Intraventricular hemorrhage
Definition
Intraventricular hemorrhages (IVH) are bleeds in the subependymal germinal matrix and ventricular system of the brain.
Incidence
Rates of IVH in very preterm or very low birthweight (VLBW) infants (<32 weeks’ gestation or <1500 g) vary between 20% and 25%, with about 6% to 7% suffering from severe IVH (grade 3 or 4).
Pathophysiology
The germinal matrix, which is lining the lateral ventricles, is the site of glial and neuronal precursor cells and involutes by 34 gestational weeks. The rich microvasculature of this temporary structure is poorly supported by connective tissue and extremely fragile.
In addition, cerebral circulation in the preterm infant is often pressure passive, ie, cerebral blood flow varies with systemic blood pressure, due to immature cerebrovascular autoregulatory mechanisms. Any disturbance in cerebral blood flow or an increase in cerebral venous pressure can lead to rupture of the capillary network with bleeding in the germinal matrix and possible extension into the ventricular system.
Venous infarction in the periventricular white matter area (periventricular hemorrhagic infarction [PVHI]) may follow secondary to impaired drainage and thrombosis of the medullary veins due to compression of distal terminal veins by an intraventricular hematoma.
Inflammatory cytokines and reactive oxygen species are also important mediators in the mechanisms of microvascular disruption, cerebral blood flow dysregulation, and periventricular reperfusion injury.
Finally, obstruction of cerebrospinal fluid (CSF) flow can lead to progressive ventricular dilation (see the Hydrocephalus section) with pressure-induced infarction of adjacent white matter and subsequent atrophy.
Risk factors
The risk of IVH and level of severity increase with lower gestational age and lower birthweight.
Risk factors are related to conditions that can lead to either fluctuating, increased or decreased cerebral blood flow or increased cerebral venous pressure.
They are also associated with systemic inflammation.
Antepartum conditions include
Absence of antenatal steroids administration
Maternal hemorrhage
Chorioamnionitis or maternal infections
Peripartum conditions are
Requirement for neonatal transport
Vaginal delivery
Vigorous resuscitation
Postnatal conditions include
Severe respiratory distress syndrome, asynchronous ventilator breathing pattern, hypoxemia, hypercarbia, hypocarbia, pneumothorax, pulmonary hemorrhage, patent ductus arteriosus, acidoses requiring sodium bicarbonate, hypotension requiring inotropes, hypertension, sepsis, and seizures.
Furthermore, candidate genes that may modulate the risk for IVH due to their involvement in the processes of inflammation, hemostasis, or vascular stability are currently being investigated.
Clinical presentation
Signs and symptoms
90% of IVH occur within the first 72 hours of life with progression over the following week. The majority of infants will be asymptomatic and diagnosed following screening cranial ultrasound.
Signs and symptoms may be subtle and include changes in level of consciousness, cardiorespiratory pattern (apnea, bradycardia, hypotension), movement quantity and quality, muscle tone, and eye position/movement. In severe cases, stupor and coma, a sudden drop in blood pressure, nonreactive pupils, decerebrate posturing, flaccidity, and seizures may be present. Distension of the anterior fontanelle or cranial sutures may also be observed.
Any unexplained decrease in hematocrit or failure to increase the hematocrit following blood transfusion should also raise the concern for a possible intracranial bleed.
If lumbar puncture is performed in the context of suspected sepsis, CSF can reveal the presence of red blood cells, high-protein content, and low glucose level.
Condition variability
IVH are graded in severity according to Papile classification system.
Grade 1: Bleeding is limited to the germinal matrix (Figure 22-1).
Grade 2: Bleeding occurs in the ventricular system without dilatation (Figure 22-2).
Grade 3: Bleeding fills over half of the lateral ventricle with resulting dilatation (Figure 22-3A, B).
Grade 4: Bleeding occurs in the ventricular system with parenchymal involvement.
