Central Pattern of Hypoxic-Ischemic Encephalopathy

The central pattern of hypoxic-ischemic encephalopathy (HIE) usually occurs with profound asphyxia, when there is an abrupt interruption of the blood supply, depriving the neonatal brain of oxygen and glucose. Highly metabolic structures such as the thalami, basal ganglia, and brainstem are more vulnerable to hypoxia and ischemia, more specifically the ventral lateral thalami, posterolateral lentiform nuclei, posterior midbrain, hippocampi, lateral geniculate nuclei, and perirolandic cerebral cortex (Fig. 30-3).⁵ Quadriparesis, choreoathetosis, seizures, mental retardation, and cerebral palsy have been associated with profound asphyxia.⁶ Ultrasound and CT have low sensitivity to detect early ischemic changes in the deep structures of the brain. The most common pattern on ultrasound is transient or persistent hyperechogenicity, which may progress to cavitation in the basal ganglia and thalami, particularly in the globus pallidus and ventral lateral nuclei of the thalamus. With more severe insults involving the cortex and subcortical white matter, ultrasound and CT may depict indirect evidence of edema, such as effacement of the sulci, loss of gray-white matter differentiation, and compressed lateral ventricles.

MRI is the imaging modality of choice for neonatal encephalopathy. MRS performed 24 hours after the insult is considered sensitive for hypoxic-ischemic brain injury. Elevated lactate and diminished N-acetyl-aspartate (NAA) are the most common MRS findings in neonates with neurologic and developmental abnormalities (e-Fig. 30-4). Lactate rises after the hypoxic-ischemic event, peaking at 3 to 5 days, whereas NAA starts to decline around the third day. Although a minimally elevated lactate level (lactate/choline ratio <0.15) may be detected in the normal neonatal brain at term, an increased lactate level relative to the total creatine peak in the basal ganglia provides an early indication of brain injury before changes may be apparent on conventional T1- and T2-weighted imaging. It has been suggested that resuscitation may rapidly clear lactate and that a secondary increase in lactate may occur after 12 to 24 hours. The metabolites tend to normalize after about day 5, although in some cases abnormal metabolite ratios persist. Persistently elevated lactate levels in the basal ganglia provide prognostic information about the severity of the brain injury and the subsequent neurodevelopmental outcome. False-negative MRS findings also may occur, with normal spectral findings but abnormal outcomes.

DWI is a sensitive technique for assessment of acute brain injury. DWI also shows deep gray matter and perirolandic gray matter lesions before they are seen with conventional MRI. If DWI is performed in the first few hours after the injury, it may underestimate the extent of the injury or even show normal results. Paralleling the clinical presentation of HIE, in which neonates may actually transiently improve before demonstrating a more permanent decline in neurologic functioning because of delayed cell death via apoptotic mechanisms, some patients demonstrate mild brain damage for the first few days and then proceed to demonstrate extensive brain involvement around 5 days after the injury. Apparent diffusion coefficient (ADC) values always evolve over time; they decrease initially after the injury, with the nadir around 3 to 5 days, and increase (via facilitated diffusion) later in the chronic phase. As ADC values increase, a point of transient “pseudonormalization” exists in which injured tissue can be misdiagnosed as “normal.” Conventional MRI findings are usually unremarkable during the first few days but then begin to demonstrate first an increased T1-weighted signal and a decreased T2-weighted signal in the subacute period followed by an increased T2-weighted signal in the more chronic period. Evidence suggests that hypothermia therapy delays the onset of MR changes (in metabolic, diffusion, and conventional imaging) associated with injury and, in particular, delays the onset of pseudonormalization in the ADC signal.⁷

Peripheral Pattern of Hypoxic-Ischemic Encephalopathy

The peripheral pattern of HIE usually results from a period of decreased blood supply to the brain (rather than a near total and abrupt interruption) and is thought to develop as a result of a compensatory shunting of blood to vital brain structures, such as the brainstem, thalami, basal ganglia, hippocampi, and cerebellum, at the expense of less metabolically active structures, namely the cerebral cortex and white matter (Fig. 30-5). Therefore the brainstem, cerebellum, and deep gray matter structures generally are spared from injury in mild to moderate hypoxic-ischemic insults. More prolonged insults result in injury to the intervascular border (watershed) zones, which are relatively hypoperfused as a result of this shunting. Neurologic examination varies depending on the severity of the insult, from asymptomatic in mild cases to proximal extremity weakness or spasticity and cerebral palsy in persons who sustain severe insults.⁶ Increasing severity of watershed-distribution injury is associated with impaired neurocognitive functioning, including language, visuoperceptual, and executive functioning impairments.

