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Special Discussion│Clinical Applications of Multimodal MRI in Neonatal Encephalopathy
Hou Ana, Fu Jianhua
Chinese Journal of Practical Pediatrics 2023 Vol.38(5): 344-349
Neonatal encephalopathy has various types, such as hypoxic-ischemic encephalopathy, bilirubin encephalopathy, hypoglycemic encephalopathy, encephalopathy of prematurity, sepsis-associated encephalopathy, genetic metabolic encephalopathy, and mitochondrial encephalopathy. Magnetic resonance imaging (MRI) technology can be used for diagnosis and assessment of the condition, making it an ideal imaging examination method for neonatal encephalopathy. Although conventional MRI is the most widely used, it often fails to achieve early diagnosis and precise identification and cannot assess brain function. Currently, multimodal MRI techniques, including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), hydrogen proton magnetic resonance spectroscopy (H1-MRS), and fluid-attenuated inversion recovery (FLAIR), have advantages such as high sensitivity, strong specificity, high signal contrast, and the ability to reflect brain tissue metabolic levels. These can compensate for the shortcomings of conventional MRI technology and have broad application prospects for early diagnosis and differentiation of neonatal encephalopathy, as well as assessing brain function and predicting prognosis.
Magnetic Resonance; Multimodal; Encephalopathy; Neonate
Funding Project: Major Social Development Project of Liaoning Province (2020JHI/1030001) Author Affiliation: Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004 Corresponding Author: Fu Jianhua, Email: [email protected]
Neonatal encephalopathy can be caused by various factors such as asphyxia, hyperbilirubinemia, hypoglycemia, prematurity, sepsis, genetic metabolic diseases, and mitochondrial diseases. Accurate identification, early intervention, and prognosis assessment are crucial. Magnetic resonance imaging (MRI) technology features high spatial resolution, high tissue contrast, and multi-planar imaging capabilities, providing objective and detailed examination results, superior to ultrasound and CT in determining the type and severity of encephalopathy. Moreover, MRI examination is radiation-free, making it more suitable for neonatal examinations. Although conventional MRI techniques such as T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) have been widely applied in neonatal clinics, they often fail to show significant signal changes in the early stages of lesions, and due to the variety of types of neonatal encephalopathy and brain injury, conventional MRI sometimes struggles to differentiate between different types of damage. Additionally, conventional MRI has certain limitations for encephalopathy primarily characterized by changes in brain tissue metabolism and function.
Various imaging modalities, based on conventional MRI, provide more sensitive and specific assessments of lesions. Common imaging techniques include diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), hydrogen proton magnetic resonance spectroscopy (H1-MRS), and fluid-attenuated inversion recovery (FLAIR). Recently, reports have increasingly emerged on the use of various imaging techniques to reflect the characteristics of lesions in neonatal encephalopathy, underscoring the importance of understanding the characteristics of multimodal MRI for disease recognition and examination method selection.
1 Common Multimodal MRI Techniques Principles and Parameters
1.1 DWI DWI’s principle is to use pulse sequences to detect changes in the diffusion of water molecules in tissues. When acute injury occurs, the diffusion of water molecules is restricted, and DWI will show increased signal intensity in the affected area. The apparent diffusion coefficient (ADC) can also be used to quantify the degree of diffusion restriction. When cytotoxic edema occurs, the lesion area appears as high signal in the DWI sequence and low signal in the ADC image, with a decrease in ADC value.
1.2 DTI DTI analyzes the directionality of water molecular movement based on DWI, and can non-invasively study the internal neural structure of the brain through fiber tract imaging, providing clues for the formation of connections between various functional areas of the brain. Common parameters used in DTI include fractional anisotropy (FA), ADC, axial diffusivity, and radial diffusivity.
1.3 SWI Paramagnetic or diamagnetic substances can alter the local magnetic field, presenting different phase information. Most magnetic susceptibility changes in human tissues are related to different forms of iron in blood or bleeding. SWI can form image contrast based on the different magnetic susceptibilities of tissues, providing high specificity for diagnosing intracranial hemorrhage and calcification. Additionally, due to the magnetic field inhomogeneity caused by deoxyhemoglobin in blood vessels and the significant phase difference with surrounding tissues, SWI can also serve as a non-invasive venography technique.