PVHI is observed with 15% of IVH, including grade 1 and 2, although the vast majority (80%) is associated with large bleeds. Therefore, some authors prefer to use a separate notation for PVHI indicating whether or not a grade 1, 2, or 3 IVH is accompanied by PVHI (grade 4 IVH being referred to as grade 3 IVH with ipsilateral hemorrhagic infarction).
Diagnosis
IVH are identified by cranial ultrasound as echodense lesions originating from the germinal matrix that can extend into the ventricles.
Echodensities observed with PVHI are typically unilateral, usually involving periventricular white matter in the frontoparietal territory, and always associated with an ipsilateral IVH (Figure 22-4).
About 25% of lesions seen with PVHI are bilateral with an asymmetric pattern.
Routine cranial ultrasound screening is recommended for all preterm neonates born <30 weeks’ gestational age between 7 to 14 days.
However, because most IVH occur within the first 3 days, cranial ultrasound should be performed during this time window in cases of asphyxia or unstable clinical course.
Management
Medical
Prevention of IVH by ensuring cardiorespiratory and metabolic stability to avoid sharp changes of cerebral perfusion in the preterm newborn during delivery and in the first days of life is crucial. Therefore, transport of high-risk mothers to a tertiary care center with special obstetric and NICU facilities should be strongly encouraged to facilitate antepartum interventions such as glucocorticoids administration and delivery room resuscitation by an experienced team.
Cesarean section could be considered for a subset of mothers at risk of preterm delivery to decrease risk of severe IVH, although this recommendation is not universally accepted.
Following birth, prevention strategies include avoiding maneuvers that can lead to fluctuation or sudden increase in blood pressure or hypocarbia are warranted. Ventilated infants with asynchronous breathing (ie, spontaneous breathing is not synchronized with the ventilator) may benefit from muscle paralysis.
If IVH occur, maintaining cerebral perfusion notably by stabilizing arterial blood pressure within the normal ranges remains important to hinder progression. Monitoring of vital and neurological signs (including head circumference measurement), hematocrit, serum sodium, as well as acid-base balance can help identify any hemodynamic changes or worsening of the IVH.
Serial cranial ultrasound should be performed every 4 to 7 days to document progress and complications, more specifically ventricular dilation.
Surgical
A consultation with the neurosurgeon is recommended when severe IVH are complicated by hydrocephalus.
Early developmental/therapeutic interventions
There is currently no treatment to stop intraventricular bleeding.
So far, studies have focused on prophylactic pharmacologic interventions to diminish rates of IVH.
Prenatal glucocorticoids—with a preference for betamethasone over dexame-thasone—are the only agents that have consistently proven to be effective in reducing the incidence of IVH by almost 50%. However, repeated doses of betamethasone do not confer any additional neuroprotective advantage.
Antenatal phenobarbitone and vitamin K, and postnatal phenobarbital are not associated with lower rates of any grade or severe IVH.
The use of a neuromuscular blocking agent (pancuronium) in ventilated infants with asynchronous respiratory patterns appears to reduce rates of IVH, but safety and long-term effects have not been well documented. Therefore, muscle paralysis should be considered, but used with caution in a selected group of infants.
Prophylactic indomethacin also reduces rates of grade 3-4 IVH without, however, any significant long-term effect on neurodevelopmental outcomes.
Although vitamin E is associated with lower rates of IVH, it is not recommended due to a higher risk of sepsis.
Finally, prophylactic procoagulants and anticoagulants such as factor VIII concentrates or ethamsylate have yielded conflicting results, thus limiting support for routine use.
There is currently no strong evidence that developmentally supportive care reduces IVH. Maintaining the head in a neutral midline position with a 30° elevation could minimize alteration in cerebral blood flow by avoiding occlusion of the jugular vein. However, the impact on IVH rates has not been investigated.
Prognosis
Early predictors: Severe IVH, especially in the presence of PVHI, are associated with worse prognosis.
Outcomes
About 5% to 10% of preterm infants with grade 3-4 IVH will develop neonatal seizures.
