Periventricular leukomalacia

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Periventricular leukomalacia
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Drawing of the lateral and third ventricles of the brain. Periventricular leukomalacia involves death of the white matter surrounding the lateral ventricles in fetuses and infants. (Image from Gray's Anatomy, 1918 edition)
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Periventricular leukomalacia (PVL) is a form of white-matter brain injury, characterized by the necrosis (more often coagulation) of white matter near the lateral ventricles. [1] [2] It can affect newborns and (less commonly) fetuses; premature infants are at the greatest risk of neonatal encephalopathy which may lead to this condition. Affected individuals generally exhibit motor control problems or other developmental delays, and they often develop cerebral palsy or epilepsy later in life. The white matter in preterm born children is particularly vulnerable during the third trimester of pregnancy when white matter developing takes place and the myelination process starts around 30 weeks of gestational age. [3]

Contents

This pathology of the brain was described under various names ("encephalodystrophy", "ischemic necrosis", "periventricular infarction", "coagulation necrosis", "leukomalacia", "softening of the brain", "infarct periventricular white matter", "necrosis of white matter", "diffuse symmetrical periventricular leukoencephalopathy"), and more often by German scientists, but the worldwide dissemination was the term periventricular leukomalacia, introduced in 1962 B. A. Banker and J. C. Larroche. The term can be misleading, because there is no softening of the tissue in PVL. Vlasyuk and Tumanov [4] in 1985 published the world's first monograph devoted to PVL. Vlasyuk (1981) first revealed the high incidence of optic radiation lesions and demonstrated that PVL is a persistent process where old necrosis can join new foci of PVL at different stages of development.

In the process of morphogenesis focuses PVL pass through three stages: 1) necrosis, 2) resorption, and 3) the formation gliosis scars or cysts. [1] Cysts occur when large and confluent focuses of PVL, with mixed necrosis (kollikvacia in the center and coagulation rim at the periphery). Around the foci is generally defined area of other lesions of the brain white matter - the death of prooligodendrocytes, proliferation mikrogliocytes and astrocytes, swelling, bleeding, loss of capillaries, and others (the so-called "diffuse component PVL"). However, diffuse lesions without necrosis are not PVL.

Presentation

It is often impossible to identify PVL based on the patient's physical or behavioral characteristics. The white matter in the periventricular regions is involved heavily in motor control, and so individuals with PVL often exhibit motor problems. However, since healthy newborns (especially premature infants) can perform very few specific motor tasks, early deficits are very difficult to identify. [5] As the individual develops, the areas and extent of problems caused by PVL can begin to be identified; however, these problems are usually found after an initial diagnosis has been made.

The extent of signs is strongly dependent on the extent of white matter damage: minor damage leads to only minor deficits or delays, while significant white matter damage can cause severe problems with motor coordination or organ function. Some of the most frequent signs include delayed motor development, vision deficits, apneas, low heart rates, and seizures.

Delayed motor development

Delayed motor development of infants affected by PVL has been demonstrated in multiple studies. [6] One of the earliest markers of developmental delays can be seen in the leg movements of affected infants, as early as one month of age. Those with white matter injury often exhibit "tight coupling" of leg joints (all extending or all flexing) much longer than other infants (premature and full-term). [7] Additionally, infants with PVL may not be able to assume the same positions for sleeping, playing, and feeding as premature or full-term children of the same age. [6] These developmental delays can continue throughout infancy, childhood, and adulthood.

Vision deficits

Premature infants often exhibit visual impairment and motor deficits in eye control immediately after birth. However, the correction of these deficits occurs "in a predictable pattern" in healthy premature infants, and infants have vision comparable to full-term infants by 36 to 40 weeks after conception. Infants with PVL often exhibit decreased abilities to maintain a steady gaze on a fixed object and create coordinated eye movements. [8] Additionally, children with PVL often exhibit nystagmus, strabismus, and refractive error.

Seizures

Occurrence of seizures is often reported in children with PVL. In an Israel-based study of infants born between 1995 and 2002, seizures occurred in 102 of 541, or 18.7%, of PVL patients. [9] Seizures are typically seen in more severe cases of PVL, affecting patients with greater amounts of lesions and those born at lower gestational ages and birth weights.