Ultrasound lacks sensitivity in assessing partial prolonged hypoxia-ischemia because it provides poor visualization of the triple watershed zone. CT also is not sensitive to the early changes but may show effacement of the gray-white junction, hypoattenuation with mass effect from acute edema, or hypoattenuation with volume loss in the watershed zone. Similar to central HIE, in the acute phase, MRI can detect lactate and restricted diffusion with corresponding low ADC values in the affected brain regions, which predominantly involve the cortex and underlying white matter along the parasagittal frontal-parietal cortex. With time, increased T2/fluid attenuated inversion recovery signal and mass effect related to edema may develop. Chronically, gliosis and volume loss mainly involving the deep portion of the gyri result in mushroom-shaped gyri, known as ulegyria, which sometimes is associated with an epileptogenic focus. Atrophic changes and gliosis predominately involve the subcortical white matter in the border zone between the anterior and the middle cerebral arteries, in the parasagittal watershed zone, and in the parietal lobes at the border zone of the three major cerebral arteries, that is, the triple watershed zone.

Arteriovenous Malformations

AVMs are abnormal thin-walled vessels that connect arteries to veins without intervening capillaries. Most cases of AVM manifest later in childhood or in early adulthood. Neonates with an AVM tend to present with systemic cardiac manifestations or seizures related to the parenchymal hypoperfusion. Macrocephaly and hydrocephalus related to abnormally increased venous pressure and spontaneous hemorrhage are less common in the neonatal period.

In symptomatic patients, early diagnosis and emergency endovascular embolization is important because progression to atrophy and leukomalacia may occur rapidly. Unenhanced CT is useful to detect acute hemorrhaging, but it lacks the sensitivity necessary to detect the underlying vascular malformation. CT angiography (CTA) involves significant radiation exposure but provides exquisite anatomic detail of a nidus (if present), feeding arteries, draining veins, and the presence of possible aneurysms. MR angiography (MRA) is excellent for the detection of hemorrhage and to delineate the AVM, although smaller vascular malformations may go undetected. The flow void seen in the tangled vessel of the nidus has been described as a “bag of black worms.” High-resolution T1-weighted sequences are important to define the location of the nidus. Three-dimensional (3D) time-of-flight MRA has slightly less special resolution than does CTA, but it does not expose the neonate to radiation. Time-resolved MRA has less special resolution than 3D Time-of-flight (TOF) MRA and CTA, but it may provide sufficient information to differentiate feeding arteries and draining veins.

Vein of Galen Malformation

Malformations involving the vein of Galen are true congenital arteriovenous connections between thalamic perforating, choroidal, and anterior cerebral arteries with the embryonic median prosencephalic vein. Associated cardiovascular anomalies may be present, such as aortic coarctation and secundum atrial septal defect.⁸ The most common clinical presentation is high-output cardiac failure. The prognosis is mainly related to the number of abnormal arteriovenous connections and the amount of associated parenchymal injury from arterial steal and hypoperfusion. The most common is the choroidal type with innumerous connections, which usually is fatal. The mural type with one to four connections has a better prognosis and is less likely to present in the neonatal period. This type usually presents during infancy as developmental delay, hydrocephalus, and seizures, or in older children as hemorrhage. Endovascular therapy is the treatment of choice. Prenatal and postnatal spontaneous thrombosis has been reported.

Malformation of the Dural Sinuses

Saccular malformations of the dural sinus are rare; when they occur, they are associated with thrombosis, likely related to slow flow. The neonatal venous system has poor capacity to establish collateral circulation, and the drainage to the cavernous sinus is not yet developed. The propagation of the venous thrombosis within a dural sinus malformation may cause venous infarcts. The treatment of choice is preventive anticoagulation.

