AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Families and caregivers of preterm infants and those threatened with preterm delivery must face 2 major unknowns regarding these newborns: Will this child survive? If the child survives, will long-term sequelae be present, especially developmental sequelae? These questions are of particular importance because the answers can influence subsequent medical decisions, such as aggressiveness of care. Several acquired lesions of the central nervous system (CNS) specifically affect infants born prematurely and result in long-term disability. This chapter reviews one of the important CNS lesions, periventricular hemorrhage-intraventricular hemorrhage (PVH-IVH), which involves the periventricular white matter (motor tracts) and is associated with long-term disability.

PVH-IVH remains a significant cause of both morbidity and mortality in infants who are born prematurely. Sequelae of PVH-IVH include life-long neurological deficits, such as cerebral palsy, developmental delay, and seizures. PVH-IVH is diagnosed primarily through the use of brain imaging studies, usually cranial ultrasonography. As PVH-IVH can occur without clinical signs, serial examinations are necessary for the diagnosis.

Although classified according to anatomic involvement by Papile, a modified classification based on the pathophysiological processes that result in hemorrhage is also useful. Still, PVH-IVH remains a serious problem, despite recent decreases in incidence, due to increased survival of extremely low birthweight infants (ie, <1000 g) as well as severity of sequelae.

Pathophysiology

Site of origin

The site of origin of PVH-IVH is the subependymal germinal matrix, a region of the developing brain that regresses by term. During fetal development, the subependymal germinal matrix is a site of neuronal proliferation as neuroblasts divide and migrate into the cerebral parenchyma. By approximately 20 weeks' gestation, neuronal proliferation is completed; however, glial cell proliferation is still ongoing. The germinal matrix supports the division of glioblasts and differentiation of glial elements until approximately 32 weeks' gestation, at which time regression is nearly complete. Cells of the germinal matrix are rich in mitochondria and, therefore, are quite sensitive to ischemia.

Supplying this area of metabolically active differentiating cells is a primitive and fragile retelike capillary network. Arterial supply to the plexus is through the Heubner artery and the lateral striate arteries, which are within the distribution of the anterior and middle cerebral arteries, respectively. This fragile capillary network is the site at which PVH-IVH hemorrhage occurs. Venous drainage is through the terminal vein, which empties into the internal cerebral vein; this in turn empties into the vein of Galen. At the site of confluence of the terminal vein and the internal cerebral vein, blood flow direction changes from a generally anterior direction to a posterior direction.

Anatomic classification

PVH-IVH can be classified into 4 grades of severity. This classification, which is useful for prognostic reasons when counseling parents and caregivers, is described in Table 1. Note that this classification is based on radiological appearance rather than a pathophysiological description of events leading to PVH-IVH.

Table 1. Classification of PVH-IVH

Grade	Radiological Appearance – Site of Hemorrhage
I	Subependymal region and/or germinal matrix
II	Subependymal hemorrhage with extension into lateral ventricles without ventricular enlargement
III	Subependymal hemorrhage with extension into lateral ventricles with ventricular enlargement
IV	Intraparenchymal hemorrhage

Pathogenesis

PVH-IVH hemorrhage is now thought to be caused by capillary bleeding. Two major factors that contribute to the development of PVH-IVH are (1) loss of cerebral autoregulation and (2) abrupt alterations in cerebral blood flow and pressure. Most healthy infants who were born prematurely have some ability to regulate cerebral blood flow through a process called autoregulation. However, autoregulation is lost under some circumstances. Perlman and Volpe have demonstrated that the alteration from autoregulation to a pressure-passive circulatory pattern appears to be an important step in the development of PVH-IVH. When a pressure-passive circulatory pattern is challenged with fluctuations of cerebral blood flow and pressure, hemorrhage can occur.

The autoregulatory abilities of neonates vary proportionally to gestational age at time of birth. The range of perfusion pressures over which a premature neonate can control regional cerebral blood flow is narrower and lower than that of infants born at term. In the absence of autoregulation, the systemic blood pressure becomes the primary determinant of cerebral blood flow and pressure, a pressure-passive situation.

Multiple events can result in rapid changes in the cerebral circulation, potentially overwhelming the autoregulatory mechanisms of the neonate. These events include asynchrony between spontaneous and mechanical breaths; birth; noxious procedures of caregiving; instillation of mydriatics; tracheal suctioning; pneumothorax; rapid volume expansion (iso-osmotic or hyperosmotic as in sodium bicarbonate); rapid colloid infusion (eg, exchange transfusion); seizures; and changes in pH, PaCO₂, and PaO₂. Specific metabolic derangements (eg, hypocarbia, hypercarbia, hypoxemia, acidosis) also can disrupt the autoregulatory abilities in infants.

