Behavioral & Cognitive Disorders
Apr. 12, 2022
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This article includes discussion of neonatal intraventricular hemorrhage and post-hemorrhagic hydrocephalus. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the authors review intraventricular hemorrhage in the neonate with respect to its clinical setting, cause, course, and management. Although the occurrence rate of intraventricular hemorrhage is lessening, the incidence is maintained due to improved survival of very low birth weight infants. Therefore, our continued understanding of the condition is still important for the clinician.
• Intraventricular hemorrhage originates in the germinal matrix of the infant born at less than 34 weeks gestation.
• Intraventricular hemorrhage results from brain blood flow perturbations brought on by defective cerebral autoregulation in association with the medical problems of prematurity.
• Management of intraventricular hemorrhage consists of monitoring for ventricular dilation and drainage of cerebrospinal fluid (CSF) by one of several possible methods.
• Neurologic sequelae are significant and related to the severity of the hemorrhage.
The common clinical setting for intraventricular hemorrhage is the premature infant with respiratory distress requiring mechanical ventilation. The event often occurs on the first day of life (44).
The clinical syndrome of intraventricular hemorrhage varies. There may be catastrophic deterioration with decerebrate posturing, fixed pupils, and coma; a less disastrous picture with variable signs that fluctuate with altered level of consciousness and hypotonia; or the development of hemorrhage and possibly ventricular dilation without marked clinical signs. The subsequent clinical syndrome depends on the progress of the hemorrhage and its effects on the ventricles and brain parenchyma.
Intraventricular hemorrhage can result in a multitude of long-term sequelae, including cognitive delay, cerebral palsy, and a variety of other motor and behavioral deficits. Some estimates put the occurrence rate of seizures with grade III or grade IV intraventricular hemorrhage at 5% to 10% and the rate of hydrocephalus in these patients at more than 50% (46). A large study at Children’s Hospital in Boston, Massachusetts, also noted a marked increase in white matter damage with intraventricular hemorrhage (23).
According to data from the U.S. Census Bureau, the NICHD Neonatal Network, and the CDC, intraventricular hemorrhage is responsible for between 3000 and 4000 new cases of developmental delay in the U.S. each year.
Ventriculomegaly may occur related to posthemorrhagic hydrocephalus. This hydrocephalus may then progress causing either a transient or progressive ventriculomegaly. Acute hydrocephalus shows up within days and is secondary to impaired absorption of CSF due to particulate blood clots. Subacute hydrocephalus will be apparent within weeks and is secondary to an obliterative arachnoiditis in the posterior fossa where blood collects after intraventricular hemorrhage. Impairment of flow in this situation is typically at the fourth ventricle outflow and is only rarely caused by an obstruction at the aqueduct. Ventricular dilation may be seen within 1 to 3 weeks of intraventricular hemorrhage. Traditional signs of hydrocephalus often do not present until days to weeks after ventricular dilation has occurred. In a premature infant, it takes less force to compress white matter than it takes to separate the sutures, which also requires stretching the dura.
Grade IV intraventricular hemorrhage can result in porencephaly, leaving cavitary lesions that communicate with ventricles. Fluid-filled cysts may cause obstruction and increased intracranial pressure. Total brain volume is thereby decreased (40).
Ventriculomegaly secondary to white matter injury typically develops slowly, without increased intracranial pressure or rapid head growth, and evolves to a stable size (17). Periventricular leukomalacia has been determined to result in the setting of intraventricular hemorrhage when decreased cerebral blood flow occurs. Periventricular leukomalacia appears as multiple cystic foci in the periventricular white matter, which is due to coagulation necrosis.
In a study from the Netherlands of 214 preterm infants with intraventricular hemorrhage from 1990 to 2003, 94 were grade III and 120 were grade IV (05). Twenty-eight percent of infants with grade III died, whereas 37% of those with grade IV died. Of the 144 surviving infants, 65% had ventricular dilation requiring intervention. Good outcome was seen in 86% of grade III hemorrhage patients. Cerebral palsy was seen in 80% of shunted grade IV intraventricular hemorrhage, but none of the shunted grade III infants.
