Open access peer-reviewed chapter
Abstract
Neuroimaging plays a key role in management of critically ill neonates with neurological problems. Magnetic Resonance Imaging (MRI) is the most commonly used neuroimaging modality in evaluation of neonatal encephalopathy, because MRI provides better image quality and accurate delineation of the lesion. Newer modalities of MRI like Diffusion Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI) are useful in identifying the brain lesion and also in predicting the neurodevelopmental outcome. Magnetic Resonance Angiography (MRA) and Magnetic Resonance Venography (MRV) are used to assess the cerebral arteries and veins with or without the use of contrast material. Arterial Spin Labelling (ASL) MRI and Phase Contrast (PC) MRI are newer modalities of MRI used to assess the cerebral perfusion without the use of contrast material. Magnetic Resonance Spectroscopy (MRS) is a functional MRI modality used to assess the level of brain metabolites which help us in diagnosing neuro metabolic disorders, peroxisomal disorders and mitochondrial disorders. Several predictive scores are available based on the size and location of lesions in MRI, and these scores are used to predict the neurodevelopmental outcome in term neonates with encephalopathy. MRI at term equivalent age in preterm neonates used to predict neurodevelopmental outcome in later life.
Keywords
- neuroimaging
- magnetic resonance imaging
- diffusion weighted imaging
- diffusion tensor imaging
- magnetic resonance spectroscopy
- arterial spin labelling
1. Introduction
Neuroimaging is an important and inevitable modality in diagnosis of critically ill neonates with neurological problems, and also helps in prognostication. Currently cranial ultrasonography (CUS), computerised tomography (CT), and magnetic resonance imaging (MRI) are the most widely available neuroimaging modalities for the evaluation of critically ill neonates. The ideal neuroimaging technique gives us information which helps in identifying the underlying diagnosis, determine the management and in predicting the neurodevelopmental outcome.
2. Cranial ultrasonography
CUS still remains the most popular neuroimaging modality, even though advanced neuroimaging techniques like CT and MRI are available. The presence of fontanelles in neonates provides an acoustic window for neuroimaging using CUS.
The main advantages of CUS are that it can be done at bedside, absence of ionising radiation, can be repeated many times and there is no need for sedation. Even though CUS can be used to detect congenital anomalies of brain, congenital infections and in identification of hemorrhagic, ischemic and cystic lesions of brain, now a days CUS is mainly used in screening all preterm neonates born before 32 weeks for clinically unsuspected Intraventricular Hemorrhage (IVH), Peri Ventricular Leukomalacia (PVL), and Ventriculomegaly due to Post Hemorrhagic Hydrocephalus [1].
The role of CUS in term neonates is very less in this current era. In neonates with hypoxic ischemic encephalopathy, abnormalities in cerebral blood flow may be the early sign which can be diagnosed with transcranial doppler ultrasound, but the role of CUS as sole imaging modality in term neonates with encephalopathy is very limited. CUS can be used as a initial screening modality followed by MRI as definitive neuroimaging modality.
The main limitation of CUS in neonates is the posterior fossa could not be visualized properly, and subtle anomalies in the grey white matter can be missed due to lack of myelination in the neonatal brain.
3. Computerised tomography
CT scan is very rarely used now as a neuroimaging technique in neonates because of the risk of exposure to harmful ionizing radiation and also the advent of safer MRI technique. In the past decade CT scan was considered more sensitive in detecting acute hemorrhage and calcifications in brain, which is replaced with the advent of advanced MR sequences with better image quality and higher field strength which delineates the calcifications and acute hemorrhage better. The main problem related to MRI is the longer scan times and the requirement of MRI compatible life support systems while scanning the critically ill neonate.
A comparative study between CT scan, conventional MRI and diffusion weighted MRI done in term newborns with encephalopathy showed Diffusion weighted MRI is the most sensitive technique in assessing brain injury in neonates with encephalopathy, especially for cortical injury, white matter injury and focal lesions such as stroke [2].
CT scan can be used as imaging modality in urgent situations when MRI is not available, and when baby’s condition is too critically ill which will not allow longer scan times with MRI.