The loss of autoregulatory ability coupled with rapid alterations in cerebral blood flow and pressure can result in hemorrhage. The capillaries of the immature germinal matrix possess neither tight junctions between endothelial cells nor a strong basement membrane. Therefore, increased flow and pressure may rupture the delicate capillaries, leading to bleeding.

In a series of investigations, Perlman, McMenamin, and Volpe described the relationship between cerebral blood flow and respiratory pattern in preterm infants. Their findings suggest that when mechanical breaths are not synchronized with efforts of the patient, beat-to-beat fluctuations in blood pressure occur, resulting in fluctuations in cerebral perfusion and subsequent PVH-IVH. Interventions to reduce the fluctuations by suppressing the respiratory efforts of the infant by pharmacological muscle blockade prevented hemorrhage. Patients without asynchrony between mechanical ventilation and patient efforts had stable blood pressures, stable cerebral perfusion, and a lower incidence of hemorrhage. Similar experimental models have demonstrated a relationship between rapid volume expansion following ischemia or hemorrhagic shock and PVH-IVH.

Based on the above discussion, the development of PVH-IVH appears to occur in 2 steps; the loss of cerebral autoregulation is followed by rapid changes in cerebral perfusion. Additionally, because the range of arterial pressures over which a prematurely born neonate can maintain autoregulation is narrow, abrupt large changes in blood pressures can overwhelm the ability of the neonate to protect the cerebral circulation and result in PVH-IVH. Experimental models also describe this development. Host factors can modify mechanisms of PVH-IVH. Among others, such factors include coagulopathy, acid-base balance, hydration, and hypoxia-ischemia.

The above mechanisms account for grades I, II, and III PVH-IVH. The pathogenesis of grade IV hemorrhages differs. Grade IV hemorrhages appear to result from hemorrhagic venous infarctions surrounding the terminal vein and its feeders, probably primarily related to increased venous pressure following or associated with the development of lower-grade hemorrhages. Indeed, the use of the term periventricular hemorrhagic infarction has been suggested rather than using the term grade IV hemorrhage, resulting in the following modification of Table 1:

Table 2. Modification of Grade Descriptions of Table 1

Grade	Radiological Appearance – Site of Hemorrhage
Mild (approximates grade I)	Subependymal region and/or germinal matrix
Moderate (approximates grade II)	Subependymal hemorrhage with minimal filling (10-40%) of lateral ventricles with no or little ventricular enlargement
Severe (approximates grade III)	Subependymal hemorrhage with significant filling of lateral ventricles (>50%) with significant ventricular enlargement
Periventricular hemorrhagic infarction	Intraparenchymal venous hemorrhage

Pathogenesis of sequelae

The major sequelae of PVH-IVH relate to the destruction of cerebral parenchyma and the development of posthemorrhagic hydrocephalus. Furthermore, the sequelae of ventricular-peritoneal shunt placement (primarily infection) can contribute to poor neurodevelopmental outcomes.

Following parenchymal hemorrhages, necrotic areas form cysts that can become contiguous with the ventricles (porencephalic cysts). Cerebral palsy is the primary neurological disorder observed after PVH-IVH, though mental retardation and seizures can ensue as well.

The occurrence of cerebral palsy is related to the anatomical structure of the periventricular region of the brain. The cortical spinal motor tracts run in this region. The white matter is arranged such that tracts innervating the lower extremities are nearest to the ventricles, followed by those innervating the trunk, the arm, and, finally, the face. This anatomical arrangement accounts for the greater degree of motor dysfunction of the extremities as compared to the face (spastic hemiplegia in unilateral lesions and spastic diplegia or quadriplegia in bilateral lesions). In addition to destruction of periventricular motor tracts, destruction of the germinal matrix itself can occur. The long-term effects of the loss of glial cell precursors are unknown.

The second mechanism by which long-term neurological outcome can be altered is through the development of posthemorrhagic hydrocephalus. The mechanisms by which hydrocephalus develop include (1) decreased absorption of cerebral spinal fluid (CSF) secondary to obstruction of arachnoid villi by blood and debris or the development of obliterative arachnoiditis (ie, communicating hydrocephalus) and (2) obstruction to CSF circulation (ie, obstructive hydrocephalus).