Extracranial Hematomas

The major types of extracranial hematomas are subgaleal hematoma, caput succedaneum, and cephalohematoma (also see Chapter 23). Subgaleal hematomas may enlarge rapidly and lead to potentially life-threatening hypovolemia. Anemia, coagulopathy, metabolic acidosis, renal impairment, and skull fracture have been reported as predictors of poor outcome. Early recognition and management are essential. An extracranial hematoma is caused by rupture of the emissary veins between the dural sinuses and the scalp veins; the hemorrhage accumulates between the epicranial aponeurosis of the scalp and the periosteum. Upon imaging, extracranial hematomas appear as a hemorrhagic collection overlying the calvarium and crossing the sutures. They may extend underneath the attachments of the occipitofrontalis muscle to the orbital margins anteriorly, the temporal fascia laterally, and the nuchal ridge posteriorly.

Caput succedaneum and cephalohematomas are rarely associated with complications. Cephalohematomas are subperiosteal hemorrhages confined by cranial sutures. Cephalohematomas are not of clinical significance but may be associated with skull fracture and epidural hematomas. Blood degradation within a hematoma may cause mild jaundice. Typically, hematomas increase in size after birth, and a small proportion of them calcify. Caput succedaneum represents edema, which may be accompanied by hemorrhage, within the subcutaneous tissues. Caput succedaneum is common after vaginal delivery, particularly when vacuum extraction is used. Typically, resolution occurs within a few days without complications.

Subdural Hematomas

Small subdural hematomas, particularly in the posterior fossa or caudal to the occipital lobes, are not uncommon after vaginal births and have been described in up to 30% of neonates. Subdural hematomas are usually asymptomatic and occur as a result of a dural tear during vaginal delivery, characteristically involving the tentorium. Although most subdural hematomas are venous in origin, large subdural hematomas may be caused by arterial bleeding. Most lethal cases are related to large infratentorial hemorrhages with compression of the brainstem. Interhemispheric subdural hematomas related to tearing of the inferior sagittal sinus and subdural hematomas along the convexity related to tearing of cortical veins are less frequent than those involving the tentorium. Associated subarachnoid hemorrhage related to tearing of cortical veins is not infrequent. Large subdural hematomas may cause parenchymal infarction as a result of either impaired arterial supply or, more likely, obstruction of the venous drainage, leading to hemorrhagic venous infarction. Large subdural hematomas may interfere with cerebrospinal fluid (CSF) reabsorption and cause hydrocephalus. Subdural hematomas that are not evacuated undergo absorption or evolve into subdural hygromas, which can persist for several months.

Finally, subdural hematoma is the most common presentation of nonaccidental trauma, which should be considered in addition to late hemorrhagic disease of the newborn.

Bacterial Infections

The most common bacterial neonatal brain infections are caused by group B streptococcus, Escherichia coli, Streptococcus pneumoniae, Haemophilus influenzae type B, and Listeria monocytogenes. Imaging should be performed in neonates with bacterial meningitis if a rapid response to treatment does not occur or if a focal neurologic deficit develops. Complications of meningitis include empyema, ventriculitis, hydrocephalus, infarction, venosinus thrombosis, cerebritis, or abscess. In uncomplicated meningitis, imaging is usually normal. Leptomeningeal enhancement may be seen as a result of vascular engorgement.

Ventricular enlargement resulting from impaired CSF absorption by fibrinous inflammatory exudate is the most common imaging finding in persons with meningitis and does not necessarily indicate ventriculitis. Ventriculitis usually presents with ependymal enhancement and sometimes with a pus-fluid level. Ventriculitis often is associated with hydrocephalus and sometimes with intraventricular abscess. Sterile subdural effusions are not uncommon in neonates with meningitis; however, in a very small percentage of cases (approximately 2%), empyemas develop. Subdural collection with a signal intensity different from that of CSF, peripheral enhancement sometimes with septa, and signal abnormality involving the brain parenchyma are suggestive of empyema. Cerebritis is not uncommon in autopsies of neonates with meningitis despite normal findings of in vivo imaging. When imaging findings are present, cerebritis appears as an area of vasogenic edema with or without patchy areas of enhancement and/or cortical enhancement that may resolve with treatment. If the infection progresses, the enhancing areas become more confluent, and later an abscess forms with restricted water diffusivity and an enhancing capsule. Neonatal Citrobacter koseri (diversus) meningitis is rare but often is complicated by formation of abscesses, with a predilection for the frontal lobes. Neonatal pneumocephalus also has been reported as a complication of C. koseri meningitis. Citrobacter meningitis usually has a poor neurologic outcome (e-Fig. 30-7).

