentally regulated structural risk factors in the local vascular supply , ( Fig. 52.4 ):
- a.
The arterial supply to the subependymal germinal matrix is derived particularly from the anterior cerebral artery (through the Heubner artery), the middle cerebral artery (through the deep lateral striate branches and the penetrating branches from the surface meningeal branches), and the internal carotid artery. The terminal branches of the Heubner artery and the lateral striate arteries constitute a vascular end zone and cause vulnerability to ischemic injury.
- b.
The arterial supply feeds an elaborate capillary bed in the germinal matrix. These capillaries are fragile; they are relatively large, irregular, endothelial-lined vessels that show discontinuous glial end-feet of the blood-brain barrier, relative lack of pericytes, immature basal lamina characteristics, and developmentally regulated characteristics including a high morphometric ratio of the vascular diameter to wall thickness. ,
- c.
The rich microvascular network drains into a deep venous system, which eventually terminates in the great cerebral vein of Galen. At the usual site of germinal matrix hemorrhage, the direction of blood flow in the venous system changes in a peculiar U-turn. , This feature may increase the risk of GM-IVH and even periventricular hemorrhagic infarction.
Fig. 52.4
Anatomic and Structural Vascular Risk Factors for Germinal Matrix Hemorrhage in Preterm Infants. (A) Arterial supply to the subependymal germinal matrix at 29 weeks of gestation. (B) Veins of the galenic system, midsagittal view. Note that the medullary, choroidal, and thalamostriate veins come to a point of confluence to form the terminal vein. The terminal vein, which courses through the germinal matrix, empties into the internal cerebral vein, and the major flow of blood changes direction sharply at that junction. (A, From Hambleton G, Wigglesworth JS. Origin of intraventricular hemorrhage in the preterm infant. Arch Dis Child. 1976;51:651–659; B, the composite figure was produced with permission and after modifications from the figures in Inder et al. Preterm intraventricular hemorrhage/posthemorrhagic hydrocephalus. In: Volpe’s Neurology of the Newborn , ch. 24, 637–698.e21.)
- a.
- 2.
Perinatal clinical factors: birth asphyxia, subtle cranial trauma due to vaginal/forceps delivery, severity of prematurity-related respiratory distress, and the use of hypertonic solutions such as bicarbonate.
- 3.
Physiologic immaturity: fluctuating cerebral perfusion volumes due to the mismatch between the systemic and cerebral blood flow and regional variations in blood flow velocities in different parts of the brain. In addition to cranial trauma during birth, fluctuations in regional and overall cerebral perfusion during resuscitation at birth and subsequent intubation, ventilation, and periods of hypo-/hyperoxia have been implicated. Periods of systemic hypotension, patent ductus arteriosus , and hypercarbia may also contribute to the risk. , , In term infants, intracranial and IVH can occur if the infant has coagulation abnormalities, arteriovenous malformations, and sinovenous thromboses. Genetic abnormalities in the formation of extracellular matrix components can also increase the risk. ,
Pathogenesis of Periventricular Hemorrhagic Infarction
Nearly 15% of all cases of GM-IVH develop periventricular hemorrhagic infarction (PVHI), lesions composed of hemorrhagic necrosis in the periventricular white matter dorsal and lateral to the external angle of the lateral ventricles (see Fig. 52.5 ). The incidence of PVHI is inversely related to gestational age; extremely low birth weight infants are at the highest risk. , The main pathologic event in the development of PVHI is GM-IVH; the sequence of events is obstruction of terminal veins, impaired blood flow in the medullary veins, and venous infarction. Microscopically, the lesions show perivascular hemorrhages in a fan-shaped distribution, arising from the medullary veins in periventricular white matter. , The most frequent sequelae of PVHI are one or more porencephalic cysts that may or may not communicate with the lateral ventricle ( Fig. 52.6 ). The severity of periventricular leukomalacia can be graded by several systems, one of which is shown in Table 52.2 .
| Sonographic Appearance | Temporal Evolution | Neuropathological Correlation |
|---|---|---|
| Echogenic foci, bilateral, posterior > anterior | 1 week | Necrosis with congestion and/or hemorrhage (size >1 cm) |
| Echolucent foci (“cysts”) | 1–3 weeks | Cyst formation secondary to tissue dissolution (size >3 mm) |
| Ventricular enlargement, often with disappearance of “cysts” | ≥2–3 months | Deficient myelin formation; gliosis, often associated with collapse of the cyst |
Posthemorrhagic Ventricular Dilatation and Posthemorrhagic Hydrocephalus
PHVD and PHH may occur after GM-IVH. When ventricular dilatation occurs secondary to periventricular leukomalacia or PVHI or both, this entity is called PHVD. It progresses gradually over several weeks and is typically not associated with raised intracranial pressure or rapid changes in head circumference. When IVH obstructs the CSF flow at any point along the ventricular system with impaired CSF dynamics, the term PHH is used.