Causes

Predisposing factors

Those generally considered to be at greatest risk for PVL are premature, very low birth-weight infants. It is estimated that approximately 3-4% of infants who weigh less than 1,500 g (3.3 lb) have PVL, and 4-10% of those born prior to 33 weeks of gestation (but who survive more than three days postpartum) have the disorder. [2] Gestational CMV infection also produces PVL in neonates. [10]

Injury pathway

Two major factors appear to be involved in the development of PVL: (1) decreased blood or oxygen flow to the periventricular region (the white matter near the cerebral ventricles) and (2) damage to glial cells, the cells that support neurons throughout the nervous system. [9] These factors are especially likely to interact in premature infants, resulting in a sequence of events that leads to the development of white matter lesions.

The initial hypoxia (decreased oxygen flow) or ischemia (decreased blood flow) can occur for a number of reasons. Fetal blood vessels are thin-walled structures, and it is likely that the vessels providing nutrients to the periventricular region cannot maintain a sufficient blood flow during episodes of decreased oxygenation during development. [2] Additionally, hypotension resulting from fetal distress or cesarean section births can lead to decreased blood and oxygen flow to the developing brain. These hypoxic-ischemic incidents can cause damage to the blood brain barrier (BBB), a system of endothelial cells and glial cells that regulates the flow of nutrients to the brain. A damaged BBB can contribute to even greater levels of hypoxia. Alternatively, damage to the BBB can occur due to maternal infection during fetal development, fetal infections, or infection of the newly delivered infant. Because their cardiovascular and immune systems are not fully developed, premature infants are especially at risk for these initial insults.

Damage caused to the BBB by hypoxic-ischemic injury or infection sets off a sequence of responses called the inflammatory response. Immediately after an injury, the nervous system generates "pro-inflammatory" cytokines, which are molecules used to coordinate a response to the insult. [11] These cytokines are toxic to the developing brain, and their activity in an effort to respond to specific areas of damaged tissue is believed to cause "bystander damage" to nearby areas that were not affected by the original insult. [12] Further damage is believed to be caused by free radicals, compounds produced during ischemic episodes. The processes affecting neurons also cause damage to glial cells, leaving nearby neurons with little or no support system.

It is thought that other factors might lead to PVL, and researchers are studying other potential pathways. A 2007 article by Miller, et al., provides evidence that white-matter injury is not a condition limited to premature infants: full-term infants with congenital heart diseases also exhibit a "strikingly high incidence of white-matter injury." [13] In a study described by Miller, of 41 full-term newborns with congenital heart disease, 13 infants (32%) exhibited white matter injury.

Diagnosis

As previously noted, there are often few signs of white matter injury in newborns. Occasionally, physicians can make the initial observations of extreme stiffness or poor ability to suckle. The preliminary diagnosis of PVL is often made using imaging technologies. In most hospitals, premature infants are examined with ultrasound soon after birth to check for brain damage. Severe white matter injury can be seen with a head ultrasound; however, the low sensitivity of this technology allows for some white matter damage to be missed. Magnetic resonance imaging (MRI) is much more effective at identifying PVL, but it is unusual for preterm infants to receive an MRI unless they have had a particularly difficult course of development (including repeated or severe infection, or known hypoxic events during or immediately after birth). [5] No agencies or regulatory bodies have established protocols or guidelines for screening of at-risk populations, so each hospital or doctor generally makes decisions regarding which patients should be screened with a more sensitive MRI instead of the basic head ultrasound.

PVL is overdiagnosed by neuroimaging studies and the other white matter lesions of the brain are underestimated. It is important to differentiate PVL from the following major white matter lesions in the cerebral hemispheres: edematous hemorrhagic leukoencephalopathy (OGL), telentsefalny gliosis (TG), diffuse leukomalacia (DFL), subcortical leukomalacia (SL), periventricular hemorrhagic infarction (PHI), intracerebral hemorrhage ( ICH), multicystic encephalomalacia (ME), subendymal pseudocyst. Diffuse white matter lesions of the cerebral hemispheres of the brain, accompanied by softening and spreading to the central and subcortical areas are more likely DFL, PHI and ME. [1]

Prevention

Preventing or delaying premature birth is considered the most important step in decreasing the risk of PVL. Common methods for preventing a premature birth include self-care techniques (dietary and lifestyle decisions), bed rest, and prescribed anti-contraction medications. Avoiding premature birth allows the fetus to develop further, strengthening the systems affected during the development of PVL.

An emphasis on prenatal health and regular medical examinations of the mother can also notably decrease the risk of PVL. Prompt diagnosis and treatment of maternal infection during gestation reduces the likelihood of large inflammatory responses. Additionally, treatment of infection with steroids (especially in the 24–34 weeks of gestation) have been indicated in decreasing the risk of PVL. [14]

It has also been suggested that avoiding maternal cocaine usage and any maternal-fetal blood flow alterations can decrease the risk of PVL. [2] Episodes of hypotension or decreased blood flow to the infant can cause white matter damage.