Fungal Infection (Candida)

Candida is a neonatal commensal fungus. Infection is caused by organisms that are already present in the intestine and other locations. The key risk factors are catheters and use of wide-spectrum antibiotics; premature infants are particularly susceptible. At first the inflammation consists of neutrophils, and later it consists of epithelioid cells and giant cells. It causes meningitis, multiple enhancing hemorrhagic microabscesses, macroabscesses, and extensive brain necrosis. Multiple macroabscesses within the subcortical and periventricular regions and basal ganglia are the most common imaging findings in the neonate; however, imaging findings may be normal.

Herpes Simplex Virus Type 2 Infections

Women who have their first outbreak of herpes simplex virus type 2 genital herpes during pregnancy are at high risk of miscarriage or delivering a baby with a low birth weight. The infection can be passed to the neonate in utero or, most commonly, during birth. The most serious risk to the infant is herpes simplex virus type 2 encephalitis. Signs and symptoms in the newborn are nonspecific, with irritability, a high-pitched cry, fever, and poor feeding. Diagnosis is made via a viral culture or polymerase chain reaction (PCR) of the CSF. If the infection occurs early in pregnancy, it may cause hydranencephaly, basal ganglia calcifications, and microphthalmia (the classic TORCH pattern). Late pregnancy or intrapartum transmission involves the bilateral gray and white matter diffusely, which rapidly develops into whole brain necrosis. Multiple cortical hemorrhagic foci and sometimes leptomeningeal enhancement often are present. With time, cystic white matter changes develop (Fig. 30-8).⁹

Enterovirus and Parechovirus Infection

Enterovirus and parechovirus belong to the family Picornaviridae. Enteroviruses are well known for causing neonatal hepatitis, myocarditis, and meningoencephalitis, which can lead to death or severe long-term morbidity. Parechoviruses recently have been reported as causing severe neonatal infection, including involvement of the CNS. The diagnosis is made by PCR; however, PCR for enterovirus does not detect parechovirus. Meningoencephalitis in the neonatal period causes extensive white matter abnormalities, which appear as hyperechogenicity on ultrasound, hypoattenuation on CT, increased signal on T2-weighted MRI images, and decreased signal on T1-weighted MRI images, with or without restricted water diffusivity (e-Fig. 30-9). This pattern of injury easily may be misinterpreted as white matter injury of prematurity or as being caused by hypoxic-ischemic injury, particularly the partial prolonged type.¹⁰

Congenital Cytomegalovirus Infection

CMV is the most common congenital viral infection in the United States. Between 30% and 50% of women of childbearing age in the United States have never been infected with CMV, and about 1% to 4% have a primary CMV infection during a pregnancy. The transmission rate to the fetus is about 33%. More than 5000 children each year experience permanent problems caused by CMV infection in the United States. Maternal antibodies, which protect the fetus from rubella and toxoplasmosis, do not prevent fetal transmission of CMV, but they do lessen the severity of the disease. Chorioretinitis occurs in 15% to 20% of cases. Diagnosis of CMV infection in the newborn is usually made via a urine culture. No cure exists for CMV infection. Treatment is primarily supportive.

