Understanding How Neuroimaging Can Time Asphyxial Injury
By Armand Leone, Jr., MD, Esq.
If you have ever experienced that frustrated feeling of receiving a report from a Neuroradiologist, claiming that the Neuroimaging studies are inconsistent with the timing of injury in an otherwise good liability Birth Trauma case, this discussion is for you and if you haven’t had the experience, here is what you will want to know.
There are a number of indirect markers of hypoxic ischemic encephalopathy (HIE), but neuroimaging is argued to be the most direct and accurate test for showing both the brain injury and the time when it occurred. If the timing of the injury on neuroimaging does not correlate with the timing of the obstetrical deviations, then the ability to prove causation can be lost. Demonstrating deviations from standards of obstetrical care, in a child with neurological impairment, are insufficient, without proof of causation, to support recovery in brain damaged infant cases. Causation is often the most difficult evidentiary hurdle to overcome in order to win a hypoxic ischemic brain injury case.
In order to understand the importance of neuroimaging, it is first important to understand certain anatomic and physiologic considerations of the neonate. Change in the vascular supply to the neonatal brain and the differences in the metabolic rates of various brain structures explain the different patterns of injury that are seen on imaging in hypoxic ischemic injury during gestation and parturition. The age of the baby at the time of insult, the acuteness of the hypoxic event, the length of time the hypoxic event lasted, the imaging study used and the time between injury and imaging are important factors for determining the injury pattern. Prior to about 36 weeks of gestation, the vascular watershed zones between overlapping arterial territories supplying the brain are found centrally in the white matter next to the ventricles. This watershed zone moves outward with development and lies under the cortex in the peripheral subcortical grey matter area of the brain. The acute and chronic radiographic appearances of pre-term and term HIE are readily visualized on CT and MRI images.
Areas of hypermetabolic activity in the brain of a fetus less than 36 weeks are the thalami and the brainstem, and severe hypoxic ischemic injury during this time affects not only the periventricular white matter, but these deep gray matter structures as well. In term infants, hypermetabolic areas are the lateral thalami, globus pallidus, posterior putamina, hippocampi, brain stem and sensorimotor cortex. Hypoxic ischemic injury during this time period causes abnormalities in these structures, but the ability to detect these abnormalities requires neuroradiological expertise because they are subtle and difficult to see. Ultimately, the extent and exact pattern of injury depends on the severity and duration of the hypoxic insult.
The mechanism of cellular injury that underlies these hypoxic ischemic injuries is a cascade of deleterious events resulting from decreased oxygenated blood flow. Acidosis, release of inflammatory mediators and excitatory neurotransmitters, free radical formation, calcium accumulation and lipid peroxidation combine to cause loss of vascular autoregulation, impairment of cellular metabolism and eventual neuronal death. Reperfusion and reoxygenation following the cessation of an ischemic event causes further neuronal damage from cytotoxic free radical formation.
Early Markers of Fetal Distress
It is also important to understand the evolution of the identification of fetal distress and related injury to the newborn. Electronic Fetal Heart (EFM) monitoring (cardiotocography) has been used for decades during labor to measure the fetal heart rate during labor and to detect abnormal patterns that indicate a lack of blood flow to the fetus and neonatal distress. However, many articles have appeared claiming that EFM does not correlate well with actual outcomes and has a significant amount of subjectivity in the interpretation. Non-reassuring tracings do not always result in compromised babies, and reassuring tracings do not preclude intrapartum injuries, especially those that occur at or about the moment of birth.