Treatment

Current treatments

Currently, there are no treatments prescribed for PVL. All treatments administered are in response to secondary pathologies that develop as a consequence of the PVL. Because white matter injury in the periventricular region can result in a variety of deficits, neurologists must closely monitor infants diagnosed with PVL in order to determine the severity and extent of their conditions.

Patients are typically treated with an individualized treatment. It is crucial for doctors to observe and maintain organ function: visceral organ failure can potentially occur in untreated patients. Additionally, motor deficits and increased muscle tone are often treated with individualized physical and occupational therapy treatments. [6]

Treatment challenges

The fetal and neonatal brain is a rapidly changing, developing structure. Because neural structures are still developing and connections are still being formed at birth, many medications that are successful for treatment and protection in the adult central nervous system (CNS) are ineffective in infants. Moreover, some adult treatments have actually been shown to be toxic to developing brains. [5]

Future treatments

Although no treatments have been approved for use in human PVL patients, a significant amount of research is occurring in developing treatments for protection of the nervous system. Researchers have begun to examine the potential of synthetic neuroprotection to minimize the amount of lesioning in patients exposed to ischemic conditions. [15]

Prognosis

The prognosis of patients with PVL is dependent on the severity and extent of white matter damage. Some children exhibit relatively minor deficits, while others have significant deficits and disabilities.

Minor tissue damage

Minor white matter damage usually is exhibited through slight developmental delays and deficits in posture, vision systems, and motor skills. [6] [8] Many patients exhibit spastic diplegia, [2] a condition characterized by increased muscle tone and spasticity in the lower body. The gait of PVL patients with spastic diplegia exhibits an unusual pattern of flexing during walking. [16]

Progression

Those patients with severe white matter injury typically exhibit more extensive signs of brain damage. Infants with severe PVL suffer from extremely high levels of muscle tone and frequent seizures. Children and adults may be quadriplegic, exhibiting a loss of function or paralysis of all four limbs.

Cerebral palsy

Many infants with PVL eventually develop cerebral palsy. The percentage of individuals with PVL who develop cerebral palsy is generally reported with significant variability from study to study, with estimates ranging from 20% to more than 60%. [2] [6] One of the reasons for this discrepancy is the large variability in severity of cerebral palsy. This range corresponds to the severity of PVL, which can also be quite variable. [17] More white matter damage leads to more severe cerebral palsy; different subtypes are identified and diagnosed by a neurologist.

Despite the varying grades of PVL and cerebral palsy, affected infants typically begin to exhibit signs of cerebral palsy in a predictable manner. Typically, some abnormal neurological signs (such as those previously mentioned) are visible by the third trimester of pregnancy (28 to 40 weeks after conception), and definitive signs of cerebral palsy are visible by six to nine months of age. [18]

Epilepsy

Another common but severe outcome of PVL patients is the development of epilepsy. The link between the two is not entirely clear; however, it appears that both genetic and early environmental factors are involved. [19] One study estimated that 47% of children with PVL also have epilepsy, with 78% of those patients having a form of epilepsy not easily managed by medication. [20] Many of these affected patients exhibit some seizures, as well as spastic diplegia or more severe forms of cerebral palsy, before a diagnosis of epilepsy is made.

Frequency

Unfortunately, there are very few population-based studies on the frequency of PVL. As previously described, the highest frequency of PVL is seen in premature, very low birth weight infants. These infants are typically seen in the NICU in a hospital, with approximately 4-20% of patients in the NICU being affected by PVL. [21] On a large autopsy material without selecting the most frequently detected PVL in male children with birth weight was 1500-2500 g., dying at 6–8 days of life. Diffuse brain damage with softening (diffus leucomalacia, DFL) are found more frequently in children weighing less than 1500 g. However, PVL is not a DFL. [1]

Research

Animal research

Animal models are frequently used to develop improved treatments for and a more complete understanding of PVL. A rat model that has white matter lesions and experiences seizures has been developed, as well as other rodents used in the study of PVL. These animal models can be used to examine the potential efficacy of new medications in the prevention and treatment of PVL. [15]

Clinical research

Current clinical research ranges from studies aimed at understanding the progression and pathology of PVL to developing protocols for the prevention of PVL development. Many studies examine the trends in outcomes of individuals with PVL: a recent study by Hamrick, et al., considered the role of cystic periventricular leukomalacia (a particularly severe form of PVL, involving development of cysts) in the developmental outcome of the infant. [22]

Other ongoing clinical studies are aimed at the prevention and treatment of PVL: clinical trials testing neuroprotectants, prevention of premature births, and examining potential medications for the attenuation of white matter damage are all currently supported by NIH funding.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Head injury</span> Serious trauma to the cranium

A head injury is any injury that results in trauma to the skull or brain. The terms traumatic brain injury and head injury are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of injuries, there are many causes—including accidents, falls, physical assault, or traffic accidents—that can cause head injuries.