4. Magnetic resonance imaging
MRI is the most commonly used modality of neuroimaging in evaluation of Neonatal Encephalopathy. MRI is considered as the standard neuroimaging modality in term neonates with encephalopathy. Even though conventional MRI sequences are helpful in diagnosis of neurological problems, advanced MRI techniques such as Magnetic Resonance Spectroscopy (MRS) and Diffusion Weighted Imaging (DWI) are useful in identifying the exact etiology.
5. Indications for MRI in neonates
5.1 To identify the cause for neonatal encephalopathy
Neuroimaging plays a key role in diagnosis of genetic and metabolic disorders and it helps to differentiate metabolic disorders from other causes of neonatal encephalopathy (Figure 1) [3].
Figure 1.
Etiologies of neonatal encephalopathy.
5.2 To predict the neurodevelopmental outcome in Term neonates with HIE and in Very preterm neonates
6. Newer MRI techniques
Several newer MRI techniques are used now, which helps in enhancing the accuracy of diagnosis and also in prognostication.
6.1 Diffusion weighted imaging
DWI is currently an indispensable modality of neuroimaging. DWI having been used most commonly in adults for evaluation of stroke, currently it has been widely used in neonatal neuroimaging for both diagnosis and prognostic purposes.
DWI uses the diffusion properties of hydrogen molecules within the substance, when these hydrogen molecules move freely they diffuse away, so signal loss will occur in DWI. The movement of hydrogen molecules during application of magnetic gradient affects the signal and direction of movement of hydrogen molecules. When there is diffusion restriction or reduced diffusion, the movement of hydrogen molecules are limited which is seen as high signal intensity in DWI.
The quantitative calculation of diffusion or the rate of diffusion is expressed as the Apparent Diffusion Coefficient (ADC). ADC mapping used to find out the site and extent of injury. The areas with diffusion restriction appear brighter with high signal intensity in DWI and appear darker with low signal intensity in ADC mapping. ADC values should be interpreted cautiously after 1–2 weeks, because pseudonormalization occurs during the sub-acute stage after ischemic event had occurred. ADC pseudonormalization represents apparent return to normal values on ADC maps, but DWI still shows high signal intensity. This ADC pseudonormalization does not represent resolution of ischemic brain damage.
After an acute ischemic event, there is net shift of water from the fast diffusing extracellular compartment to slow diffusing intracellular compartment, hence there is a net slowing of water diffusion or diffusion restriction. In the sub-acute stage after an ischemic event, the cell walls break down in the infarcted area and there is increased diffusion. This increased diffusion in damaged tissues during the sub-acute stage is called pseudonormalization as the damaged tissues have diffusion equivalent to that of normal brain tissue. This pseudonormalization occurs after 2 weeks in myelinated brain but it occurs earlier in unmyelinated neonatal brain [4].
DWI can be used as supplemental MRI technique along with conventional MRI in recognising the pattern of brain damage and also in predicting the motor outcome [5].
The below figures are the DWI and corresponding ADC mapping images of the neonate with stroke showing hyperintense lesions in DWI in the left temporo-parietal cortex and hypointense in ADC on the same location in brain (Figures 2 and 3).
Figure 2.
Perinatal stroke DWI.
Figure 3.
Perinatal stroke ADC.
DWI provides evidence of cerebral injury before conventional MRI in term babies with neonatal encephalopathy.
6.2 Diffusion tensor imaging
Diffusion Tensor Imaging (DTI) uses the property of diffusion anisotropy. The ADC of intracellular water is lower than that of extracellular water, because the movement of intracellular water is restricted by the intracellular structures and cell membrane. Myelin also impairs the exchange of water molecules across cell membranes. When water moves parallel to axons, it moves freely within the myelin layers without crossing the lipid membranes. The water ADC values are greater when parallel to axons than perpendicular to them. This spatial variation in ADC values within the brain is called diffusion anisotropy.
The diffusion anisotropy is evaluated and expressed as Fractional Anisotropy (FA) mapping. FA values usually ranging between 0 and 1. The anisotropy value of the white matter of neonatal brain is initially low and increases as the myelination increases.
