Hypoxic–Ischemic Encephalopathy (Preterm, Term, and Adult)



Fig. 1
Severe asphyxia in a preterm neonate. DWI image shows hyperintensity in the thalami



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Fig. 2
T1WI in a preterm neonate who suffered severe asphyxia shows hyperintensity in the thalami and posterior lentiform nuclei. The high signal in T1 can persist into the chronic stage




Mild-to-Moderate Asphyxia


The most characteristic pattern of injury in mild-to-severe asphyxia in preterm babies is determined by direct injury and hemorrhage of the germinal matrix. The germinal matrix is a highly cellular region that lines the walls of the lateral ventricles in fetal life and from where neurons and glia arise and migrate. It is most active between the second half of the first trimester and the first half of the second trimester. Thereafter, it starts to involute by the first half of the third trimester so that by the 34th week, the germinal zones have almost completely involute. For this reason, germinal matrix hemorrhages are infrequent before this age [3]. A very important anatomic landmark to recognize is the caudothalamic notch. The caudothalamic notch is a groove where the last remnant of the germinal matrix to involute – the ganglionic eminence – is located. The caudothalamic notch is a groove located between the caudate head and the thalamus and is where most of germinal matrix hemorrhages originate. The pathogenesis of germinal matrix hemorrhage is related to the relative higher vascularization of this region and the properties of the vascular bed in it. The capillaries in this region are fragile, mainly because they are lined only by simple endothelium and lack the muscular or collagenous layers that are present in the larger blood vessels. Second, cells that compose their endothelium have high concentration of mitochondria reflecting their high oxidative metabolic requirements. This makes them susceptible to hypoxic conditions. It is believed that first, this fragile endothelium suffers a loss of integrity due to hypoxia and then with restoration of the normal circulation by resuscitation, bleeding ensues. This hemorrhage can be localized in the caudothalamic notch or extend to the ventricles. The prevalence of intraventricular hemorrhage in preterm neonates weighting less than 2 Kg has been estimated at approximately 25 % and most of them are related to hemorrhages of the germinal matrix. Also, it is known that most hemorrhages happen within the first 24 h of life and that infants who are very premature and with a very low birth weight are at higher risk for developing intraventricular hemorrhage [18, 19].

Germinal matrix hemorrhages are divided in four grades reflecting their locations and degree of dilatation of the ventricles (Table 1).


Table 1
Germinal matrix hemorrhage (GMH) – periventricular hemorrhage (IVH) grading


















Grade I

Subependymal GMH (mostly in the caudothalamic groove)

Grade II

GMH and IVH with or without mild ventriculomegaly

Grade III

GMH and IVH with ventriculomegaly

Grade IV

Above + periventricular parenchymal hemorrhagic infarction (not true GMH)

Grades I–III are hemorrhages that arise from the germinal matrix and have variable extension to the lateral ventricles. Grade IV hemorrhages are not germinal matrix hemorrhages but are parenchymal periventricular hemorrhagic infarcts, probably venous in origin, with extension to the ventricular system. There is a correlation between higher hemorrhage grade and higher perinatal mortality rates as well as a higher prevalence of long-term neurological sequelae [10].

Germinal matrix and intraventricular hemorrhages can be adequately evaluated with cranial US (Figs. 3, 4, and 5), keeping in mind that sometimes the findings can be subtle and difficult to visualize. US of the posterior fossa by a posterior fontanelle approach, as a complement to the classic anterior fontanelle examination, can help to better visualize the posterior supra- and infratentorial structures. This can help to diagnose subtle intraventricular hemorrhages when the ventricles are not dilated and cerebellar hemorrhages that are believed to be underdiagnosed. These last types of hemorrhages are clinically silent but are not uncommon and are recognized in 10–20 % of autopsies. In fact, cerebellar hemorrhages are believed to be no different in origin than caudothalamic notch hemorrhages also arising from germinal matrix remnants within the external granule cell layer of the cerebellum and in the subependymal layer of the roof of the fourth ventricle [3, 20, 21]. Cerebellar hemorrhages are seen as lentiform or crescent-shaped hyperechoic lesions located posterior and peripheral in the cerebellar hemispheres. MRI is usually the next study used most of the times to detect concomitant injuries such as white matter injury of prematurity or deep gray matter injury.