Finally, because the development of PVH-IVH is related to alterations in cerebral blood flow, injury to other portions of the brain must be considered. Two disorders that may coexist with PVH-IVH are global hypoxic-ischemic injury and periventricular leukomalacia (PVL). PVL is a disorder of the periventricular white matter, similar to periventricular hemorrhagic infarction. However, the mechanism of PVL, nonhemorrhagic ischemic necrosis, differs substantially from that of all grades of PVH-IVH, including periventricular hemorrhagic infarction. Both PVL and global hypoxic-ischemic injury can significantly affect the neurologic outcome in infants affected with these disorders.

The significance of alterations in cerebral blood flow is perhaps of greater importance than previously recognized, not only in the generation of hemorrhage but in more diffuse brain injury as well. For example, numerous studies have demonstrated alterations in cerebral blood flow during rapid infusions of indomethacin, raising concern that prophylactic use might improve the risk of PVH-IVH while increasing the risk of periventricular leukomalacia. Fortunately, this has not been shown to be true. Indeed, in a large follow-up study of patients receiving indomethacin prophylaxis, Ment demonstrated that while indomethacin prophylaxis did not result in improved motor outcomes, cognitive and verbal outcomes were improved with prophylaxis. The pathophysiology described above might appear inconsistent with that observation; however poorly understood alterations in cerebral blood flow distribution and cellular energy utilization might beneficially be effected by indomethacin.

Frequency

United States

Incidence of PVH-IVH in infants of very low birth weight (<1500 g) or infants of less than 35 weeks' gestation has been reported to be as high as 50%. This incidence appears to have fallen in recent years. Although no firm estimates of incidence can be made at this point, a multicenter study conducted by Ment et al in 1994 reported rates of 12-18% with and without indomethacin prophylaxis respectively, were observed. Reasons for the decline in incidence of PVH-IVH are not entirely clear but probably are related to improvements in obstetric care as well as improvements in neonatal respiratory and fluid management.

International

Because the incidence of PVH-IVH is inversely proportional to gestational age, and because resource availability appears to influence aggressiveness of intervention and survival, international incidences of PVH-IVH would be expected to vary dramatically. However, there is no reason to think that international rates of PVH-IVH differ from those reported above, provided similar resources are available.

Mortality/Morbidity

Mortality from severe (high-grade) PVH-IVH is 27-50%. An inverse relationship between extent of hemorrhage and survival exists. Mortality from low-grade hemorrhage is significantly lower (5%).

Sex

Post-hoc analysis of patients enrolled in a multicenter trial investigating indomethacin prophylaxis for PVH-IVH suggests a possible link between sex and effectiveness of prophylaxis. However, this observation has not been confirmed or investigated further.

Age

• Although all infants who are born prematurely should be considered at risk for PVH-IVH, neonates delivered at less than 32 weeks' gestation are at significant risk. Beyond approximately 32 weeks' gestation, the germinal matrix has regressed to the point that hemorrhage is significantly less likely. Risk of developing PVH-IVH is inversely proportional to gestational age.
• Postnatally, most hemorrhages occur when the neonate is younger than 72 hours, with 50% of hemorrhages occurring on the first day of life. The extent of hemorrhage is greatest when the neonate is aged approximately 5 days. PVH-IVH can occur when the individual is older than 3 days, especially if a significant life-threatening illness arises. This forms the basis for screening programs and recommendations for screening at 7 days of age.
• Although intraventricular hemorrhage is uncommon in infants who are born at term, the disorder has been reported, especially in association with trauma and asphyxia. The site of hemorrhage in term infants is usually the choroid plexus, a difference from the site of PVH-IVH in infants who are born prematurely.

CLINICAL

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History

History of the patient can be entirely noncontributory in PVH-IVH. Caregivers or parents might note nonspecific subtle signs. However, in some patients, events that result in loss of autoregulation of cerebral blood flow can be obtained.

Physical

• The presentation of PVH-IVH varies significantly.
• Most infants are asymptomatic or demonstrate subtle signs that are easily overlooked. PVH-IVH subsequently is found on surveillance sonography.
• One subgroup of infants with PVH-IVH presents with the following:
• • A sudden unexplained drop in hematocrit
  • Possible physical findings related to anemia (eg, pallor, poor perfusion) or hemorrhagic shock
• Another subgroup of infants with PVH-IVH presents with extreme signs.
• • A sudden and significant deterioration associated with anemia, metabolic acidosis, glucose instability, respiratory acidosis, apnea, hypotonia, and stupor is present.
  • Physical findings related to these signs include poor perfusion, pallor or an ashen color, irregularities of respiratory pattern, signs of respiratory distress including retractions and tachypnea, hypotonia, and altered mental status (eg, decreased responsiveness, coma).
  • Additional neurological signs, such as fullness of the fontanels, seizures, and posturing, also may be observed.
  • Progression can be rapid and may result in shock and death.
• Between the 2 extremes of presentation, infants might demonstrate varying degrees of neurological and systemic signs.