Progressive ventricular dilation will be complicating the course of 65% to 75% of infants with grade 3-4 IVH and 20% to 30% will require permanent shunting.
Hemorrhagic lesions in the cerebellum or basal ganglia can be concurrent findings if proper imaging is performed.
Mortality rate is higher with severe IVH (grade 3—20% to 30%, grade 4—30% to 40%).
Periventricular leukomalacia
Definition
Periventricular leukomalacia (PVL) is injury to the cerebral white matter.
Two components have been recognized.
Focal or cystic PVL is the generally symmetrical cystic-necrotic injury observed in the deep cerebral white matter adjacent to the lateral ventricles.
Diffuse or noncystic PVL is characterized by more widespread peripheral glial scarring (astrogliosis and microgliosis), which follows microscopic necrotic injury and evolves over several weeks.
Incidence
The incidence of cystic PVL, which has been decreasing over the years, is around 3% in infants born very preterm or with VLBW infants. This form of PVL is rare after 34 weeks of gestation.
The diffuse type is, however, much more common with up to 50% of VLBW exhibiting noncystic white matter lesions on neuroimaging studies, with higher rates observed with lower gestational ages.
Pathophysiology
Before 32 weeks of gestation, underdevelopment of the long penetrating vessels of the middle cerebral arteries and the peripheral short penetrating arteries leaves certain areas of the white matter—the “watershed areas”—poorly perfused. A drop in blood pressure coupled with immature cerebrovascular autoregulation exposes the watershed areas to ischemia.
Cystic PVL follows a severe ischemic insult resulting from loss of all cellular elements including oligodendrocytes, axons, and neurons.
Diffuse, noncystic PVL is characterized by injury following more chronic sublethal ischemia and reperfusion, which trigger generation of free radicals (reactive oxygen and nitrogen species) by microglial cells and excitotoxins (glutamate) release that are toxic to premyelinating oligodendrocytes.
Maternal/neonatal infections and other inflammatory processes also contribute to death of preoligodendrocytes through mechanisms involving cytokines release, especially interferon-γ and TNF-α, by activated microglia and inflammatory cells. Damage to preoligodendrocytes will ultimately lead to cerebral hypomyelination.
Risk factors
Antepartum and neonatal conditions leading to cerebral hypoperfusion increase the risk of developing PVL and include disturbed uteroplacental circulation, severe hypotension, severe hypocarbia (through cerebral vasocon-striction), hypoxemia, marked hypercarbia (through impairment of cerebral blood flow autoregulation), intraventricular hemorrhage, hypoplastic left heart syndrome, patent ductus arteriosus with retrograde cerebral diastolic flow, and extracorporeal membrane oxygenation.
Chorioamnionitis and early-onset sepsis are additional important risk factors.
Clinical presentation
Signs and symptoms
Periventricular echodensities are usually observed at 3 to 5 days of life on cranial ultrasound, but can appear later.
Presence at birth suggests an antenatal etiology.
Evolution toward cystic PVL occurs in the following 7 to 14 days and can be confirmed by 3 to 4 weeks of life.
Preterm neonates who develop PVL do not manifest any overt neurological signs and symptoms.
Apneic and bradycardic spells are more frequent and profound in infants who develop PVL, but it is not clear whether these events represent a consequence of white matter injury or rather contribute to the latter.
Condition variability
PVL can be graded in severity according to a four-level classification system based on cranial ultrasound findings.
Grade 1: Periventricular echodensities persisting for more than 7 days
Grade 2: Periventricular echodensities evolving into small localized cysts
Grade 3: Extensive periventricular cystic changes involving the frontoparietal and occipital regions
Grade 4: Periventricular cystic changes extending to subcortical white matter
Diagnosis
Cystic PVL is diagnosed on cranial ultrasound (Figure 22-5).Lesions are usually symmetrical involving both sides, but can also be unilateral in about 20% of cases. Most common localization is in the parietal-occipital region. Cystic PVL should be distinguished from PVHI following severe IVH.