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Fig. 3
US image in a preterm patient. Coronal (a) and sagittal (b) images demonstrate bilateral areas of subependymal echogenicity, right greater than left. The sagittal image confirms the location in the caudothalamic groove. Choroid plexus is large and thought not to be related to the hemorrhage. GMH grade I


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Fig. 4
US coronal (a) and sagittal (b) images in a preterm neonate demonstrate extension of the left side hemorrhage into the lateral ventricles, right greater than left. The ventricles are not enlarged. GMH grade II


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Fig. 5
US coronal (a) and sagittal (b) images in a preterm neonate demonstrate bilateral intraventricular hemorrhage with enlargement of the lateral ventricles. GMH grade III

Another common manifestation that can be seen in mild-to-moderate asphyxia in preterm babies is periventricular leukomalacia (PVL), also known as white matter injury of prematurity. This type of injury also appears to be inversely related to gestational age at birth. Its pathogenesis is believed to be related to selective vulnerability of oligodendrocyte precursors and to perturbations in cerebral blood flow in a context of anatomic and physiological immaturity of the blood vessels in preterm patients [22, 23]. These oligodendrocyte precursors are late precursors known as preoligoendrocytes, and the white matter in the period prior to myelination is populated with them. This is the period of higher risk for PVL, as these late precursor cells are believed to be even more susceptible to hypoxia than the earlier precursor cells or the mature oligodendrocytes [24]. This explanation is supported by the fact that the prevalence of PVL declines after 32 weeks, the same time that the population of these late precursors in the periventricular white matter maturates into oligodendrocytes. Also, damage to a particular subpopulation of vulnerable neurons plays a role in the development of PVL. These are called subplate neurons and they contribute to cortical development and in particular to the formation of thalamocortical connections. They form a transient cell population that peaks at approximately 24 weeks (the onset of the developmental window of vulnerability) and later undergoes apoptosis [25]. The subplate which can reach up to four times the width of the cortical plate has been shown by MRI to be affected by hypoxic injury.

PVL is most commonly seen in the peritrigonal region and adjacent to the foramina of Monro [33, 37]. It can have a cavitary or non-cavitary presentation, this last type being more frequent. The most commonly encountered neurological sequelae are motor and visual impairments because of the direct injury to the corticospinal tracts and geniculocalcarine tracts that pass through affected regions in the periventricular white matter [3, 26]. Spastic diplegia is also a common motor sequelae of PVL, in which the degree of motor impairment is greater in the lower extremities, and occurs more frequently in preterm infants with PVL than in term infants [3, 11]. At a histological level, PVL evolves first with necrosis and cavitation that thereafter progress to porencephalic cysts. Later, these cysts collapse resulting in gliosis and loss of white matter volume that is seen in imaging studies [3, 26].

By US, there are four stages of PVL that somewhat correlate with its histological characteristics. First, there is congestion in the periventricular white matter, which in US is seen as increased echogenicity that usually adopts an elongated and globular morphology, sometimes referred as “flares.” This increased echogenicity usually is seen in the first 48 h. In the second stage, there is a relative return to normal which occurs mostly by the 2–4 weeks. In the third stage, the development of cysts is evident in US at approximately 3–6 weeks (Fig. 6). Finally, in the fourth and last stage, there is resolution of the cysts, with evidence of volume loss with enlargement of the lateral ventricles. This last stage happens at approximately 6 months of age [27].

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Fig. 6
US coronal (a) and sagittal (b) images in a preterm neonate demonstrate the third stage of PVL with the development of bilateral periventricular cysts

US is usually used as the first examination in evaluating suspected HII cases. Nevertheless, it lacks the sensitivity and positive predictive value and, as mentioned before, the study can be normal in patients that develop PVL. Conversely, in other cases, US shows increased echogenicity in the periventricular areas of normal neonates. The presence of prolonged hyperechogenicity of the periventricular white matter has a fairly low sensitivity and positive predictive value for the detection of PVL [28]. Serial US examinations improve substantially the detection of transient cystic lesions and can be better than MRI studies for this purpose. This is important because it has prognostic value as most of patients with cystic changes present neurological sequelae [29]. For these reasons, the primary roles of US are to detect germinal matrix hemorrhages in the immediate postnatal period and detect cystic changes later in perinatal life [3].