Long-term outcomes are defined by the associated major neurologic sequelae. In the study by Brouwer and colleagues, 36% of infants were surgically treated and had cerebral palsy, whereas 23% had cognitive disability (05). Fewer grade III infants had poor outcome compared to the grade IV patients. In the subgroup of infants less than 32 weeks gestational age with intraventricular hemorrhage and shunt, 50% developed cerebral palsy. Severe findings included spastic hemiplegia, much more severe hypotonia, and a developmental quotient less than 50. Grade IV intraventricular hemorrhage is definitely the strongest predictor of adverse outcome.
Mild deficits include a low development quotient, behavioral difficulties, speech delay, sensorineural hearing loss, hypotonia, and spasticity. Moderate deficits include spastic hemiparesis in addition to the above findings.
More severe grades of intraventricular hemorrhage are significantly related to cognitive disability at follow-up at 2 to 9 years. Fifty to seventy-five percent of grade III and grade IV intraventricular hemorrhage survivors in the study by Ment and colleagues had disabling cerebral palsy (27). At 14 years old, adolescents with intraventricular hemorrhage were in special education classes much more often than non-intraventricular hemorrhage ex-premies. Major neurologic deficits were more commonly seen in grades III and IV intraventricular hemorrhage. Even grade I/II intraventricular hemorrhage was related to a 2-fold increased risk of needing special education, typically having behavioral deficits (39).
The effects of low-grade hemorrhage, however, are controversial. A study concluded that the neurodevelopmental outcomes of low-grade hemorrhage in extremely low gestational age infants did not differ from those without hemorrhage (29), whereas a similar study concluded the opposite (22).
Although there is wide and often confusing variation among the studies of sequelae, the general pattern reveals greater levels of permanent disability with larger hemorrhages (44).
A 29-week premature infant was born following early labor with a birth weight of 1400 g. The infant required mechanical ventilation to maintain blood gases, and the chest x-ray showed hyaline membrane disease. On the second day of life, the infant showed decreased tone with rapid variations in blood pressure. A cranial ultrasound demonstrated a right germinal matrix hemorrhage (grade I). A scan 3 days later revealed blood extending into the ventricle and possibly into the parenchyma (grade IV). Ventricular size was followed by ultrasound and gradually increased for several weeks. The problem was temporized by VP shunt placement, and the ventricular size stabilized.
Intraventricular hemorrhage occurs in the clinical setting of the sick, premature infant who is receiving mechanical ventilation. The cause is related to the fragile germinal matrix, which persists in prematurity (16) as it is influenced by difficulties associated with the care of the premature infant.
Intraventricular hemorrhage in the newborn is due to germinal matrix hemorrhage. The germinal matrix houses a complex capillary bed, which matures throughout development. At the time when intraventricular hemorrhage typically occurs, this network is very immature. Preterm infants have an underdeveloped basement membrane surrounding microvessels. They have less type IV collagen, laminin, and fibronectin, which all aid in endothelial development and stability. This fragile basement membrane puts the area at high risk (45). The capillaries enter the terminal veins essentially at right angles, making them more susceptible to mechanical stress.
The subependymal germinal matrix is located ventrolateral to the lateral ventricles. This matrix shrinks to almost complete involution by 36 weeks. Before 28 weeks, hemorrhage is most likely to occur near the body of the caudate nucleus. Between weeks 28 and 32 of gestation, the germinal matrix lies at the level of the head of the caudate at or posterior to the foramen of Monro (the most common site of intraventricular hemorrhage) and is most pronounced in the thalamostriate groove (16).
The largest hemorrhages are seen in the least mature infants (24 to 28 weeks). Intraventricular hemorrhage may extend into the lateral ventricular system, frequently obstructing cerebrospinal fluid (CSF) flow in the posterior fossa and basilar cisterns. Occasionally, obstruction occurs at the aqueduct of Sylvius and at the arachnoid villi.