The differences in regional diffusion of the brain structure used to study the myelination of brain as well as ischemic and non-ischemic areas of the brain.
In DWI magnetic resonance gradients are applied in one to three directions, but in Diffusion Tensor Imaging (DTI) magnetic resonance gradients are applied in many directions, from 6 to 30 or more.
Fractional anisotropy measured using DTI in full term neonates found that there is significant correlation between white matter structural variation and neurodevelopmental outcome [6].
DTI performed at term equivalent age in 32 Extremely Low Birth Weight infants showed different FA values in white matter regions among infants with or without white matter abnormalities associated with prematurity and/or Cerebral Palsy (CP). Low FA values of Region of Interests in DTI are related with later development of spastic CP in preterm infants with white matter abnormalities [7].
In a study compared DTI in 10 full term neonates without brain injury and 22 neonates with hypoxic ischemic encephalopathy and concluded that DTI can quantify the white matter injury in neonates with hypoxic ischemic encephalopathy [8].
A systematic review of 19 studies showed that low FA values in white matter regions are associated with poorer scores on neurodevelopmental clinical assessments at follow up. This review showed DTI of the key white matter tracts not only identifies the extent of damage but also predict the neurodevelopmental outcome [9].
Another systematic review included 11 studies were DTI data of very preterm and moderate to late preterm neonates at their term equivalent age compared with term controls found that DTI showed statistically significant diffusion measures in the white matter of preterm neonates which is associated with neurodevelopmental disability in later life. Hence, DTI can be used as a prognostic tool for neurodevelopmental disability in preterm neonates [10].
6.3 Magnetic resonance angiography
Magnetic Resonance Angiography (MRA) is a specific type of MRI, in which the arteries are specifically looked without seeing the overlying tissues. MRA may or may not require contrast material depending on the vessels being scanned. MRA plays a key role in evaluation of neonatal arterial ischemic stroke (NAIS). MRA is able to find out the etiology of NAIS such as thrombus, embolism or cerebral vascular disorder like Moyamoya disease [11].
The below Figure 4 showing narrowing of left middle cerebral artery in MRA.
Figure 4.
Perinatal stroke MRA.
6.4 Magnetic resonance venography
Magnetic Resonance Venography (MRV) is a type of MRI exam in which the veins are clearly visible without the overlying tissues and MRV often requires contrast material to enhance the visibility of veins. MRV is the gold standard investigation for diagnosing Cerebral Sinus Venous Thrombosis (CSVT). MRV used to diagnose CSVT in neonates underwent cardiac surgery and in neonates who received therapeutic hypothermia [12, 13].
6.5 Arterial spin labelling MRI
Arterial Spin Labelling (ASL) MRI is an advanced MRI technique used to assess the cerebral perfusion without the use of intravenous contrast. The protons of the intravascular arterial blood are labelled with radiofrequency pulses and that labelled protons are used as endogenous tracer to evaluate the brain perfusion [14].
Higher perfusion values in ASL MRI in neonates with HIE are associated with worse neurodevelopmental outcome. In a study done in 28 neonates with HIE, the median perfusion in basal ganglia and thalami was higher in neonates with adverse outcome than in neonates with favourable outcome. ASL MRI can predict outcome in neonates with HIE. ASL MRI can add an extra element along with DWI and MRS in predicting the outcome in HIE. The combined information of ASL and MRS is the best predictor of outcome [15].
Brain growth and maturation is one of the most important processes that occur during the neonatal life. Advanced MRI tools such as DWI, DTI and ASL have been used to observe the process of brain maturation in neonates. ASL MRI provides quantitative measure of regional brain function and aging is associated with changes in regional brain function. ASL has been used to see changes in perfusion during the maturation of brain in neonates [16].
6.6 Phase contrast MRI
Phase-Contrast (PC) MRI is another technique of assessing the cerebral blood flow. PCMRI provides fast and reliable global cerebral blood flow measurement.