MRI allows better visualization of the periventricular white matter lesions and is a useful complement to cranial US especially among patients without cystic lesions. It also allows better depiction of hemorrhages and/or white matter volume loss which also has prognostic value [29]. In MR images, early injury to the white matter appears as foci of T1 hyperintensity in the larger areas of T2 hyperintensity. These T1 hyperintense foci must be distinguished from hemorrhages, and they do not produce T2 shortening. These T1 abnormalities may represent focal areas of mineralization, while in the white matter reactive gliosis develops [30]. These changes are usually evident at the third–fourth days post injury, and then they give way to a mild T2 shortening of the white matter at days 6–7. The high T2 signal is most evident in the peritrigonal regions (Figs. 7 and 8).

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Fig. 7
(a, b) T2WI of a preterm neonate who suffered mild-to-moderate asphyxia shows T2 hyperintensity in the periventricular white matter in the setting of PVL. Also, dark fluid levels can be seen inside the lateral ventricles compatible with intraventricular hemorrhage. Small left side periventricular cyst is present


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Fig. 8
T2WI of a preterm neonate who suffered moderate asphyxia demonstrates characteristic hyperintensity in the periventricular white matter, more pronounced at the level of the peritrigonal regions compatible with PVL. Also, note the “wavy” appearance of the ventricular walls

CT is usually avoided in neonates because of the exposure to ionizing radiation. It does not provide much more information than the US and MRI, but it could be important and helpful in confirming PVL end-stage injuries later in life. In the last stage of PVL, MRI and CT show a characteristic loss of volume of the periventricular white matter and centra semiovale with secondary enlargement of the lateral ventricles in particular their trigones. MRI and CT also show the characteristic irregular outline and wavy appearance of the outer wall of the lateral ventricles. MRI better shows the loss of volume in the corpus callosum, particularly in the posterior aspect of the body and splenium [31].


Table 2
HII in preterm neonates
















Severe

Injury in the deep gray matter, mostly the thalami but also the basal ganglia, dorsal brainstem, cerebellum, and corticospinal tracts as well as a diminished volume of the cerebral hemispheric white matter

Mild to moderate

Germinal matrix hemorrhage

IVH

PVL



HII in the Term Neonate


As mentioned before, HII is also considered an important cause of death, neurodevelopmental disorders, and disability in term neonates, although its incidence and prevalence has declined over the last decade and is now estimated to be between 2 and 4 per 1,000 live term births [3, 32, 33]. Risk factors for HII can be divided in antepartum factors and intrapartum factors. Antepartum risk factors include maternal hypotension, infertility treatment, multiple gestation, prenatal infection, gestation ≥41 weeks, and thyroid disease. Among the most important intrapartum factors are forceps delivery, breech extraction, umbilical cord prolapse, abruptio placentae, tight nuchal cord, maternal fever, prolonged membrane rupture, abnormal cardiotocography, shoulder dystocia, and thick meconium. The most popular hypothesis is that most of the HII cases are attributable only to antepartum risk factors; however, there are new reports that point to the intrapartum factors as necessary to develop this condition. In approximately 10 % of HII cases, there are postnatal complications such as sepsis, shock, and/or severe respiratory distress [3335].

The clinical manifestations at birth of HII in term infants include nonspecific signs and symptoms that evolve over a period of days. Data suggest that the infants at risk for severe HII can be reliably identified by a group of clinical manifestations that include evidence of intrapartum distress (e.g., fetal heart rate abnormality), severe functional depression (low 5 min Apgar score), need for resuscitation in the delivery room, severe fetal acidemia, abnormal early neurologic examination, and abnormal electroencephalogram. These patients, in the first hours after a severe insult, may present with depressed consciousness, periodic breathing or apnea, or bradycardia. In cases where severe injury to cortical regions has ensued, hypotonia and seizures may occur. In patients that survive, severe HII typically develops including quadriparesis, choreoathetosis, severe seizure, and/or mental retardation. In cases of moderate HII, spastic diplegia or quadriplegia almost always develops and is usually referred to as cerebral palsy. On the other hand, in mild cases of HII, term infants may develop mild developmental delay or recover completely.

The imaging patterns can be subdivided depending on the severity of the hypoxic injury into severe and partial asphyxia (Table 2).