Because PVL is clinically silent, routine cranial ultrasound should be performed in the first 2 weeks of life in preterm infants born <30 weeks of gestation or following severe hypoxic-ischemic (eg, cardiopulmonary collapse/resuscitation)or inflammatory events (eg, severe necrotizing enterocolitis). PVL found on cranial ultrasound should be confirmed by brain MRI.
Noncystic PVL is better visualized using conventional cerebral magnetic resonance imaging (MRI) at term-equivalent age although advanced imaging techniques are sometimes required.
Management
Medical
Measures to prevent cerebral hypoperfusion and maternal/neonatal infection are central to minimize risk of PVL.
Antenatal betamethasone should be administered to women with impending preterm delivery.
Neonatal care should then focus on close monitoring of blood pressure and carbon dioxide tension, especially in ventilated neonates, to avoid severe hypotension or hypocarbia.
The use of cerebral near-infrared spectroscopy (NIRS) holds great promises to promptly detect changes in brain oxygenation and intervene accordingly.
Early developmental/therapeutic interventions
Interventions are primarily preventative and target infections/inflammation (antenatal glucocorticoids), excitotoxicity (topiramate), and free radical attack (indomethacin, vitamin K, antioxidants).
So far, antenatal glucocorticoids are the only pharmacological agents that have proven to decrease the incidence of PVL, especially when clinical chorioamnionitis is present.
Early involvement with physical, occupational, and speech therapy is important in infants with PVL, as muscle tone and feeding problems often develop.
Prognosis
Early predictors: The presence of cystic lesions is highly predictive of severe long-lasting neurodevelopmental handicaps.
Outcomes: Mortality rate is higher in infants with cystic PVL due to intensive care withdrawal from underlying severe illness.
Hydrocephalus
Definition
Progressive posthemorrhagic hydrocephalus (PHH) is ventricular dilation due to obstruction to CSF circulation following an intraventricular bleed.
This entity should be distinguished from nonprogressive ventricular dilation or ventriculomegaly occurring in the context of periventricular cerebral atrophy.
This section does not address issues pertaining to congenital hydrocephalus.
Incidence
Among VLBW infants with IVH, about 25% will develop PHH.
About 10% of preterm infants with grade 1-2 IVH develop PHH, whereas this proportion increases to 50% to 75% with grade 3-4 IVH.
Pathophysiology
PHH of acute onset develops secondary to impaired CSF reabsorption at the level of arachnoid villi and transependymal channels, which are obstructed by microthrombi.
In the more subacute-chronic presentation, interference with CSF flow occurs due to obliterative fibrosing arachnoiditis, ie, fibrosis around the ependyma, the foramina of the fourth ventricle and in the subarachnoid space.
Less commonly, the foramen of Monro or the aqueduct of Sylvius may be blocked by a blood clot, ependymal scarring tissue, or meningeal fibrosis.
The propensity for thrombosis and fibrosis results from a combination of specific CSF characteristics following IVH. Inefficient fibrinolysis is observed due to low plasminogen and high plasminogen activator inhibitor CSF concentrations. In addition, increased levels of transforming growth factor-β1, which upregulates the production of extracellular matrixproteins such as fibronectin or laminin, and carboxyterminal propeptide of type I procollagen lead to enhanced collagen synthesis.
Risk factors
Severity of initial IVH is associated with risk of PHH as well as likelihood of requiring permanent ventricular shunting.
Clinical presentation
Signs and symptoms
Radiological signs of PHH are usually observed 1 to 3 weeks following an intraventricular bleed.
Because onset is initially slowly progressive, physical findings are absent.
Increased intracranial pressure may only occur several days to weeks after the onset of ventricular dilation. Signs suggestive of raised intracranial pressure include
Increased head growth velocity, fullness of the anterior fontanelle, widespread cranial sutures
Apnea and bradycardia
Vomiting or feeding intolerance
Altered level of consciousness, hypo- or hypertonia and seizures
Speed of progression depends on the severity of initial IVH, with high-grade IVH more likely to rapidly evolve.