Most studies show that ineffective blood flow autoregulation and fluctuations in perfusion in the germinal matrix lead to rupture of vessels and intraventricular hemorrhage. Asynchronous breathing, hypercarbia, hypovolemia, restlessness, seizures, patent ductus arteriosus, and excessive handling all correlate with the fluctuations (33). In the premature infant, these risks are increased by elevation in blood flow caused by the pressure passive state of the cerebral circulation. Premature infants have a deficient ability to accommodate increased systolic blood pressure (31). Exchange transfusions (20), rapid infusion of colloid, and rapid volume expansion are treatment-related causes. Red blood cell transfusion given to very low birth weight (VLBW) infants during the first week of life doubles the risk of severe intraventricular hemorrhage. Transfusion is also associated with extension of hemorrhages from grade 1 to grades 3 and 4 (03).
Most studies show that the incidence of intraventricular hemorrhage is higher in thrombocytopenic infants (43). One study of 408 preterm infants showed that platelet mass below the 10th percentile in the first 2 days of life was associated with severe intraventricular hemorrhage (47).
Acute umbilical inflammation or chorionic vasculitis in infants born within 1 hour of rupture of membranes and those with amnionic epithelial necrosis have been associated with increased incidence of intraventricular hemorrhage. The mechanism behind this process is either related to the fetal inflammatory response, maternal circulating cytokines, or both (15).
Fetal risk factors include coagulation disorders, twin-twin transfusion, fetomaternal transfusion, and fetal distress. Other risk factors include infants who are small for gestational age, low Apgar scores, and low cord blood pH (03).
Ureaplasma organisms may cross the immature blood-brain barrier in VLBW infants. Using PCR detection in serum, one study correlated the organism with a 2-fold increase in intraventricular hemorrhage (42). Ureaplasma species are associated with bronchopulmonary dysplasia and all grades of intraventricular hemorrhage. The organism provokes preterm labor and prolonged rupture of membranes, which are both also risk factors for intraventricular hemorrhage. Ureaplasma infections upregulate the inflammatory cytokine cascade (21).
Incidence reports of intraventricular hemorrhage vary widely. It is currently believed that approximately 20% to 25% of VLBW preterm infants develop intraventricular hemorrhage. Kadri and colleagues observed an intraventricular hemorrhage incidence of nearly 70% in infants less than 1000 g, and nearly 50% in infants 1000 to 1500 g (20).
The number of low birth weight infants is increasing, whereas the mortality rate of these infants is decreasing. Although the incidence of intraventricular hemorrhage is declining, the survival of more small infants maintains a significant number of cases of intraventricular hemorrhage in the neonatal intensive care unit. These changes may be attributed to improved perinatal care. Ruegger and colleagues showed that the rates of VLBW (< 1500 g) infants or those of gestational age younger than 32 weeks significantly increased from 0.76% to 0.97% (36). They found no significant change in mortality rate or survival overall, but noted that overall survival free of complications improved from 66.9% to 71.7%. In infants less than 26 weeks gestational age, there were significantly lower mortality rates. There was a significant overall decrease in intraventricular hemorrhage incidence from 6.1% to 4.1%. Although mortality has remained unchanged, a greater number and percentage of preterm and VLBW infants survive without major complications.
The sum of these data is that the overall occurrence rate of intraventricular hemorrhage is less, but the clinical problem continues as more VLBW babies survive (44).
The most effective prevention of intraventricular hemorrhage is prevention of premature birth. The second step in prevention is recognizing when delivery is imminent. The use of tocolytic agents is the last line of defense for preventing premature birth. Although this approach may decrease prematurity and the number of very low birth weight infants, the effect on long-term outcome is difficult to discern. A study suggested that tocolytic exposure could reduce the incidence of death and severe intraventricular hemorrhage (32).
The mother and fetus should be transported to a center that specializes in high-risk delivery. Regionalization of care increases patient volumes and improves physician coverage.
Delayed cord clamping may lessen the need for red blood cell transfusion (03). A 30- to 45-second delay in clamping the cord and positioning the infant below the perineum or incision site for C-section results in an 8% to 24% increase in blood volume. Immediate clamping may lead to hypotension and poor perfusion. The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists recommends delayed cord clamping in preterm infants when feasible (08). A study also demonstrated reductions in intraventricular hemorrhage with delayed cord clamping (12).
Although it could be argued that decreasing the amount of exposure to labor might decrease the stress on the cerebral blood vessels and reduce the incidence of intraventricular hemorrhage, The Israel National Very Low Birth Weight Infant database between 1995 and 2004 demonstrated no benefit from C-section (34). Other reports have yielded conflicting results on this point.