The brain is the most commonly affected organ. CMV interferes with normal fetal brain development and is associated long-term with mental retardation, blindness, deafness, or epilepsy. Depending on the timing of infection during fetal development, neonates with congenital CMV may have microcephaly, predominately periventricular calcifications, ventriculomegaly, lissencephaly, polymicrogyria, cerebellar hypoplasia, dysplastic white matter, and porencephaly.¹¹ Other findings include intrauterine growth restriction, hepatosplenomegaly, cardiomyopathy, echogenic bowel, and hydrops. CT can detect and characterize diminutive periventricular and subependymal calcifications. CMV is also the leading infectious cause of sensorineural hearing loss; CT may demonstrate a Mondini malformation with an absent interscalar septum, a large vestibule, and an enlarged vestibular aqueduct.

Congenital Toxoplasmosis Infection

It is estimated that 400 to 4000 cases of congenital toxoplasmosis occur each year in the United States. In the first trimester, maternal infection is less likely to result in congenital infection (2% to 10%), but when it occurs, it is more likely to be severe or to result in abortion. Severe congenital toxoplasmosis meningoencephalitis is associated with intrauterine growth restriction, hydrocephalus, microcephaly, calcifications, porencephaly, or hydranencephaly. Maternal infection after 20 weeks of gestation has a much higher rate of transmission to the fetus (20% to 30%). The sequelae are generally less severe but still include blindness, epilepsy, and mental retardation.

Although the neurologic outcome is good in the absence of brain abnormalities, congenital toxoplasmosis may be unrecognized until late in infancy when infants present with seizures or other neurologic symptoms. Nonshadowing cerebral and hepatic calcifications are the most typical ultrasound findings. Intracranial calcifications may be periventricular or random in distribution. Other less specific imaging findings are subependymal cysts, echogenic lenticulostriate and thalamostriate arteries (candlestick sign), and cystic white matter changes. CT is sensitive for the detection and characterization of cerebral calcifications and may demonstrate hydrocephalus and microcephaly. The ocular calcifications seen on CT may mimic retinoblastoma. Because of its high sensitivity and absence of ionizing radiation, MRI may be used serially throughout pregnancy to evaluate for the development of brain abnormalities. Acutely, the fetal brain abnormality consists of white matter signal abnormality such as loss of the intermediate zone layer in young fetuses. In fetuses with advanced gestational age, cystic lesions with a mural nodule are characteristic; however, MRI is not sensitive for small calcifications. After birth, calcifications, variable degrees of white matter dysplasia and gliosis, and cortical malformations all may be detected on MRI.

Congenital Hiv Infection

HIV transmission to the fetus or neonate occurs in utero, intrapartum, or postpartum via breast milk. Without treatment, about 30% of pregnant women with HIV pass the infection to their fetus. Intrapartum treatment with protease inhibitors, elective caesarean section, and avoiding breastfeeding decreases the transmission to the fetus to less than 2%. HIV penetrates the blood-brain barrier via macrophages (the so-called “Trojan horse”) very early in the course of disease and incites a subacute encephalitis with perivascular mononuclear inflammatory cell infiltration. Neuroimaging findings usually are normal in neonates with HIV. The onset of neurologic decline generally occurs between 2 months to 5 years. Atrophy, delayed myelination, corticospinal tract degeneration, cervical lymphadenopathy, benign lymphoepithelial cysts in the parotid glands, aneurysms, opportunistic infections, progressive multifocal leukoencephalopathy, and CNS lymphoma are all associated late findings of congenital HIV infection.

Congenital Rubella Infection (German Measles)

Congenital rubella infection is extremely rare as a result of vaccination and screening of pregnant women. The most common manifestation is rash, fever, and symptoms of an upper respiratory tract infection. Most people are exposed to rubella during childhood and develop antibodies to the virus and thus are immune. Rubella infection during early pregnancy can pass through the placenta to the fetus and cause serious birth defects, including heart abnormalities, mental retardation, blindness, and deafness. Imaging usually shows nonspecific findings such as microcephaly, ventriculomegaly, abnormal myelination, and calcifications, particularly of the basal ganglia.