Many infants with PHH have had inflammatory ependymitis, obstruction of the aqueduct of Sylvius or the fourth ventricle by blood clot(s), and/or basilar arachnoiditis. As expected, the incidence of PHH is higher in premature infants surviving severe IVH, and it increases with the severity of IVH (grades II–IV). However, the predictors of PHH are still not well known. Once IVH has been noted, serial sonograms should be performed to monitor ventricular size until it has either stabilized or hydrocephalus has progressed to a point that treatment is necessary. A time lag between ventricular dilatation and rapid head growth is noted because of a paucity of cerebral myelin, relative excess water content in white matter, and a relatively large subarachnoid space. This can be detected by serial ultrasound scans.
Clinical Features
The usual clinical scenario in a case of GM-IVH is a preterm infant with respiratory distress syndrome requiring mechanical ventilation. The three basic modes of presentation are:
- 1.
Clinically silent presentation
- a.
Most common presentation
- b.
Very subtle
- c.
Not apparent clinically
- d.
Picked up by a routine ultrasound scan or an unexplained fall in hematocrit
- a.
- 2.
Saltatory presentation
- a.
Second most common presentation
- b.
Progresses over a period of many hours
- c.
Stuttering course
- d.
Usual presenting signs noted are alteration in level of consciousness, decreased spontaneous movements, abnormal eye position and movement, and abnormal popliteal angle (tightness due to meningeal irritation)
- a.
- 3.
Catastrophic presentation
- a.
Least common presentation
- b.
Progresses very fast over a period of minutes to hours
- c.
Neurologic features noted are encephalopathy (ranging from stupor to coma), apneas, seizures, decerebrate posturing, fixed gaze and fixed pupils, flaccid quadriparesis, and bulging anterior fontanelle
- d.
Systemic features noted are hypotension, bradycardia, temperature instability, and metabolic acidosis
- a.
Diagnosis
Cranial ultrasound is the most reliable screening tool to detect and assess the severity of IVH. Advantages of ultrasound are its high resolution, portability, lack of radiation, and cost-effectiveness. The grading scale developed by Papile in 1978 and later modified by Volpe, with the addition of a grade IV, is used most frequently (see Fig. 52.5 ).
Clinical Management
Prevention of GM-IVH
The following interventions may protect against IVH , , :
- 1.
Antenatal interventions:
- a.
Antenatal glucocorticoids, particularly when given ≤48 hours prior to delivery.
- b.
Antenatal magnesium sulfate may protect through antiinflammatory effects, not against IVH; may be considered in deliveries at <34 weeks’ gestation within 24 hours.
- a.
- 2.
Interventions during delivery:
- a.
Delivery in a tertiary care perinatal center.
- b.
Delayed cord clamping by 30 to 60 seconds in vigorous preterm infants.
- c.
Postnatal interventions.
- d.
Prophylactic indomethacin may protect against patent ductus arteriosus and IVH; a Cochrane review suggests that prophylactic indomethacin may protect against or lower the incidence of IVH, including severe IVH, although there is some inconsistency in long-term benefits.
- a.
- 3.
Postnatal interventions—may lower fluctuations in cerebral perfusion and improve autonomic stability in the first 72 hours, the period of highest risk for IVH:
- a.
Neutral head positioning using gel pillows during the first 72 hours of life, which may reduce cerebral blood flow fluctuations. Head positioning toward one side can alter cerebral perfusion by altering jugular blood flow. The effect of these interventions is not conclusive yet. Elevated head positioning, defined as the head raised 30 degrees above the bed, aims to reduce cerebral venous pressure and improve oxygenation. Two studies examining the combination of these strategies continued for 4 days showed decreased progression to PVHI in premature infants weighing <1000 g but not an overall reduction in the incidence of IVH.
- b.
Minimal handling during care and procedures, which can promote autonomic stability. Although not proven, this intervention is logical and does not seem to have negative effects. Minimizing stimulation can definitely reduce fluctuations in cerebral blood flow. Minimizing painful procedures is also logical and may even have a positive effect on brain development; multiple painful experiences could negatively impact the development of white matter and subcortical gray matter. Reducing heel sticks, venous blood draws, routine tracheal suctioning, lumbar punctures, and other procedures is easy and humane. Umbilical arterial catheters for blood draws can also help monitor hemodynamic stability and reduce unnecessary noxious stimuli. There may be benefits of reducing unnecessary stimulation even with procedures as innocuous as diaper changes.