Another favorable factor in reducing intraventricular hemorrhage is the use of antenatal corticosteroids (25). One study demonstrated reductions in mortality, intraventricular hemorrhage, and (11).
Correction of coagulation abnormalities in the premature with fresh frozen plasma results in a decreased incidence of intraventricular hemorrhage (09).
Measures that do not have uniform support include ethamsylate (19) or indomethacin (28; 13). Head positioning or tilting has not been shown to affect the probability of intraventricular hemorrhage (10).
Intraventricular hemorrhage should be suspected in any premature infant who deteriorates and should be screened for in all premature infants. It can present as seizures, apnea, and/or bradycardia, enlarging head size, encephalopathy, etc. The differential includes infection including meningitis and sepsis, apnea of prematurity, gastroesophageal reflux, seizures due to other causes, drug withdrawal, metabolic disorder, and many others.
The test of choice to screen for intraventricular hemorrhage is ultrasound, which detects germinal matrix hemorrhage, hemorrhage into the ventricles, and parenchymal hemorrhage with good sensitivity and specificity.
Ultrasound may also differentiate hemorrhagic ventricular dilatation from periventricular hemorrhagic infarction, which usually results in one large porencephalic cyst. The latter can also be differentiated from periventricular leukomalacia, which appears as multiple small cysts (30).
The American Academy of Neurology guidelines state that all infants less than 30 weeks old should be screened between 7 and 14 days postpartum, and then have another ultrasound at 36 to 40 weeks postmenstrual age to assess for ventriculomegaly and white matter damage.
The onset of intraventricular hemorrhage is on the first postnatal day in about 50% of cases; 25% of cases occur on the second postnatal day and 15% on the third postnatal day. Infants less than 2000 g at birth who develop intraventricular hemorrhage often do so in the first few hours of life. The lower the birth weight, the earlier the onset of the hemorrhage. Screening on the fourth postnatal day will likely detect 90% of intraventricular hemorrhage. Progression, which occurs in 20% to 40% of cases of intraventricular hemorrhage, reaches its maximal extent by 3 to 5 days after initial diagnosis. Therefore, additional scanning after diagnosis should be within 5 days after diagnosis (43).
CT scans may identify other lesions, such as extracerebral hemorrhages, posterior fossa lesions, and certain cerebral parenchymal abnormalities. For later evaluation, it is suggested that MRI may be a better imaging modality (27). MRI gives excellent detail, but the limitations of MRI are the transport of the patient and the long time to run the scan.
Assigning a grade to intraventricular hemorrhage is most important in the characterization of intraventricular hemorrhage. The grade of intraventricular hemorrhage is determined by both the presence and amount of blood, which is determined with a coronal ultrasound scan, whereas the amount is determined on parasagittal scan. The grades of hemorrhage are as follows:
• Grade I: Germinal matrix hemorrhage with no or minimal intraventricular hemorrhage (less than 10% of ventricular area on parasagittal view). This accounts for a significant percentage of the hemorrhages.
• Grade II: Intraventricular hemorrhage involving 10% to 50% of the ventricular area. This accounts for a variable percentage, depending on the study.
• Grade III: Involvement greater than 50% of ventricular area, accounting for about 25% of all intraventricular hemorrhage cases. However, it accounts for 60% to 95% of intraventricular hemorrhage in infants greater than 500 g and less than 700 g (20).
• Grade IV: Hemorrhage into the parenchyma in addition to intraventricular hemorrhage.
Follow-up with serial ultrasound scans is the best way to monitor ventricular dilation. Assessments should be done every 5 to 10 days after diagnosis. Five days would be appropriate for larger bleeds, whereas 10 days would be more appropriate for the smallest bleeds. This is important because the signs and symptoms of hydrocephalus that would be observable in an adult often show up days to weeks after ventricular dilation, if at all (44).
Serial lumbar puncture should, in theory, help with the management of posthemorrhagic hydrocephalus. The use of this modality has declined in most centers.
Ventricular dilation rate varies. In infants with mild intraventricular hemorrhage and minimal progression, surveillance of ventricular size and clinical condition is enough. These infants (approximately 65%) will have spontaneous arrest and resolution (02). In infants with progressive ventricular dilatation, intervention may be necessary. Neurodevelopmental outcomes were significantly improved in infants treated with shunting early (05).