APGAR scores were developed in 1952 prior to much of today’s technology to clinically assess whether an infant was likely to survive and evolved later into an indication of whether a child had suffered birth asphyxia. It was developed before the use of aggressive neonatal resuscitation protocols used when a compromised baby is born today. The APGAR scoring rates the Activity, Pulse, Grimace, Appearance and Respiration of the newborn to determine an overall APGAR score. However, both the subjectivity of the APGAR scoring process and the use of immediate post-partum resuscitation make the APGAR score unreliable as an indicator of intrapartum asphyxial injury. Of more concern for plaintiffs is that the artificially elevated APGAR scores are used by defense counsel to argue that, in face of “good” APGAR scores, no intrapartum injury could have occurred and whatever the infant’s problems are either occurred in utero prior to labor or are genetically based. This legerdemain is abetted by ACOG’s official publications stating that APGARS higher than 3 at 1 minute and 3 at 5 minutes are inconsistent with hypoxic-ischemic brain injury. A diagnosis of hypoxic brain injury is properly made by pediatric neurologists, and pronouncements by ACOG are politically motivated and designed to thwart use of the APGAR score to prove causation in these cases.
Other indirect markers of hypoxic ischemic brain injury have been developed both for purposes of legal proofs, to demonstrate the existence and timing of an intrapartum injury. Blood lymphocyte counts, platelet counts, normoblast counts, nucleated red blood cell levels, umbilical artery pH levels, and differences in base excess values in umbilical arterial and venous bloods are all used as indirect laboratory markers to try to time the hypoxic ischemic brain injury. The determination of when hypoxic ischemic encephalopathy occurred, the rate at which it advanced and when it ended has been historically made by integrating information from clinical, laboratory and placental findings. Most cases do not have positive findings on all of these indirect markers, which provide grist for the mill for the experts to argue the presence and absence of causation.
Neuroimaging with ultrasound, CT and MRI provides a direct way to visualize the brain structures and see injury directly. These imaging techniques also show the pattern of injury and changes of the brain seen on early sequential imaging allow neuroradiologists to determine when an asphyxial insult occurred. Neuroimaging provides credible proof of the hypoxic ischemic injury and, more recently, allows early diagnosis of HIE so that neonatologists can provide hypothermic neuroprotective therapy within 5 to 6 hours and preferably by 4 hours after birth. Prior to the development of neuroprotective therapy, CT scan was usually performed and only to identify hemorrhage or tumors for which therapy existed. The importance of detailed neuroimaging did not arise until meaningful therapy for HIE was developed. Since there is now a clinical benefit for early neuroimaging, it is hoped that more neonates who may be compromised during the birthing process will received diagnostic imaging early, which provides a legal benefit in helping to disprove or prove causation in obstetrical malpractice cases.
MRI is the most sensitive and specific imaging technique for examining infants with suspected hypoxic ischemic injury. Conventional T1 and T2 imaging and newer MRI sequencing techniques, such as diffusion-weighted imaging, help exclude other causes of encephalopathy such as hemorrhage, infarction, neoplasm or congenital malformations, as well as demonstrating HIE injury. Hypoxic ischemic injury to gray matter results in characteristic T1 hyperintensity (increased signal brightness on the images) and variable T2 intensity depending on when the imaging is performed in relation to the time of the injury. Hypoxic ischemic injury to white matter generally results in T1 hypointensity (decreased signal brightness on the images) and T2 hyperintensity due to edema in the injured tissue. MR spectroscopy provides biochemical analysis of cerebral tissue and shows the levels of lactate, choline, creatine, N-acetylaspartate (NAA) and glutamine. Elevate lactate and decreased NAA levels are common findings in infants suffering HIE with permanent neurological sequelae. MR spectroscopy during the first 24 hours after birth is extremely sensitive to determining the severity of the hypoxic ischemic brain injury. Unfortunately, MRI imaging is not always available at the institution where the baby is born and, even when it is, is difficult to perform on an infant who has various indwelling catheters, wires and tubes for both safety and technical reasons.
Cranial ultrasound is a convenient, noninvasive low cost imaging modality for unstable babies. It is sensitive for detecting hemorrhage, PVL and hydrocephalus. It can detect HIE changes in the deep brain structures, but is less able to detect edema in the subcortical areas. However, ultrasonography is operator dependent and is less sensitive to structural abnormalities in the cerebrum and the brainstem. Furthermore, parenchymal abnormalities such as PVL and cerebral edema identified on ultrasound are often non-specific.