- c.
Promoting cerebral autoregulation. Prevention of hypotension and hypoperfusion can reduce fluctuations in cerebral perfusion. Maintaining mean BP >30 mm Hg can lower the risk of severe IVH. Examination of cutaneous perfusion and monitoring of urine output can help assess blood flow to internal organs, although the best perfusion, be it the use of fluid boluses or vasopressors, needs careful consideration. The impact of these measures on systemic blood flow is better known than on cerebral perfusion.
- d.
Gentle ventilation, with a safe degree of hypercapnia in the first 3 days. If possible, the use of percutaneous measurements such as pulse oximetry and transcutaneous CO 2 measurements can be helpful.
- a.
Posthemorrhagic Hydrocephalus (PHH)
Posthemorrhagic ventricular dilatation is noted in 30% to 50% of infants with grade III or IV IVH and can damage the surrounding white matter due to increased pressure. One-third of these infants recover, but others require intervention. Infants with obstructive changes, such as those with aqueductal clots, develop ventricular dilatation more frequently. Others with nonobstructive changes develop ventriculomegaly over longer periods. There is no consensus on the best therapeutic measures ; some centers are relatively conservative and carefully monitor these infants, whereas others use a more aggressive approach with an initial lumbar puncture followed by surgical insertion of a ventricular access device such as an Ommaya reservoir to stop ongoing damage to the white matter. Ventriculoperitoneal shunts are utilized in infants with progressive PHVD after early intervention.
PHVD can be identified with increasing ventriculomegaly on serial cranial ultrasounds. Infants <32 weeks’ gestation are at higher risk. The ventricular index (VI), or width, or the Levene index is used to monitor ventricular size ( Fig. 52.7 ). , It is a measurement of the distance from the falx to the lateral border of the lateral ventricle in a coronal view taken at the level of the foramen of Monro. Although originally described as an “index,” it is actually a measurement of width, not an actual ratio. The VI is the distance between the falx and the lateral wall of the anterior horn in the coronal plane at the level of the third ventricle. The anterior horn width (AHW) is the width of the distance from the medial walls of the lateral ventricles at the widest points. Intervention should be considered when patients show severe dilatation with measurements the VIs measuring higher than the 97th percentile +4 mm, and the AHWs more than 10 mm.
Doppler ultrasound can help measure the resistive index (RI) in the assessment of the need for ventricular drainage. The RI is a calculation of the systolic and diastolic velocities in the cerebral arteries. Normal RI values are 0.65 to 0.85. A high RI (>0.85) may indicate low blood-flow velocity and high resistance in patients with PHVD, suggesting a need for ventricular drainage.
There are several possible approaches to protect from white matter injury. Nonsurgical management may involve serial lumber punctures to relieve CSF pressure and remove debris from the ventricles. A typical therapeutic lumbar puncture is performed to remove 10 mL/kg of CSF on 2 to 3 consecutive days, and ultrasound surveillance is used to monitor the VI and AHW. If the VI and AHW decrease appropriately, weekly ultrasound surveillance is continued until the infant is ≥32 weeks’ GA and the ventricles are stable. If ventricular dilation persists, surgical intervention is considered. There are several options for neurosurgical management of progressive PHVD.
If the infant is too small or clinically unstable, a temporizing procedure is often performed first.
There are 3 options for temporary surgical management of PHVD ( Fig. 52.8 ):
- 1.
Ventriculosubgaleal shunt. A catheter is placed with the proximal tip in the lateral ventricle of the brain and the distal end in a pocket in the subgaleal space to divert the CSF flow. This closed system can decompress the ventricular system without the need for frequent spinal taps. The risk of electrolyte abnormalities is low. However, some infants may have overdrainage, hemorrhages, CSF leaks, or infections (see Fig. 52.4 ).
- 2.
External ventricular drain (EVD). A drain is placed into the ventricular system and tunneled under the skin to exit the scalp into an external collection chamber. The EVD eliminates the need for percutaneous tapping and allows controlled CSF removal. There are risks of infection and electrolyte abnormalities related to CSF removal. EVD insertion is generally used for specific clinical situations such as meningitis (see Fig. 52.5 )
- 3.
Ventricular access device. A catheter is placed with the proximal end in the ventricular system and the distal end attached to a silicone dome implanted in a subgaleal pocket. It allows for serial, percutaneous CSF aspirations through the dome. There is a small but measurable risk of infection with these serial taps ( Fig. 52.6 ).