<span class="mw-page-title-main">Cerebral palsy</span> Group of movement disorders that appear in early childhood

Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sensation, vision, hearing, and speaking.

<span class="mw-page-title-main">Colpocephaly</span> Medical condition

Colpocephaly is a cephalic disorder involving the disproportionate enlargement of the occipital horns of the lateral ventricles and is usually diagnosed early after birth due to seizures. It is a nonspecific finding and is associated with multiple neurological syndromes, including agenesis of the corpus callosum, Chiari malformation, lissencephaly, and microcephaly. Although the exact cause of colpocephaly is not known yet, it is commonly believed to occur as a result of neuronal migration disorders during early brain development, intrauterine disturbances, perinatal injuries, and other central nervous system disorders. Individuals with colpocephaly have various degrees of motor disabilities, visual defects, spasticity, and moderate to severe intellectual disability. No specific treatment for colpocephaly exists, but patients may undergo certain treatments to improve their motor function or intellectual disability.

Porencephaly is an extremely rare cephalic disorder involving encephalomalacia. It is a neurological disorder of the central nervous system characterized by cysts or cavities within the cerebral hemisphere. Porencephaly was termed by Heschl in 1859 to describe a cavity in the human brain. Derived from Greek roots, the word porencephaly means 'holes in the brain'. The cysts and cavities are more likely to be the result of destructive (encephaloclastic) cause, but can also be from abnormal development (malformative), direct damage, inflammation, or hemorrhage. The cysts and cavities cause a wide range of physiological, physical, and neurological symptoms. Depending on the patient, this disorder may cause only minor neurological problems, without any disruption of intelligence, while others may be severely disabled or die before the second decade of their lives. However, this disorder is far more common within infants, and porencephaly can occur both before or after birth.

<span class="mw-page-title-main">Kernicterus</span> Medical condition

Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration in the blood is too high, a condition known as hyperbilirubinemia. Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the central nervous system, potentially causing irreversible neurological damage. Depending on the level of exposure, the effects range from clinically unnoticeable to severe brain damage and even death.

<span class="mw-page-title-main">Brain damage</span> Destruction or degeneration of brain cells

Neurotrauma, brain damage or brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage.

Hypotonia is a state of low muscle tone, often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength. Hypotonia is a lack of resistance to passive movement, whereas muscle weakness results in impaired active movement. Central hypotonia originates from the central nervous system, while peripheral hypotonia is related to problems within the spinal cord, peripheral nerves and/or skeletal muscles. Severe hypotonia in infancy is commonly known as floppy baby syndrome. Recognizing hypotonia, even in early infancy, is usually relatively straightforward, but diagnosing the underlying cause can be difficult and often unsuccessful. The long-term effects of hypotonia on a child's development and later life depend primarily on the severity of the muscle weakness and the nature of the cause. Some disorders have a specific treatment but the principal treatment for most hypotonia of idiopathic or neurologic cause is physical therapy and/or occupational therapy for remediation.

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Gray matter heterotopia is a neurological disorder caused by gray matter being located in an atypical location in the brain.

<span class="mw-page-title-main">Intraventricular hemorrhage</span> Medical condition

Intraventricular hemorrhage (IVH), also known as intraventricular bleeding, is a bleeding into the brain's ventricular system, where the cerebrospinal fluid is produced and circulates through towards the subarachnoid space. It can result from physical trauma or from hemorrhagic stroke.

Spastic quadriplegia, also known as spastic tetraplegia, is a subset of spastic cerebral palsy that affects all four limbs.

Neonatal encephalopathy (NE), previously known as neonatal hypoxic-ischemic encephalopathy, is defined as a encephalopathy syndrome with signs and symptoms of abnormal neurological function, in the first few days of life in an infant born after 35 weeks of gestation. In this condition there is difficulty initiating and maintaining respirations, a subnormal level of consciousness, and associated depression of tone, reflexes, and possibly seizures.Hypoxia refers to deficiency of oxygen, Ischemia refers to restriction in blood flow to the brain. The result is “encephalopathy” which refers to damaged brain cells. Encephalopathy is a nonspecific response of the brain to injury which may occur via multiple methods, but is commonly caused by birth asphyxia, leading to cerebral hypoxia.