1.4 H1-MRS Due to the differing chemical environments surrounding the atomic nuclei of various compounds, slight changes in the magnetic field occur, resulting in different resonance frequencies. Therefore, H1-MRS can produce different signals by identifying differences in resonance frequencies, reflecting the concentration of metabolites in brain tissue. Commonly detected metabolites include: (1) N-acetylaspartate (NAA): an important marker of neurons and axons; a decrease in NAA suggests neuronal and axonal damage; (2) Choline (Cho): reflects the total choline content in the brain; the height of its peak is usually related to the synthesis and breakdown of cell membranes. A reduction in Cho may be associated with delayed myelination, changes in cell types, or a reduction in cell numbers; (3) Lactate (Lac): normally has a low concentration that cannot be detected. In pathological conditions, changes in energy metabolism can lead to elevated lactate levels and the appearance of a lactate peak; (4) Others: Creatine (Cr), Glutamine (Glx), etc., with Cr concentration relatively stable, often used as the denominator in peak area ratios to compare the relative concentrations of different metabolites. The peak area ratio of various metabolites, such as NAA/Cr, can be seen as a metabolic marker of neuronal and axonal functional status, where a decrease indicates neuronal or axonal loss and functional disruption.
1.5 FLAIR FLAIR is a type of inversion recovery sequence that suppresses high signals from cerebrospinal fluid in T2WI, causing cerebrospinal fluid to appear as a low signal, thus making lesions near the cerebrospinal fluid areas around the ventricles and the peripheral parts of the cerebral hemispheres clearer.
2 Applications of Multimodal MRI Techniques in Neonatal Encephalopathy
2.1 Hypoxic-Ischemic Encephalopathy (HIE) HIE is a common cause of neonatal mortality and childhood disability, occurring in 1 to 3 cases per 1000 live births. Moderate to severe HIE often leaves children with motor and cognitive impairments, and even cerebral palsy and other neurodevelopmental outcomes. Common affected areas in HIE include watershed areas at the ends of major intracranial vascular branches and deep gray matter such as the thalamus and basal ganglia.
Conventional MRI can display cortical damage, subcortical white matter damage, cerebral infarction, cerebral edema, and involvement of the basal ganglia and posterior limb of the internal capsule (PLIC). Among these, deep gray matter damage in the basal ganglia is a characteristic manifestation of severe HIE, and abnormal signals in the PLIC have also been used to differentiate between moderate or severe HIE and predict poor outcomes related to motor and sensory abnormalities. Although conventional MRI can show the lesion site, signal changes in the early stages of the lesion appear late and are difficult to identify, leading to certain limitations in assessing the severity and extent of the lesions.
DWI has extremely high sensitivity for early detection of HIE, especially the ADC value. The lower the ADC value, the more severe the cytotoxic edema. DWI can detect cytotoxic brain edema within hours after asphyxia, while conventional MRI only begins to show abnormalities on the third day. Although DWI has significant clinical implications for early identification of HIE-affected areas, it may exhibit pseudo-normalization by the seventh day. Therefore, it is recommended to use DWI combined with conventional MRI for the best timing for diagnosing HIE, which is between 3 to 5 days after birth. In DTI, FA helps assess the severity of HIE and the risk of seizures. Kline-Fath et al. reported that children with seizures after HIE have more severe brain injuries, and DTI examinations found significantly reduced FA values in the PLIC and corpus callosum.
H1-MRS studies related to HIE show that children with moderate to severe HIE have reduced NAA concentrations in the basal ganglia, and the Lac concentration in that area is significantly higher than that of normal or mildly injured individuals. Additionally, studies have found a high correlation between the decrease in ADC values in DWI and the increase in Lac/NAA in H1-MRS in the lesion area.
2.2 Bilirubin Encephalopathy (BE) When serum bilirubin exceeds the binding capacity of albumin or when the blood-brain barrier is immature, unconjugated bilirubin can enter the brain, causing acute bilirubin encephalopathy (ABE). In severe cases, this can progress to permanent neurological dysfunction, known as chronic bilirubin encephalopathy (CBE), also referred to as kernicterus. Common affected areas in BE include the basal ganglia region, including the globus pallidus, subthalamic nucleus, hippocampal gyrus, red nucleus, oculomotor nucleus, and lateral geniculate body, with the globus pallidus being the primary affected area where abnormalities can be detected by MRI.