Congenital Syphilis Infection

Syphilis is a sexually transmitted bacterial infection that can be transferred from mother to fetus through the placenta. It is estimated that in up to 50% of cases of congenital syphilis, the neonate is born prematurely, is stillborn, or dies shortly after birth. Nevertheless, congenital syphilis rarely manifests with neurologic symptoms in the neonatal period. Only a few patients present with meningitis, choroiditis, hydrocephalus, or seizures. Severe ischemic-hemorrhagic lesions involving predominantly unilateral periventricular white matter, which are thought to be a result of endarteritis, have been reported in neonates. Other findings of congenital syphilis are generalized lymphadenopathy, hepatosplenomegaly, jaundice, and rash. The findings of CNS syphilis, such as leptomeningeal enhancement (particularly involving the basal meninges) and intraparenchymal mass (gumma), as well as frontal bossing, saddle nose deformity, mulberry molars, peglike upper frontal incisor, and saber shin, typically are observed later in infancy or childhood.

Congenital Varicella Infection

The incidence of congenital varicella syndrome after maternal varicella infection during the first two trimesters is <1%. As with CMV and toxoplasmosis, intrahepatic and intracranial calcifications are very common. Intrauterine encephalitis, cortical atrophy, and porencephaly have been reported in cases of congenital varicella infection before 20 weeks of gestational age. Other possible fetal abnormalities are polyhydramnios, limb hypoplasia, and contractures, as well as paradoxical diaphragmatic motion as a result of unilateral paralysis. Neonates may demonstrate dysfunction of the autonomic nervous system (neurogenic bladder), hydroureter, esophageal dilation, aspiration pneumonia, and cutaneous lesions in a dermatomal distribution.¹²

Congenital Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus (LCMV) primarily infects rodents, but it also can infect humans through inhalation of aerosolized particles of rodent urine, feces, or saliva; through ingestion of contaminated food; or through direct contact of open wounds to virus-infected blood. Human-to-human transmission may occur via the placenta or through solid-organ transplantation. The disease is usually mild in healthy individuals, but it may cause serious consequences to immunosuppressed persons and pregnant women. Miscarriage, birth defects, and long-term neurologic problems may result from congenital LCMV. LCMV causes chorioretinitis, ependymitis with ependymal calcifications, polymicrogyria, and microcephaly or hydrocephalus. These findings are similar to those of congenital toxoplasmosis and CMV; however, hepatosplenomegaly usually is not present in persons with LCMV.

Kernicterus (Bilirubin Encephalopathy)

Kernicterus is caused by markedly elevated or sustained unconjugated hyperbilirubinemia. Kernicterus usually develops in the first week of life; however, it may occur as late as the third week. Severe hemolytic conditions, especially Rh hemolytic disease with hydrops fetalis, are the most common causes. Other risk factors include prematurity, polycythemia, resolving hematomas, sulphonamide (co-trimoxazole) administration, G6PD deficiency, and Crigler-Najjar and Gilbert syndromes. Although risk factors are usually present, kernicterus has been reported in otherwise healthy babies. Acutely, kernicterus manifests as lethargy, decreased feeding, hypotonia or hypertonia, a high-pitched cry, spasmodic torticollis, opisthotonus, the setting sun sign, fever, seizures, and even death. In severe cases, kernicterus results in a tetrad of movement disorder, auditory dysfunction, oculomotor impairments, and dental enamel hypoplasia of the deciduous teeth. Persons with mild cases are still at risk for isolated hearing loss or some degree of neurologic, cognitive, learning, and movement disorders.

Pathologically, kernicterus causes damage to the globi pallidi, subthalamic nuclei, and hippocampi (CA2 and CA3 regions). Ultrasound and CT are not sensitive in detecting early abnormalities in persons with kernicterus. On MRI, an increased signal initially is seen on T1-weighted images; this signal is inconsistent. Increased signal on T2-weighted images of affected areas develops later (Fig. 30-10), when hyperechogenicity may appear on ultrasound and hypoattenuation may appear on CT.¹³ Restricted diffusion usually is not seen in persons with kernicterus unless it is associated with other conditions, such as hypoxia-ischemia. Conventional T1 spin echo images appear to be more reliable than 3D T1 spoiled gradient echo images, because the latter are associated with a high signal in normal subthalamic nuclei, which may cause false-positive results. A metabolite signature of acute kernicterus has been proposed on MRS using an echo time of 35 ms with elevated ratios of taurine, glutamate, glutamine, and myo-inositol and a decreased ratio of choline relative to creatine with no significant elevation of lactate.