Causes

Prematurity is the most important risk factor for PVH. However, other factors have been associated with the development of hemorrhage.

• Rapid volume expansion (eg, the correction of hypotension with volume infusions)
• Asynchrony between mechanically delivered and spontaneous breaths in infants on ventilation
• Hypertension or beat-to-beat variability of blood pressure
• Coagulopathy
• Hypoxic-ischemic insults
• Respiratory disturbances (eg, hypercarbia, hypocarbia pneumothorax, hypoxemia, rapid alterations in blood gasses)
• Acidosis
• Infusions of hypertonic solutions (eg, sodium bicarbonate)
• Anemia
• Vacuum-assisted delivery
• Frequent handling
• Tracheal suctioning

DIFFERENTIALS

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WORKUP

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Imaging Studies

• Cranial sonography
• • Sonography is the diagnostic tool of choice for screening examination and follow-up of individuals with PVH-IVH. Current recommendations by the Quality Standards Subcommittee of the American Academy of Neurology suggest that all infants younger than 30 weeks gestational age be screened by cranial ultrasonography at 7-14 days postnatal life and at 36-40 weeks postmenstrual age.
  • Sonography is also the diagnostic tool of choice for the follow-up of individuals with PVH-IVH and posthemorrhagic hydrocephalus. Serial sonography is indicated weekly to follow for progression of hemorrhage and the development of posthemorrhagic hydrocephalus.
• CT scan
• • Prior to the availability of sonography, CT scanning was used for diagnosis and follow-up.
  • CT scanning is no longer used for diagnosis and follow-up in view of the safety and cost effectiveness of sonography.

Other Tests

• Although not as useful as sonography, frontal-occipital circumference can be used as an adjunct test in monitoring the progression of posthemorrhagic hydrocephalus.

TREATMENT

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Medical Care

Supportive care includes the correction of underlying medical disturbances that might be related to the development of PVH-IVH as well as cardiovascular, respiratory, and neurological support.

• Correction of anemia, acidosis, and hypotension, as well as ventilatory support, might be required in those neonates who present with acute deterioration.
• Serial lumbar puncture, though once used to prevent progressive hydrocephalus, is not indicated.

Surgical Care

Surgical support for PVH-IVH is limited to intervention for posthemorrhagic hydrocephalus. Because most patients with hydrocephalus following PVH-IVH demonstrate spontaneous resolution within weeks of onset, surgical intervention is usually unnecessary.

• Serial lumbar punctures have been used to manage early hydrocephalus. However, because spontaneous resolution of hydrocephalus is usually observed, the utility of this intervention has been questioned. A multicenter evaluation of serial lumbar punctures demonstrated no benefit when the individual with PVH-IVH is aged 30 months. The role of serial lumbar punctures in the management of late or rapidly progressive hydrocephalus remains controversial.
• Acetazolamide may be used to diminish CSF production and limit late or rapidly progressive hydrocephalus. Its utility in the treatment of early ventricular dilatation is probably limited.
• Ventriculostomy placement may be required for the management of significant hydrocephalus while awaiting definitive surgical drainage.
• Ventriculoperitoneal and ventriculosubgaleal shunting remain the definitive treatments for posthemorrhagic hydrocephalus requiring surgical intervention.

Consultations

• Consult neurosurgery in the event of rapidly progressive ventricular enlargement or prolonged (>4 wk) slowly progressive ventricular enlargement.
• Neurology consultation might be of value in the event of intractable seizures in an individual with PVH-IVH.
• A developmental interventionist might be of help with a patient with high-grade hemorrhages.

MEDICATION

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Pharmacological intervention in the prevention and treatment of PVH-IVH and posthemorrhagic hydrocephalus remains controversial.

Drug Category: Prostaglandin inhibitors

These agents are postulated to perform prostaglandin synthesis inhibition. They inhibit free radical formation and accelerates maturation of germinal matrix vasculature. Indomethacin has been shown to decrease the risk of high-grade PVH-IVH. However, developmental outcomes have not been shown to be improved with the use of indomethacin prophylaxis. For this reason, the role of indomethacin in the prevention of IVH remains uncertain. Analysis of patients enrolled in a multicenter trial of indomethacin prophylaxis suggests that prophylaxis is effective in male infants and not in female infants. This remains to be confirmed through prospective evaluations.

Other members of this class of drugs have not been demonstrated to be of value in reducing the incidence of PVH-IVH.

Drug Category: Carbonic anhydrase inhibitors

These agents suppress CSF production.