In term neonates, transfontanelle US is the first imaging study to be obtained when HII is suspected. Although some abnormalities can be detected by US, it has a low sensitivity and therefore a negative study should not be used as a definite evidence of an absence of hypoxic injury. If there is strong clinical suspicion of HII and US is negative, MR imaging should be obtained to evaluate the presence and severity of the injury. It is important to remember that, as mentioned before, the biochemical and histological features of HII that influence the imaging findings vary with time so that a study performed only hours after the event will be different from one done several days later.


Severe Asphyxia


In term neonates, severe asphyxia results mainly in a central pattern of injury that usually involves the deep gray matter including the putamina, ventrolateral thalami, hippocampi, dorsal brainstem, and lateral geniculate nuclei. Occasionally, the peri-rolandic cortex is also involved. The explanation for this pattern of injury is, as we mentioned before, the active state of myelination of these areas and the high concentration of NMDA receptors which makes them more susceptible to neonatal HII [6, 36]. The rest of the cortex is usually spared or shows mild abnormalities since it is generally less metabolically active. However, if the injury is prolonged, the remaining cortex will be injured and portrays a worse prognosis [10].

Transfontanelle US, although it is the most commonly used technique and usually the first one in cases of suspected HII, is less sensitive (about 50 % in the first week of life) and specific compared with CT and MRI and carries less interobserver agreement [3, 37, 38]. Its sensitivity increases when it is performed after 7 days. Early US findings include a generalized increase in cerebral echogenicity and diffuse cerebral edema with obliteration of the cerebrospinal fluid (CSF) containing spaces. Subtle increased echogenicity in the basal ganglia, thalami, and brainstem can be seen in the first week but are more apparent after 7 days [38, 39]. The presence of thalamic hyperechogenicity generally suggests a severe insult and poor outcome [40]. At a later stage, the imaging pattern reflects the loss of volume including prominence of the ventricles and extra axial CSF-containing spaces, likely due to atrophy. Doppler US during the initial US examination may be useful and improves sensitivity and specificity by showing diminished resistive indexes (<60) in the anterior and middle cerebral arteries. These lower resistive indexes have been also associated with poorer clinical outcome, even in absence of other US abnormalities [41].

MRI is probably the most accurate modality to assess neonatal HII especially when performed with diffusion-weighted imaging (DWI) in the first 24 h, when DWI is most sensitive to detect injuries which may still not be visible in conventional T1- and T2-weighted images. DWI shows high signal (with corresponding low ADC values) in the ventrolateral thalami and basal ganglia (particularly the posterior putamina), peri-rolandic regions, and along the corticospinal tracts (Fig. 9). It is important to highlight the fact that even with the high sensitivity of this technique, the findings in DWI in the first 24 h usually underestimate the ultimate extent of the injury, and although rare, some reports of normal findings in the first 24 h have been reported [17, 42]. It is believed that the reason for this delay in showing the full extent of the injury may be based in the important role of apoptosis in HII, and as explained before, the time that takes for ATP to be depleted which precedes the death of neurons and the resultant neurodegeneration at a macroscopic level. Abnormalities on DWI peak at 3–5 days. By the end of the first week, the hyperintensity in injured areas in DWI tends to decrease, phenomenon known as “pseudo-normalization” [4, 6, 10, 20]. It is important to realize that although the images seemingly improve, this does not imply that there is a real reversal or improvement of the underlying injury, just resolution of signal abnormalities on DWI. Because of the rare possibility of a false-negative DWI study when performed in the first days, it is recommended to repeat the examination at 2–4 days when the signal abnormality is expected to be greatest or perform an evaluation with proton MR spectroscopy (MRS).

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Fig. 9
(a, b) DWI in a term neonate with severe asphyxia demonstrates diffusion restriction in the ventrolateral thalami and peri-rolandic cortex

It is well known that conventional MRI sequences with T1- and T2-weighted images obtained within the first day are frequently normal and therefore are less useful than DWI to diagnose acute HII. By the second day, conventional sequences, especially T1-weighted images, start to show hyperintensity in the posterior lentiform nuclei and ventrolateral thalami (Figs. 10 and 11). Sometimes, signal intensity changes may also be seen in the dorsal brainstem and basal ganglia [36]. The T2 hyperintensity usually develops later than the T1 shortening and usually by the second week, affects the thalami and posterior putamina. As mentioned before, cortical abnormalities can also occur.