Following the onset of PHH, about 40% of cases will resolve spontaneously within 4 weeks. The remaining 60% will continue to progress for more than 4 weeks.
A subgroup of infants with PHH (10%) will demonstrate rapid progress shortly after the first evidence of ventricular dilation with severe ventriculomegaly and signs of intracranial hypertension developing within a few days.
Condition variability
Volpe describes four distinct groups to facilitate decision making regarding management.
Group 1—Slowly progressive ventricular dilation (<2 weeks): moderate dilation with appropriate head growth, stable intracranial pressure in the normal or near-normal range (<6 mm Hg), and stable resistance index (RI)
Group 2—Persistent slowly progressive ventricular dilation (>2 weeks): similar to group 1, although head growth, intracranial pressure, and RI may begin to increase
Group 3—Rapidly progressive ventricular dilation: mode-rate to severe dilation with rapid increase in intracranial pressure and head circumference (>1.5 to 2 cm/wk) as well as marked elevation of RI
Group 4—Arrested progression: spontaneous arrest of ventricular dilation or arrest following lumbar puncture.
Diagnosis
Hydrocephalus is detected by cranial ultrasound(Figure 22-3C).
Ventricular size can be determined using the Levene ventricular index (VI), which measures the distance from the midline falx to the lateral wall of the anterior horn of the lateral ventricle on coronal plane at the level of the third ventricle.
Ventricular dilation is defined as a ventricular width >97th percentile for gestational age.
The anterior horn width (AHW) is another clinical measure with values >6 mm considered to be clearly abnormal (normal <3 mm). It should be kept in mind that dilation of the posterior horns of the lateral ventricles usually precedes that of the anterior horn.
In addition, the extent of white matter involvement (ie, presence of PVHI or concomitant PVL) should be ascertained since it significantly influences prognosis.
Management
Medical
Once PHH is diagnosed, cranial ultrasound should be repeated every day or every other day to monitor rate of ventricular dilation.
When available, Doppler ultrasound measure of the RI (normal <0.85) on the anterior cerebral artery is useful to detect any disturbance in cerebral blood flow.
Head examination should also be performed daily including measurement of head circumference (abnormal if >2 mm/d on consecutive days) and inspection of fontanelles and sutures.
Neurological signs and symptoms of elevated intracranial pressure should be closely watched.
Timing of intervention and choice of therapeutic modalities remain controversial. Early intervention—ie, with a VI above the 97th percentile, but below the 97th percentile + 4 mm—has been advocated to reduce risk of subsequent permanent ventriculoperitoneal (VP) shunting, especially with grade 3 IVH. However, most centers currently start intervention with a VI >97th percentile + 4 mm (late intervention) due to lack of strong evidence. The ultimate goal of treatment is to avoid the adverse neurodevelopmental effects of raised intracranial pressure and the need for permanent shunt placement.
In infants with slowly progressive ventricular dilation (group 1 PHH), it is reasonable to closely monitor clinical signs and wait before initiating any treatment during the first 2 weeks.
Beyond 2 weeks (group 2 PHH), intervention can be withheld if physical and radiological signs remain stable with no evidence of raised intracranial pressure and if underlying IVH is limited to grade 1-2, given the high likelihood of spontaneous arrest within 4 weeks.
Serial lumbar punctures should be considered if the hydrocephalus is communicating to prevent further progression. Serial lumbar punctures are often performed as a first line or temporary intervention to stabilize or reduce ventricular size and intracranial pressure and remove some of the deleterious blood products. Fluid removal of approximately 10 to 15 mL/kg/d is suggested, but optimal volume is best determined by examining ventricular size before and after the procedure. This can be repeated for up to 3 weeks, although communication is commonly lost after 5 to 10 days.
In cases where the ventricular system does not communicate anymore with the subarachnoid space, tapping of ventricular CSF via the anterior fontanelle is an alternative. At this point, a neurosurgeon should be consulted if not already involved.