Dyskinetic cerebral palsy (DCP) is a subtype of cerebral palsy (CP) and is characterized by impaired muscle tone regulation, coordination and movement control. Dystonia and choreoathetosis are the two most dominant movement disorders in patients with DCP.

<span class="mw-page-title-main">Athetoid cerebral palsy</span> Type of cerebral palsy associated with basal ganglia damage

Athetoid cerebral palsy, or dyskinetic cerebral palsy, is a type of cerebral palsy primarily associated with damage, like other forms of CP, to the basal ganglia in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic–ischemic brain injury. Unlike spastic or ataxic cerebral palsies, ADCP is characterized by both hypertonia and hypotonia, due to the affected individual's inability to control muscle tone. Clinical diagnosis of ADCP typically occurs within 18 months of birth and is primarily based upon motor function and neuroimaging techniques. While there are no cures for ADCP, some drug therapies as well as speech, occupational therapy, and physical therapy have shown capacity for treating the symptoms.

<span class="mw-page-title-main">Ataxic cerebral palsy</span> Medical condition

Ataxic cerebral palsy is clinically in approximately 5–10% of all cases of cerebral palsy, making it the least frequent form of cerebral palsy diagnosed. Ataxic cerebral palsy is caused by damage to cerebellar structures, differentiating it from the other two forms of cerebral palsy, which are spastic cerebral palsy and dyskinetic cerebral palsy.

<span class="mw-page-title-main">Spastic cerebral palsy</span> Cerebral palsy characterized by high muscle tone

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<span class="mw-page-title-main">Ulegyria</span> Type of cortical scarring deep in the sulci

Ulegyria is a diagnosis used to describe a specific type of cortical scarring in the deep regions of the sulcus that leads to distortion of the gyri. Ulegyria is identified by its characteristic "mushroom-shaped" gyri, in which scarring causes shrinkage and atrophy in the deep sulcal regions while the surface gyri are spared. This condition is most often caused by hypoxic-ischemic brain injury in the perinatal period. The effects of ulegyria can range in severity, although it is most commonly associated with cerebral palsy, mental retardation and epilepsy. N.C. Bresler was the first to view ulegyria in 1899 and described this abnormal morphology in the brain as “mushroom-gyri." Although ulegyria was first identified in 1899, there is still limited information known or reported about the condition.

<span class="mw-page-title-main">Yoon Bo-hyun</span> South Korean gynecologist (born 1955)

Yoon Bo-hyun (Korean: 윤보현) is a South Korean physician and scientist in the medical area of obstetrics and gynecology. He researches in the area of preterm births, intra-amniotic infection or inflammation and fetal damage. For his theoretical and clinical academic achievements he received the Top Scientist and Technologist Award of Korea in 2012.

<span class="mw-page-title-main">General movements assessment</span>

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Cranial ultrasound is a technique for scanning the brain using high-frequency sound waves. It is used almost exclusively in babies because their fontanelle provides an "acoustic window". A different form of ultrasound-based brain scanning, transcranial Doppler, can be used in any age group. This uses Doppler ultrasound to assess blood flow through the major arteries in the brain, and can scan through bone. It is not usual for this technique to be referred to simply as "cranial ultrasound". Additionally, cranial ultrasound can be used for intra-operative imaging in adults undergoing neurosurgery once the skull has been opened, for example to help identify the margins of a tumour.

References

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  13. ↑ Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, et al. (November 2007). "Abnormal brain development in newborns with congenital heart disease". The New England Journal of Medicine. 357 (19): 1928–1938. doi: 10.1056/NEJMoa067393 . PMID   17989385.
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  16. ↑ Yokochi K (March 2001). "Gait patterns in children with spastic diplegia and periventricular leukomalacia". Brain & Development. 23 (1): 34–37. doi:10.1016/S0387-7604(00)00200-X. PMID   11226727. S2CID   31512514.
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  19. ↑ Gururaj AK, Sztriha L, Bener A, Dawodu A, Eapen V (March 2003). "Epilepsy in children with cerebral palsy". Seizure. 12 (2): 110–114. doi: 10.1016/S1059131102002558 . PMID   12566235. S2CID   14691323.
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  22. ↑ Hamrick SE, Miller SP, Leonard C, Glidden DV, Goldstein R, Ramaswamy V, et al. (November 2004). "Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia". The Journal of Pediatrics. 145 (5): 593–599. doi:10.1016/j.jpeds.2004.05.042. PMID   15520756.
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