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Fig. 10
(a, b) T1WI showing hyperintensity in the posterior lentiform nuclei, ventrolateral thalami, and pericentral cortex in a preterm neonate who suffered profound asphyxia


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Fig. 11
T1WI. A different patient showing T1 hyperintensity in the posterior lentiform nuclei and ventrolateral thalami

The cause of the abnormalities seen with the MRI conventional sequences in the basal ganglia and thalami remains incompletely understood, with possible explanations including hemorrhage, transient calcium deposition, lipid release from myelin breakdown, free fatty acids, and even paramagnetic effects from free oxygen radicals. In infants, cortical abnormalities are likely due to laminar necrosis [36, 43]. A possible explanation for the delay in appearance of the T2 hyperintensity changes is the high water content of the white matter, so subtle abnormalities are obscured and difficult to identify at first. The T1 shortening in posterior putamina, thalami, and peri-rolandic cortex can persist for several months. Because of all these reasons, DWI is very useful in the first days, especially in the first 24 h when conventional MR images are likely to be normal. On the other hand, conventional MRI sequences are useful at the end of the first week when the DWI images pseudo-normalize. Later, in the chronic phase, the imaging findings reflect atrophy of injured structures and T2 hyperintensity especially in the ventrolateral thalami, posterior putamina, and corticospinal tracts (Figs. 12 and 13) [36]. The major imaging differential diagnosis in newborns with bilateral basal ganglia lesions includes HII and inborn errors of metabolism. The latter ones are suspected if there is no history of HII and if other imaging features outside of the typical spectrum of HII, like localized white matter and cortical abnormalities, atrophy, or heterotopias, are seen.

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Fig. 12
(a, b) T2WI in a term neonate with chronic changes from HII shows hyperintensity in the corticospinal tracts, putamina, and ventrolateral thalami. Also, some loss of volume is noted


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Fig. 13
NECT in acute severe HII shows hypodensity of the basal ganglia. CT is not usually the imaging modality of choice in these patients


Partial Asphyxia


When partial asphyxia occurs, the pattern of injury changes and as mentioned before, the neonatal brain is more resistant to hypoxia than the adult brain. For this reason, in mild or moderate insults of short duration, there may be little or no injury [10]. Compensatory mechanisms that take place when hypoxia is established have been well studied in animal models. With prolonged fetal hypoxia, blood shunting to vital brain structures occurs, including the brainstem, basal ganglia, hippocampi, and cerebellum. Thus, less metabolically active regions of the brain receive less blood and are more susceptible to injury, specifically the cortex and white matter. This is the reason why in mild-to-moderate HII, the brainstem, cerebellum, and deep gray matter are generally spared. When the autoregulatory mechanisms are exceeded, the result is injury to the watershed zones which become relatively hypoperfused. The clinical manifestations of this process generally are seizures, hypotension, and possibly proximal extremity weakness and/or spasticity [10].

US diagnosis of this type of injury is difficult as this technique has low sensitivity for examination of the cortical and subcortical areas that are close to the calvarium. For this reason, MRI is the modality of choice when studying term infants with suspected partial asphyxia. Regarding the MRI sequences that are more useful, again DWI are the most sensitive and the first to show abnormalities in the first 24 h. These abnormalities include hyperintensity with corresponding low ADC values (diffusion restriction) in the watershed territories (Fig. 14). Interpretation of DWI is sometimes difficult because of the high content of water of the brain at this age which makes the hyperintensity of HII subtle. To facilitate the correct diagnosis, it is important to interpret DWI with the corresponding ADC map which will show areas of low signal confirming true diffusion restriction [17]. T1 and T2 images may be normal in the first 24 h, but by the second day, they show T2 hyperintensity in the cortex and subcortical areas related to cortical swelling and loss of differentiation between the gray and white matter contrast. These findings are more evident in watershed zones but occasionally can be appreciated in the hemispheres [3]. Deep gray matter structures will be most likely spared in these patients. In the chronic stage, there are signs of atrophy with loss of volume of the white matter and cortical thinning predominantly in the parasagittal watershed zones (Table 3).
Dec 11, 2016 | Posted by in NEUROLOGICAL IMAGING | Comments Off on Hypoxic–Ischemic Encephalopathy (Preterm, Term, and Adult)
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