Even though ASL MRI can be used to assess cerebral blood flow, it is challenging particularly in neonates because it has low sensitivity, poor quantification and time consuming as it requires acquisition of several images repeatedly. Hence there is a need of alternative faster and more robust technique like phase contrast MRI arises [17].
The mean or global cerebral blood flow is assessed by dividing the total blood flow to the brain by brain volume. Phase Contrast Magnetic Resonance Angiography (PCMRA) used to measure blood flow in right and left internal carotid arteries and basilar artery, total blood flow to brain is calculated by sum of blood flow in right and left internal carotid arteries and basilar artery. Brain volume is determined by sum of volume of grey and white matter in cerebrum, cerebellum and brain stem.
In a study of 21 infants, the non-invasive PCMRI based method used to assess the mean cerebral blood flow (CBF). The mean cerebral blood flow is related to brain volume and postmenstrual age. The mean CBF increases postnatally in the first year of life [18].
Similar study was done in larger cohort of 344 infants, included 172 preterm infants and 172 term infants. This study concluded that mean CBF assessed by PCMRA is dependent on body weight and estimated brain weight also this mean CBF is more in term infants when compared to preterm infants at term equivalent age [19].
6.7 Magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy (MRS) is more challenging than conventional MR imaging. Proton MRS works on the principle of detection of hydrogen nuclei in brain metabolites such as lactate, N-acetylaspartate (NAA), choline and creatine.
NAA a marker of neuronal activity. Choline, a marker for membrane turnover and myelination and Lactate, a marker of anaerobic respiration. NAA levels increase with brain maturity, but Choline and Lactate levels decrease with age as the rapid brain growth of the neonate slows down in infancy. Proton MRS used to assess these brain metabolite levels and thereby the brain maturation [20].
In a study done in 24 full term neonates with Hypoxic Ischemic Encephalopathy (HIE), conventional MR imaging and MRS was done, the differences of N-acetylaspartate / creatine (Cr), choline/Cr and lactate/Cr in the basal ganglia and thalamus in the HIE group were significantly different when compared to the control group, but there is no significant difference identified between mild to moderate HIE and severe HIE group. Hence MRS can be used as an additional tool for the diagnosis of HIE [21].
MRS used to assess the absolute concentration and concentration ratios of brain metabolites such as lactate (Lac), Creatine (Cr), N-acetylaspartate (NAA), and Choline (Cho), and to predict the outcome after hypoxic ischemic injury. Comparison of the mild HIE and severe HIE groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced NAA, and increased Lac in the infants with the worse outcome [22].
In a systematic review and meta-analysis of 32 studies of the prognostic accuracy of cerebral MRS biomarkers in infants with neonatal encephalopathy, concluded that deep gray matter Lac/NAA is the most accurate quantitative MRS biomarker within the neonatal period for prediction of neurodevelopmental outcome after NE [23].
MRS has been shown to detect abnormal accumulation of Lactate in brain parenchyma and CSF in patients with mitochondrial disorders. MRS provides a non-invasive tool for the diagnosis of mitochondrial diseases, especially in children with nonspecific findings on MRI, normal appearing MRI or a normal blood lactate/pyruvate ratio [24].
MRS shows elevated glycine levels in the brain of patients with Non Ketotic Hyperglycenemia [25]. Peroxisomal biogenesis disorder like Zellweger syndrome shows decreased NAA in proton MRS. Similarly in Pyruvate Dehydrogenase Complex deficiency MRS shows decreased NAA and Choline peak consistent with hypomyelination [26].
MRS has shown to be beneficial in diagnosing neuro metabolic disorders, mitochondrial disorders, diagnosis of HIE also in predicting the outcome after hypoxic ischemic injury and in assessing brain maturation.
7. Role of MRI in predicting neurodevelopmental outcome
MRI is used to predict neurodevelopmental outcome in term and preterm neonates.