Acetazolamide reduces production of CSF and may be useful as a temporizing adjunct.
Infants with rapid head growth and progressive ventricular dilation, apnea, change in consciousness, full anterior fontanelle, separated cranial sutures, and oculomotor abnormalities may require ventricular drainage or ventriculoperitoneal shunt placement. Considerations include an infant who is either too small or too ill to tolerate surgery and anesthesia or has bloody or proteinaceous CSF, which could occlude a shunt.
There are 3 approaches to ventricular drainage. Direct external ventricular drainage involves threading a soft silastic 21-gauge feeding catheter through a 16-gauge needle catheter to enter the lateral ventricle. An external reservoir is attached and the height adjusted to reach a drainage rate of 10 to 15 ml/kg/day. Drainage should last for 5 to 7 days. Short-term outcomes allow for temporization before ventriculoperitoneal shunt placement, with some instances being curative.
Tunneled external ventricular drains provide a decreased chance of infection and allow for longer treatment (weeks). The rate of CSF removal is determined by the height of the external drip chamber. One variation utilizes a subcutaneous ventricular catheter connected to a subcutaneous reservoir, typically in a supraclavicular subcutaneous pouch or in the subgaleal space (38). The reservoir must be percutaneously tapped periodically. The need for eventual shunt placement and the occurrence of infection is similar to the simpler tunneled external drain rates (24).
Ventriculoperitoneal shunt is currently the definitive treatment for intraventricular hemorrhage. Therefore, placement should be done as early as reasonably possible while minimizing risk. Thirty-five percent of infants with intraventricular hemorrhage and hydrocephalus end up requiring shunting (04). Severity of intraventricular hemorrhage is the most important factor for requiring shunt. The decision to convert temporizing devices to permanent shunts is based on ventricular size, rate of progression, and clinical signs (35).
A 2012 study looked at independent risk factors at the time of ventriculoperitoneal shunt placement that predicted future replacement surgery (37). Fifty-six percent of infants who had shunt placement for intraventricular hemorrhage secondary to prematurity required revision in the following 12 months. Physiological factors related to intraventricular hemorrhage, such as small abdominal size in premature infants, might be one of the reasons for shunt failure.
An alternative surgical approach involves septostomy or neuroendoscopic fenestration of the foramen of Monro (07). This approach avoids more invasive procedures and may provide a decrease in the size of the affected ventricle and an improved neurologic exam. Studies of more cases and long-term outcome would be useful with this modality.
A favorable sign overall is that there has been a reduction in the proportion of very small preterm infants who require shunts (01). The authors speculated that this reduction is related to improved neonatal medical care.
One study looked at 157 neonates born between 24 and 32 weeks gestation and found that neurodevelopmental outcome was directly related to slower increases in fractional anisotropy (microstructure) and N-acetylaspartate/choline (metabolism) in the basal nuclei and brain white matter regions as neonates matured to term-equivalent age, independent of the presence of white matter injury (06). Another study demonstrated that using a model of imaging score, ventilator days, delivery mode, antenatal steroids, and retinopathy of prematurity requiring surgery to determine risk of severe disability had a positive predictive value of 76% and an negative predictive value of 90% (41). Using a combination of amplitude-integrated electroencephalography within the first 72 hours of life and cranial MRI at term equivalent age has also been shown to be predictive of neurodevelopmental outcome at 2 years of corrected age in very preterm infants (18). Although seizures are frequently seen in extremely preterm infants, and these infants have a higher mortality, seizures alone due not predict early death (26).
In another series, 18% of an intraventricular hemorrhage cohort required permanent CSF diversion therapy (14). High intraventricular hemorrhage grade, low gestational age at birth, and increased head circumference were risk factors for posthemorrhagic hydrocephalus. Risk factors for impaired neurodevelopment were high grade intraventricular hemorrhage and increased head circumference.
Stephen L Nelson Jr MD PhD
Dr. Nelson of Tulane University School of Medicine received honorariums from BioMarin and LivaNova for speaking engagements.See Profile
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.See Profile
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