Hypoglycemia

Neonatal encephalopathy resulting from hypoglycemia typically occurs when glucose concentrations are less than 30 mg/dL in the term infant and less than 20 mg/dL in the preterm infant. The clinical presentation of neonatal hypoglycemia may be subtle, including stupor, jitteriness, seizures, respiratory abnormalities, and hypotonia. MRI is the imaging modality of choice, showing abnormalities in the posterior parietal and occipital cortex and adjacent white matter. Acutely, there is restricted diffusion on DWI as well as edema on T1- and T2-weighted imaging. MRS with an echo time of 30 ms exhibits an increased lactate-lipid peak and a decreased NAA peak in the involved areas. In the chronic phase, the involved areas evolve into encephalomalacia and atrophy. If the hypoglycemia is severe and prolonged, progression to diffuse brain damage occurs with involvement of the hippocampus, corpus striatum, and cerebellum.¹⁴

Organic Acid Disorders

Methylmalonic acidemia and proprionic aciduria are examples of organic acid disorders. These disorders cause ketoacidosis, often leading to severe acidosis, vomiting, tachycardia, lethargy, seizures, coma, and death. In these disorders, edema is present in both myelinated and unmyelinated structures. The edema involving the myelinated white matter is related to vacuolating or spongiform myelinopathy, which acutely demonstrates restricted water diffusivity because the water is trapped within vacuoles. Findings on conventional imaging include edema with increased T2 signal and decreased T1 signal involving the white matter. In more severe cases, the deep gray structures may be involved, with a predilection for the globi pallidi in persons with methylmalonic acidemia and for the putamina and caudate nuclei in persons with proprionic aciduria. MRS detects a reduction in myo-inositol and NAA and an elevation of glutamine. Elevation of lactate as a result of hyperammonia, ketoacidosis, and/or mitochondrial dysfunction also may be present during an acute metabolic crisis.

Amino Acid Disorders

Maple syrup urine disease results from an interruption of the metabolism of the essential amino acids leucine, isoleucine, and/or valine. The most severe form manifests in the first week of life with seizures, vomiting, dystonia, fluctuating ophthalmoplegia, and coma. The imaging findings are almost pathognomonic. Conventional MR shows edema in the deep cerebellar white matter, brainstem tegmentum, posterior limb of the internal capsule, perirolandic white matter, and precentral and postcentral gyrus. Restricted water diffusivity is seen acutely in the areas of vacuolating edema in the myelinated white matter. MRS shows a peak at 0.9 parts per million (ppm) related to the accumulation of abnormal branched-chain amino acids and branched-chain apha-ketoacids. The imaging findings by diffusion imaging and MRS may resolve with treatment.¹⁵

Urea Cycle Disorders

Urea cycle enzyme defects include ornithine carbamyl transferase deficiency, carbamyl phosphate synthetase deficiency, argininosuccinic aciduria, citrullinemia, and hyperargininemia, resulting in hyperammonemia and elevation of glutamate. Cases with severe impairment of elimination of nitrogen waste products manifest as irritability, lethargy, poor feeding, hypothermia, and seizures during the neonatal period.

Imaging in the acute phase shows markedly diffuse vasogenic edema, predominantly in the unmyelinated white matter, with early involvement of the subcortical U fibers and relative preservation of the myelinated white matter. The underlying pathophysiology of the urea cycle defects is related to vasogenic edema, in contrast to vacuolating myelinopathy in persons with maple syrup urine disease. As a result, the mean diffusivity maps in the urea cycle defect will show increased signal intensity in the unmyelinated white matter. In some cases, the lentiform nuclei (particularly the globi pallidi), the posterior insular cortex, and the perirolandic cortex also may be involved with increased T1 signal. This presentation causes some overlap between the conventional imaging findings of urea cycle disorders and hypoxic-ischemic injury. However, involvement of the globi pallidi and putamina in urea cycle disorders is predominant as opposed to thalami in cases of hypoxia-ischemia. MRS in patients with urea cycle defects typically demonstrates increased levels of glutamate and glutamine and decreased levels of myo-inositol, NAA, choline, and creatine.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is caused by a defect of the glycine cleavage system, which is present in the liver, kidney, and brain, leading to the accumulation of glycine in blood, urine, and CSF. The diagnosis is established by calculating the CSF/plasma glycine concentration ratio. A value of greater than 0.08 is diagnostic. Confirmation of the diagnosis requires measurement of the activity of the glycine cleavage system in liver tissue. The neonatal (classic) form of nonketotic hyperglycinemia is far more common than the infantile, late-onset, or transient phenotypes. The neonatal form presents in the first days of life with encephalopathy, hypotonia, lethargy, seizures, and characteristic hiccups, which can progress rapidly to intractable seizures, coma, and respiratory failure. The outcome is invariably poor.