Surveillance for cardiorespiratory instability (apnea, bradycardia, desaturations), CNS infection—especially after repeated CSF removal procedures—and metabolic disturbance (hyponatremia) is important.
With rapidly progressive ventricular dilation (group 3 PPH), serial lumbar punctures can be initially done as a temporary measure before proceeding to more permanent surgical options. Cranial ultrasound should be obtained before and after the procedure to ensure stabilization of ventricular size.
Surgical
Surgical treatment is considered with hydrocephalus persisting beyond 4 weeks (group 2 PHH) or with rapidly progressive ventricular dilation (group 3 PHH).
Insertion of a permanent shunt is currently the only definitive treatment for PHH. However, many preterm infants are not yet good candidates due to physiologic instability, immaturity, and small size. Therefore, ventricular drainage is usually first attempted to gain some time and may be sufficient to hinder disease progression in infants with group 2 PHH.
When lumbar punctures are not or no longer indicated, ventricular tapping through a subcutaneous reservoir—or ventricular access device—is the preferred approach to lower intracranial pressure and improve cerebral perfusion. About 10 mL of CSF per kg of body weight is withdrawn over 10 minutes. None of these methods has proven to be effective in reducing risk of VP shunt placement or long-term disability, although it has been hypothesized that acting at a lower threshold may improve outcome.
Continuous ventricular drainage can be performed through a direct external ventricular drain or through a subcutaneously tunneled external ventricular catheter.
However, the most widely used approach consists of a tunneled ventricular catheter that is connected to a subcutaneous reservoir, where CSF accumulates and is removed through serial percutaneous tapping. Alternatively, the subcutaneous reservoir can be replaced by a pocket installed in the subgaleal space, where CSF will slowly be reabsorbed (ventriculosubgaleal shunt).
Placement of a permanent VP shunt, where CSF is diverted from the lateral ventricles to the peritoneal cavity, is usually carried when ventricular dilation continues despite catheterization or when serial tapping is necessary to maintain normal head growth. It is often inevitable in infants with rapid ventriculomegaly.
Timing of intervention depends on local expertise, but common criteria include term-equivalent age, weight around 2.5 kg, and CSF protein concentration <1.5 g/L (to avoid shunt obstruction).
Cerebral MRI is usually obtained to better visualize structures and quantify the amount of parenchymal injury.
Shunt-related complications are burdensome and include skin ulceration, infection, and mechanical malfunction, which may require frequent revisions.
Early developmental/therapeutic interventions
Interventions such as early serial lumbar punctures and intraventricular fibrinolytic therapy (ie, streptokinase or urokinase) to prevent PHH following IVH have failed to demonstrate any effectiveness. Furthermore, clinical equipoise still surrounds the best treatment of PHH to avoid permanent shunt placement and improve neurodevelopmental outcomes.
Administration of acetazolamide or furesomide to decrease CSF production does not yield any benefits and the combination of the two has even been associated with worse outcomes.
Moreover, there is currently no evidence to support the use of osmotic agents such as isosorbide and glycerol.
Center experiences have been reported with ventriculosubgaleal shunts, external ventricular drainage, endoscopic third ventriculostomy (generally, used in infants >6 months old), and coagulation of the choroid plexus, but none of these interventions has yet undergone evaluation in this population through a controlled trial.
Early involvement of physical therapy is important due to high risk of plagiocephaly, torticollis, and motor complications due to tone abnormalities.
Prognosis
Early predictors: Severity of IVH prior to PHH development determines likelihood of spontaneous arrest and risk of rapid progression. In addition, mortality is higher with high-grade IVH.
Outcomes
Progression arrest is observed in about 60% of infants with PHH (40% with spontaneous arrest, 20% following lumbar punctures).
The remaining 40% require VP shunt placement including 21% to 36% of infants with grade 3 IVH complicated by PHH and 38% to 47% of those with grade 4 IVH.
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