CT scanning is the least sensitive modality for evaluating hypoxic ischemic injury because the neonatal brain has a high water content and the cerebrospinal fluid has a high protein content which makes for poor tissue contrast resolution. CT scanning has an inherent disadvantage of radiation exposure, but has the ability to provide rapid cranial imaging without the need for sedation to rule out hemorrhage or tumor in a critically ill neonate. CT scans are able to show signs of brain edema through indirect signs of loss of sulci and compressed ventricles.
There are four distinct injury patterns of brain injury which are determined by whether the baby was pre-term (less than 36 weeks) or full term and whether the hypotension was mild to moderate or severe:
Mild to Moderate Hypotension: In pre-term infants less than 36 weeks gestation that suffer an hypoxic ischemic injury from mild to moderate hypotension, the most common location for injury is the periventricular white matter, with neuronal injury presenting as PVL. Ultrasounds shortly after injury show hyperechogenic changes in the periventricular white matter, and MRI images show areas of T1 hyperintensity within larger areas of T2 hyperintensity. MRI spectroscopy can also elevate lactate levels in these areas. The brain shunts blood flow to the higher metabolic deep gray matter areas during mild to moderate hypotension to avoid injury to these structures, but the watershed areas near the ventricles are not spared. After two to six weeks, cavitation and periventricular cyst formation occur and show as hypoechoic or localized anechoic areas around the ventricles. As these cysts coalesce with the ventricles over time, ventriculomegaly occurs. Late stage imaging with CT and MRI shows enlarged ventricles with irregular margins, loss of periventricular white matter and thinning of the corpus callosum.
Severe Hypotension: In pre-term infants, the thalami, brainstem and cerebellum have high metabolic activity and become injured with severe hypotension. On ultrasound, one sees hyperechogenicity in these deep gray matter structures, and CT may show hypoattenuation. MRI imaging also shows abnormalities in these deep gray matter areas, with variable T2 signal. MR spectroscopy will also be positive. Coexisting periventricular white matter injury is usually present.
Mild to Moderate Hypotension: In the term infant, the watershed vascular territories bear the brunt of the injury, but now the primary location of the intervascular watershed is in the subcortical areas in the periphery. The injury causes edema in the cortical and the underlying subcortical areas and is best seen on MRI as hyperintense T2 signal and decreased T1 intensity caused. MR spectroscopy reveals elevate lactate concentrations in injured watershed areas. Ultrasound and CT do not show theses abnormalities well and often are reported as normal when done within 24 hours of the insult. Eventually, the CT and MRI will show brain atrophy tissue with hydrocephalus, enlarged sulci and cystic encephalomalacia.
Severe Hypotension: In the term infant, severe hypotension affects the high metabolic activity areas within the brain, the lateral thalami, globus pallidus, posterior putamina, hippocampi, brain stem and sensorimotor cortex. Early on, MRI shows abnormal T1 hyperintensity and variable T2 intensity in these structures, although the finding can be subtle at times. MR spectroscopy reveals elevated lactate concentrations in the basal ganglia and thalamus. Ultrasound can demonstrate hyperechogenicity of these structures and can also demonstrate an abnormal vascular resistive index on Doppler examination. CT scan findings show mild hypoattenuation of the thalami and basal ganglia but these findings are subtle and often reported as normal. Typically, injuries to the subcortical and cortical areas are also present and are visualized.
Timing the Injury
Neuroimaging later in life can still show whether the injury occurred pre-term, at term or injuries occurred during both periods. When a hypoxic ischemic injury occurs pre-term, the permanent injury pattern typically shows enlarged ventricles with irregular margins, loss of white matter, and thinning of the corpus callosum on MRI and CT Scan. If the pre-term injury was severe enough and the brain was not able to spare the hypermetabolic areas, the thalamus and brainstem may also demonstrate permanent abnormalities. The child with spastic cerebral palsy but with normal intellectual function is an example of pre-term white matter injury without cortical gray matter injury. Unless the alleged obstetrical deviations and avoidable hypoxic ischemic insult occurred prior to about 36 weeks of gestation, a pre-term injury pattern of enlarged irregular ventricles and reduced white matter with cortical sparing is not consistent with an obstetrical injury in a term baby.