FOLLOW-UP

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Further Inpatient Care

• Developmental intervention programs

Further Outpatient Care

• Neurological follow-up
• Developmental follow-up

Deterrence/Prevention

• Prevention of PVH-IVH begins with avoidance of conditions that do the following:
• • Interfere with autoregulation (eg, hypocarbia, hypercarbia, hypoxia, acidosis
  • Overwhelm autoregulatory abilities (eg, hypertension)
  • Contribute to rapid fluctuations of cerebral blood flow (eg, ventilatory asynchrony, rapid volume expansion, noxious stimuli, frequent handling)
• Perform correction of host factors (eg, coagulopathy, acid-base balance, hydration, hypoxia-ischemia).
• Pharmacological prophylaxis can be accomplished through the use of indomethacin. Although the mechanism of action is currently unknown, indomethacin has been shown to reduce the incidence of PVH-IVH and, specifically, high-grade hemorrhages. Follow-up of patients enrolled in a multicenter prophylaxis study conducted by Ment was less convincing. Although motor skills are not different when patients are aged 4.5 years, cognitive and social skills appear better in patients receiving prophylaxis. However, because of complications, this therapy is not universally accepted and remains controversial.
• In addition to effects on pulmonary development, prenatal treatment with glucocorticoids has a protective effect with regard to PVH-IVH.
• The use of other pharmacological modalities to prevent PVH-IVH has been proposed; however, this use is not widely accepted. The other pharmacological modalities include prenatal treatment with vitamin K and phenobarbital and postnatal treatment with Ethamsylate, phenobarbital, and vitamin E. Although positive reports concerning the efficacy of these agents exist, further investigation is required to prove conclusive evidence of benefit.

Complications

• Obstructive hydrocephalus
• Nonobstructive hydrocephalus
• Developmental impairment
• Cerebral palsy
• Seizures

Prognosis

• Grade I and grade II hemorrhage: Neurodevelopmental prognosis is excellent (ie, perhaps slightly worse than infants of similar gestational ages without PVH-IVH).
• Grade III hemorrhage without white matter disease: Mortality is less than 10%. Of these patients, 30-40% have subsequent cognitive or motor disorders.
• Grade IV (severe PVH-IVH) IVH with either periventricular hemorrhagic infarction and/or periventricular leukomalacia: Mortality approaches 80%. A 90% incidence of severe neurological sequelae including cognitive and motor disturbances exists.

Patient Education

• Prenatal
• • Specific risks of gestational age
  • Sequelae
• Postnatal
• • Provide postnatal education (if not provided previously) or reinforce prenatal education.
  • Provide results of sonography and expectations for short-term and long-term care.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Use of indomethacin
• • According to randomized controlled trials, the use of indomethacin appears to be effective in the prevention of PVH-IVH. However, this therapy is not accepted universally because of potential complications of treatment and failure to demonstrate significantly improved developmental outcomes after prophylaxis. Whether or not failure to use indomethacin (or the use of the drug with subsequent complications) could result in civil liability is not clear. Complications related to the use of indomethacin (including intestinal perforation) may also present liability.
  • In order to be effective, indomethacin must be administered within hours of birth. The number of at-risk premature patients who could conceivably receive the drug is large. Obtaining a pre-indomethacin echocardiogram to rule out an underlying cardiac condition in which patency of the ductus arteriosus is essential may be considered impractical and not cost effective. Whether or not legal risk is associated with the failure to diagnose a ductal-dependent lesion prior to administering indomethacin is not clear.

Special Concerns

• In patients with posthemorrhagic ventricular dilation that regresses, provide close follow-up care because hydrocephalus can recur.

MULTIMEDIA

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Media file 1:  Sonographic appearance of a normal neonatal brain. Image is from a coronal midline scan.
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Media file 2:  Normal neonatal brain shown with left sagittal scan.
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Media file 3:  Normal neonatal brain shown with midline sagittal scan.
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Media file 4:  Grade I hemorrhage minimal or grade I periventricular hemorrhage (PVH).
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Media file 5:  Moderate or grade II hemorrhage (subependymal with no or little ventricular enlargement).
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Media file 6:  Severe or grade III hemorrhage (subependymal with significant ventricular enlargement).
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Media file 7:  Intraventricular hemorrhage (IVH) with periventricular hemorrhagic infarction (PVHI).
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Media file 8:  Periventricular hemorrhagic infarction (PVHI) with porencephalic cyst formation.
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Media file 9:  Periventricular hemorrhagic infarction (PVHI) on MRI.
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Media file 10:  Hydrocephalus.
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REFERENCES

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Article Last Updated: Jun 19, 2006