7.1 MRI in prediction of neurodevelopmental outcome in term neonates with HIE
MRI is used to predict the outcome in term neonates after HIE. Several scoring systems developed over the past decades based on the injury pattern in MRI. A study done in 51 infants in whom MRI was done and their neurodevelopmental outcome was assessed at end of 3 months and 12 months. Score was assigned based on injury patterns in basal ganglia (BG), watershed (W), Basal ganglia / watershed (BG/W). Maximum score was assigned if the injury is more extensive. This study concluded that BG/W score was able to accurately predict good and poor neuromotor and cognitive outcome [27].
A study of 20 neonates with simplified MRI criteria was used to predict the outcome in term neonates with HIE. The MRI injury pattern was graded as follows,
Grade 1—cases with no central and less than 10% peripheral change
Grade 2—those with less than 30% central and/or 10–30% peripheral area change, and
Grade 3—those with more than 30% central or peripheral change
This study showed that all neonates with grade 3 MRI changes were died or had poor neurodevelopmental outcome, grade 1 MRI changes had normal outcome and those with grade 2 MRI changes had moderate or normal outcome, and concluded that this simplified MRI criteria is highly predictive of neurodevelopmental outcome [28].
A study done by the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network assessed the ability of MRI patterns of neonatal brain injury to predict death or Intelligent Quotient (IQ) at 6–7 years of age in infants who received hypothermia treatment for neonatal encephalopathy. The NICHD classified the injury pattern as follows:
0—normal MRI
1A—minimal cerebral lesions only with no involvement of Basal ganglia Thalami (BGT), Anterior Limb of Internal Capsule (ALIC), Posterior Limb of Internal Capsule (PLIC), or Watershed (WS) infarction
1B—more extensive cerebral lesions only with no involvement of BGT, ALIC, PLIC, or WS infarction
2A—any BGT, ALIC, PLIC, or WS infarction noted without any other cerebral lesions
2B—involvement of either BGT, ALIC, PLIC, or area of infarction and additional cerebral lesions and
3—Cerebral hemispheric devastation
The primary outcome was death or IQ <70. The disability among survivors also classified as mild, moderate and severe based on IQ score and Gross Motor Function classification system. This study concluded that 2B and 3 pattern of MRI injury is highly predictive of death or IQ <70 at 6–7years of age [29].
Similar scoring system based on MRI injury pattern also predicted the neurodevelopmental outcome at 18–24 months in neonates with HIE [30].
Even though grading systems vary, but the MRI injury patterns after neonatal hypoxic ischemic encephalopathy used to predict the future neurodevelopmental outcomes.
7.2 MRI in predicting the neurodevelopmental outcome in Preterm neonates
Preterm neonates who are born at gestational age of 32 weeks or less are more at risk of adverse neurodevelopmental outcomes. MRI at term equivalent age has been used to predict the neurodevelopmental outcome in preterm neonates.
A study done in 167 very preterm infants found that moderate to severe white matter abnormalities in MRI at term equivalent age is predictive of adverse outcomes like cognitive delay, motor delay, cerebral palsy and neurosensory impairment at 2 years of age [31].
A systematic review of 20 studies showed that the presence of moderate to severe white matter abnormalities on MRI around term equivalent age can predict the motor function and cerebral palsy in very preterm infants [32].
8. Conclusions
Neuroimaging is essential in evaluation of neonates with encephalopathy and other neurological problems. Even though CUS and CT scan also commonly used imaging modalities, MRI is more advantageous in terms of superior image quality and it provides multiple tissue parameters like location, extent, vascularity and functional status. MRI avoids the risk of exposure to ionizing radiation. MRI is the imaging of choice for better delineation of posterior fossa structures. Newer modalities of MRI like DWI, DTI, and MRS are used to accurately assess the anatomy and functional status of brain, also to predict the neurodevelopmental outcome.
The only disadvantage of MRI is requirement of stronger magnetic field and longer image acquisition time, which is a major hindrance in doing MRI in critically ill neonates. When we suspect intracranial hemorrhage in term neonates with encephalopathy, a non contrast CT scan can be done. But with the availability of safer MRI technique, with the advent of newer MRI techniques and also with the availability of MRI compatible instruments, MRI scan could be considered as initial imaging modality even in sick neonates for better assessment.
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