Depending on the imaging modalities used, sequential neuroimaging can connect the injury to the obstetrical treatment by tracking the edematous reaction and metabolites caused by hypoxia. MRI is the most sensitive modality for timing an injury but is typically the least used imaging technique because of the difficulties of performing an MRI on an acutely ill baby. MR spectroscopy shows specific chemical markers of hypoxia that are known to have well defined timelines of increasing and decreasing levels. Unfortunately, MR spectroscopy is used even less often than brain MRI in depressed infants. When spectroscopy is done, it allows very accurate timing of the injury based on the levels of lactate and NAA. Typically however, ultrasound and CT examinations are performed on depressed babies because they are easier to do and are more generally available. With these imaging studies, one often has to coordinate the findings on these differing imaging modalities to try to determine the time of the injury.
When a hypoxic ischemic injury occurs at term, neuroimaging serves two purposes. The first thing that neuroimaging can confirm is that the insult occurred after 36 weeks of gestation and, thus, could have occurred at birth. This term injury pattern is localized to the subcortical gray matter and sensorimotor cortex and the death of neuronal tissue in the subcortical and cortical brain areas leads to brain atrophy with deep sucli and increased cerebrospinal fluid around the brain.
If neuroimaging is done relatively soon after birth, neuroimaging can determine the number of hours prior to the imaging that the hypoxic ischemic injury occurred. This can be done by sequential imaging that tracks the development and resolution of cerebral edema. Cerebral edema occurs within 24 to 28 hours after injury and dissipates within the next 48 hours. It basically occurs within a day or two and then resolves in the next two days. When the brain suffers a hypoxic ischemic insult, the cascade of deleterious events causes injury to the blood brain barrier and cerebral edema occurs. This causes swelling of the brain and, when present, loss of cortical sulci, compression of the ventricles and loss of the demarcation between gray and white matter. CT and MRI can be used to track the edematous reaction and time the injury.
A good example is an acute hypoxic ischemic event that occurs about 2 hours prior to the birth due to an alleged failure to do a caesarian section at that time based on the electronic fetal heart tracing. The child begins to have seizures and has a Brain CT scan at 20 hours of life which is read as normal. A subsequent CT scan is done at 48 hours of life and is reported as loss of cortical sulci and small ventricles consistent with cerebral edema. A CT scan done at 5 days of life shows some loss of gray white matter differentiation, but no edema. A CT scan done at 1 year of age shows brain atrophy and cystic encephalomalacia. By integrating this neuroimaging data, one can say that the hypoxic ischemic insult occurred within four hours of the birth. The CT Scan done at 48 hours showed the cerebral edema diagnostic of HIE. However, cerebral edema can exist anytime between 24 – 96 hours after injury, so this CT scan can only determine that this injury occurred anytime between 48 hours before the birth and 24 hours after the birth. However, the normal CT scan at 20 hours of life indicates that the injury could not have occurred earlier than 4 hours before the birth. The neuroimaging has narrowed the timing of injury to a window between 4 hours prior to the birth. This is consistent with the evidence on the electronic fetal heart monitor and the alleged obstetrical deviations two hours prior to birth.
As Attorneys handling Birth Trauma cases, we need to consult with pediatric neuroradiologists when assembling the proofs in a brain damaged infant case and, preferably, before filing suit. It is important that the neuroradiologist have special training in pediatric neuroradiology, because there are sufficient differences in the anatomy of a neonatal and adult brain that create subtle differences in the imaging of both normal and abnormal structures. We all need to obtain the neuroimaging evidence early in the case during the investigational stage and send to a qualified pediatric neuroradiologist to review. With this knowledge in hand, we can determine which cases can be successfully litigated. In obstetrical negligence cases, the neuroimaging pictures can be worth more than a thousand words.