On MRI, abnormal myelination and a hypoplastic or dysgenic corpus callosum are seen, which progresses to diffuse cerebral atrophy. Increased T2 signal and restricted water diffusivity involving the myelinated portion of the posterior limb of the internal capsules, pyramidal tracts, middle cerebellar pedicles, and dentate nuclei have been reported. The underdevelopment of the corpus callosum is difficult to assess in the neonate because of its small size and lack of myelin, but it becomes evident later. Atrophy and delayed myelination also are common findings in other metabolic disorders, particularly in organic acidurias. MRS exhibits a large glycine peak at 3.55 ppm.

Peroxisomal Disorders

Peroxisomal disorders that manifest in the neonate are primarily a result of the failure to form viable peroxisomes (peroxisomal biogenesis disorders), resulting in multiple metabolic abnormalities. Zellweger syndrome and neonatal adrenoleukodystrophy are the most common peroxisomal disorders in the neonate, and both have pathognomonic findings on conventional MRI. Zellweger syndrome is characterized by delayed myelination, temporal and parietal polymicrogyria, and subependymal germolytic cysts adjacent to the frontal horns of the lateral ventricles. In contrast to Zellweger syndrome, neonatal adrenoleukodystrophy causes dysmyelination, mainly involving the occipital lobes, the splenium of the corpus callosum, and/or the cerebellum. Often these lesions demonstrate restricted water diffusion and peripheral enhancement. MRS in persons with Zellweger syndrome is not specific, showing a marked decrease in NAA levels in the gray and white matter, thalamus, and/or cerebellum, a decreased myo-inositol level in the gray matter if concomitant hepatic dysfunction is present, and in some cases, elevated glutamine levels.

Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency is a rare, usually underrecognized, autosomal-recessive disorder caused by genetic mutation of the genes that produce enzymes essential for the formation of molybdenum cofactor. The absence of molybdenum cofactor leads to toxic levels of sulphite, which may be detected by hypouricemia, elevated urine sulfate, and elevated S-sulfocysteine. Clinically, molybdenum cofactor deficiency manifests in the first few days of life with seizures and encephalopathy and usually leads to death within months. Imaging shows edema and cystic changes involving predominantly the basal ganglia and severe volume loss of the gray and white matter. Reduced water diffusivity may be present in the affected areas.

Mitochondrial Disorders

Mitochondrial disorders are a group of diseases caused by enzymatic defects leading to primary lactic acidosis and decreased ATP production. Pyruvate transcarboxylase, pyruvate dehydrogenase, and cytochrome c oxidase deficiencies are the most common enzymatic defects leading to primary lactic acidosis in the neonatal period. MRI is the imaging modality of choice for its capability to detect areas of reduced water diffusivity and the presence of lactate typically associated with these disorders. Characteristically, areas of increased T2 signal and reduced water diffusivity are found in the brainstem, the subthalamic nucleus, and the globus pallidum. MRS detects elevated lactate levels in the areas with abnormal signal, as well as in the normal-appearing brain. It should be noted, however, that elevated lactate is not always indicative of a mitochondrial disorder, and nondetectable lactate levels do not preclude the possibility of a mitochondrial disorder. Sometimes specific peaks can be detected—for example, elevated succinate peak at 2.4 ppm in persons with succinate dehydrogenase deficiency and an elevated pyruvate peak at 2.36 ppm in persons with pyruvate dehydrogenase complex deficiency.

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