It is generally believed that the symmetrical high signal of the globus pallidus in conventional MRI T1WI is an important marker of ABE, but early high signals in the globus pallidus cannot predict whether long-term sequelae will occur. When the signal characteristics of the globus pallidus transition from high signal on T1WI to high signal on T2WI and FLAIR sequences, it indicates the occurrence of CBE, which is associated with poor neurological outcomes. Abnormal high signals on T2WI often appear 3 to 6 months after birth. Many studies are focusing on how to display neurological functional abnormalities earlier and more specifically. Yan et al. reported that when the total serum bilirubin concentration exceeds 20 mg/L, damage to the globus pallidus and PLIC is likely to occur, with DTI sequences showing reduced ADC values in that area and increased FA values, suggesting the possibility of cellular edema in these specific areas during severe hyperbilirubinemia. H1-MRS studies in BE have found a positive correlation between total serum bilirubin levels and Glx/Cr levels in the globus pallidus region, suggesting that elevated levels of excitatory neurotransmitters such as glutamine may be related to neuronal damage in BE. Furthermore, functional magnetic resonance imaging (fMRI) has shown that increased low-frequency oscillation amplitudes in the basal ganglia region correlate positively with high bilirubin levels and are associated with motor developmental delays at 18 months.
2.3 Hypoglycemic Encephalopathy Hypoglycemia is one of the most common adverse events during the neonatal period, and severe cases can lead to permanent brain damage, often resulting in poor outcomes such as visual impairment, seizures, and cognitive deficits. The white matter in the parieto-occipital lobe during the neonatal period is denser in terms of axonal growth and synaptogenesis compared to other regions, which significantly increases its glucose requirements, making it more sensitive to hypoglycemic damage. Therefore, the white matter in the parieto-occipital region is the most commonly affected area in hypoglycemic encephalopathy.
Selective cytotoxic edema in the white matter of the parieto-occipital lobe is an early characteristic manifestation of neonatal hypoglycemic encephalopathy, with DWI sequences showing high signal changes during the acute phase. In addition to the parieto-occipital white matter, the parieto-occipital cortex, corpus callosum, basal ganglia, thalamus, and PLIC may also be affected, with DWI sequences clearly displaying restricted diffusion of water molecules in these affected areas early on. Conventional MRI can identify chronic parieto-occipital atrophy due to hypoglycemic brain injury and is helpful in prognosis assessment. H1-MRS studies in hypoglycemic encephalopathy have found that the peak NAA level in the affected area decreases, while the peak Lac level increases.
2.4 Encephalopathy of Prematurity (EoP) Premature infants are at high risk for adverse neurological outcomes, with approximately 10% of infants born before 33 weeks gestation developing cerebral palsy, and 25% to 40% experiencing motor disorders, while 25% to 50% face cognitive and behavioral issues. Adverse neurological outcomes in premature infants are associated not only with severe intraventricular hemorrhage occurring early in life but also with a series of other brain developmental issues. Volpe defined brain white matter injury (WMI) occurring during the development of premature infants and subsequent white and gray matter developmental abnormalities as EoP, which has garnered increasing attention in recent years.
Conventional MRI is currently the most commonly used detection technology for identifying WMI. Based on the classification methods of MRI for WMI, Martinez-Biarge categorized it into grades I to IV. Volpe classified WMI into mild, moderate, and severe based on neuropathological changes and MRI findings. Mild WMI cannot be detected in conventional MRI due to necrosis being <1mm, below MRI resolution, or due to pathological changes being diffuse white matter gliosis. Moderate WMI shows focal gliosis, primarily appearing as high signal on T1WI and low signal on T2WI, with high signal changes on DWI in the early stages of injury. Severe WMI presents with larger necrotic areas and shows cystic periventricular white matter softening. Additionally, studies have found that among extremely preterm infants who were not identified with WMI on conventional MRI, 20% still experience cognitive function delays. In recent years, various MRI brain injury scoring systems, including whole brain white matter scores, cortical gray matter scores, deep gray matter scores, and cerebellar scores, have been applied, which are expected to become biological markers for objectively assessing the development of white and gray matter in premature infants.
DTI technology can more sensitively assess the relationship between mild WMI and brain developmental abnormalities and neurological outcomes. Barnett et al. reported that FA decreases in the white matter of EoP infants may be related to oligodendrocyte maturation disorders and are associated with poor neurological outcomes at 20 months. It was also found that the radial diffusivity coefficient in the white matter of EoP infants increases, indicating myelination damage. Other MRI-related studies have shown that volumetric MRI reveals reduced brain volumes in EoP infants, particularly significant reductions in the volumes of the cerebral cortex, white matter, thalamus, and basal ganglia. Brain surface MRI measurements indicate reduced surface area and cortical folding in EoP infants. fMRI has found that various connections in the brain, including thalamocortical connections, are impaired in EoP infants. Therefore, multimodal MRI can compensate for the shortcomings of conventional MRI, making it more beneficial for assessing the long-term brain development and brain function of premature infants.
2.5 Sepsis-Associated Encephalopathy (SAE) SAE is a diffuse or multifocal brain dysfunction caused by the systemic inflammatory response of sepsis without clinical or laboratory evidence of direct central nervous system infection. SAE is more commonly reported in adults, with clinical manifestations including altered states of consciousness, delirium, coma, seizures, tremors, and neurological dysfunction. Pathological changes include ischemic lesions, diffuse microinfarcts, neuronal degeneration, myelin dissolution, and white matter necrosis. Abnormalities in electroencephalography are an important basis for diagnosing SAE, and studies have found that, in addition to brain function abnormalities, severe cases can also reveal structural brain damage through MRI. Becker et al. reported that in children with SAE, 21% had abnormal MRI results, confirmed by DWI, FLAIR, SWI, and conventional MRI, with 53% showing white matter signal abnormalities, and 53% showing ischemia, infarction, or thrombosis. H1-MRS can measure NAA/Cr, Lac, and other metabolite abnormalities. Studies have found that within 6 hours after sepsis, T2WI can show changes in vasogenic brain edema, while DWI and ADC images can reveal cytotoxic brain edema changes in the hippocampus and cortex, with a decrease in the NAA/Cho ratio in H1-MRS indicating neuronal damage. Regarding neonatal SAE, there is currently a lack of general understanding and objective evaluation standards. Although literature has reported the use of MRI technology in the clinical assessment of neonatal SAE, data on imaging aspects remain limited and require further research and validation.
2.6 Genetic Metabolic Encephalopathy and Mitochondrial Encephalopathy Genetic metabolic encephalopathy is a syndrome of neurological dysfunction caused by disorders in amino acid, organic acid, fatty acid, or carbohydrate metabolism, with clinical manifestations lacking specificity. Certain diseases have characteristic MRI findings that can assist clinicians in early diagnosis, thereby improving patient prognosis. Maple syrup urine disease is caused by a deficiency of branched-chain alpha-keto acid dehydrogenase complex, leading to metabolic disorders of branched-chain amino acids. A large accumulation of leucine, isoleucine, valine, and their keto acids in the body causes central nervous system symptoms such as seizures, poor responsiveness, changes in muscle tone, and feeding difficulties. MRI shows characteristic changes, with early DWI displaying typical bilateral symmetrical diffusion restriction and reduced ADC values, potentially affecting the cerebellar white matter, dorsal brainstem, bilateral thalamus, globus pallidus, cerebral peduncles, internal capsule, and corticospinal tract, hence also referred to as maple syrup urine disease-related brain edema. H1-MRS can detect the concentrations of various metabolites in the brain. Shah et al. reported that in neonatal maple syrup urine disease, branched-chain amino acids and branched-chain alpha-keto acids can appear as a resonance peak at 0.9~1.0×10−6, especially during metabolic crises. In phenylketonuria, a corresponding peak for phenylalanine can be displayed at 7.37×10−6, reflecting the accumulation of phenylalanine in the brain. SWI shows specific manifestations in some genetic metabolic encephalopathies combined with bleeding and calcification. For instance, Reddy et al. reported that intracranial hemorrhage in organic acidemia is most evident in SWI sequences, and calcification in the basal ganglia of children with methylmalonic acidemia can be clearly displayed.
Mitochondrial encephalopathy is caused by deletions or mutations in mitochondrial DNA or nuclear DNA leading to abnormalities in mitochondrial metabolic pathways. Clinically, it often presents as syndromes such as Leigh syndrome, MELAS syndrome, Alpers syndrome, and Barth syndrome. In the neonatal period, common clinical manifestations include prematurity, intrauterine growth restriction, hypotonia, respiratory distress, seizures, feeding difficulties, and hyperlactatemia, among which MRI is helpful for early recognition of mitochondrial encephalopathy. In children with Leigh syndrome, T2WI shows symmetrical high signals in the bilateral basal ganglia and brainstem, with no significant changes in T1WI, and DWI can show corresponding areas with enhanced symmetrical signals. In children with MELAS, high signals involving the cortex and subcortical white matter can be seen on DWI, T2WI, and FLAIR, with less involvement of deep white matter, and H1-MRS can detect increased lactate levels in the affected areas. These characteristic MRI changes can serve as good prompts for clinical diagnosis.
In summary, the combined application of conventional MRI and multimodal MRI technology can more sensitively, comprehensively, and accurately assess the characteristics of neonatal encephalopathy, offering greater advantages in timely identification of neonatal encephalopathy, assessing the extent of damage, and predicting neurodevelopmental outcomes. However, research on certain diseases is still limited, with current reports being case reports or small sample studies, necessitating further large-sample studies to explore the value of multimodal MRI technology in the diagnosis of encephalopathy.
(Received on 2023-01-05)
