RH Challenges. Many guidelines for diagnosing NAI depend upon the presence of RH, including those of a particular pattern (e.g. retinal schisis, perimacular folds), and based upon the theory of vitreous traction due to inflicted acceleration / deceleration forces (e.g. SBS) [134-153]. However, the specificity of RH for NAI has been repeatedly challenged. Plunkett (2001) reported RH in 2/3 of eye exams in children with fatal AI . Goldsmith and Plunkett (2004) reported a child with extensive bilateral RH in a videotaped fatal accidental short fall . Lantz et al (2004) reported RH with perimacular folds in an infant crush injury . Gilles et al (2003) reported the appearance and progression of RH with increasing intracranial pressure following head injury in children . Obi et al (2007) reported RH with schisis and folds in two children, one with AI and the other with NAI . Forbes et al (2007) reported RH with epidural hematoma in five infant AI cases . From a research perspective, Brown et al (2007) found no eye pathology in their fatal shaken animal observations . Binenbaum et al (2007) observed no eye abnormalities in piglets subjected to acceleration/deceleration levels >20 times what Prange et al (2003) predicted possible in inflicted injury [41,149].Emerson et al (2007) found no support for the vitreous traction hypothesis as unique to NAI .
The eye and optic nerve are an extension of, and therefore a window to, the CNS including their shared vascularization, meningeal coverings, innervation, and CSF spaces. RH has been reported with a variety of conditions including AI, resuscitation, increased intracranial pressure, increased venous pressure, subarachnoid hemorrhage, sepsis, coagulopathy, certain metabolic disorders, systemic hypertension, and other conditions [143,145,153]. The common pathophysiology appears to be increased intracranial pressure or increased intravascular pressure. Furthermore, many cases of RH (and SDH) are confounded by the sequence or cascade of multiple conditions (e.g. the unified hypothesis of Geddes) that often have a synergistic influence on the type and extent of RH. For example, consider the common situation of a child who has had trauma (factual or assumed) followed by seizures, apnea or respiratory arrest, and resuscitation with resultant HIE or coagulopathy. In much of the traditional NAI / SBS literature, little if any consideration has been given to any predisposing or complicating factors, and often there is no indication of the timing of the eye exams relative to the clinical course or the brain imaging [135,136,141,152].
From the research and clinical evidence base, one may conclude that (1) RH is not specific for NAI, (2) RH may occur in AI and medical conditions, and (3) that predisposing factors and cascade effects must be considered in the pathophysiology of RH.
Medical Conditions Mimicking NAI.
Also part of the controversy are the medical conditions that may mimic the clinical presentations (i.e. the triad) and imaging findings of NAI [7,9,23,31-34,109,121]. Furthermore, such conditions may predispose to, or complicate, AI or NAI, as part of a cascade that results in, or exaggerates, the triad. In some situations it may be difficult, or impossible, to tell which of these elements are “causative” and which are the “effects.” These include HIE, seizures, dysphagic choking ALTE, cardiopulmonary resuscitation, infectious or post infectious conditions (e.g. sepsis, meningoencephalitis, post-vaccinial), vascular diseases, coagulopathies, venous thrombosis, metabolic disorders, neoplastic processes, certain therapies, extracorporeal membrane oxygenation (ECMO), and other conditions [23,31,109,121]. Regarding pathogenesis of the triad (+/- other organ system involement - e.g. skeletal), and whether due to NAI, AI, or medical etiologies, the pathophysiology appears to be some combination, or sequence, of factors including increased intracranial pressure, increased venous pressure, systemic hypotension or hypertension, vascular fragility, hematologic derangement, and/or a collagenopathy imposed upon the immature CNS, including the vulnerable dural vascular plexus, as well as other organ systems [23,31,54,55,62].
Although the initial medical evaluation including history, laboratory tests, and imaging studies may suggest an alternative condition, the diagnosis may not be made because of a “rush to judgement” regarding NAI [10-18,23]. Such bias may have devastating effects upon the injured child and family. It is important to be aware of these mimics, since a more extensive workup may be needed beyond the routine “screening” tests. Also, the lack of confirmation of a specific condition does not automatically indicate the “default” diagnosis of NAI. In all cases, it is critical to review all past records dating back to the pregnancy and birth, as well as the postnatal pediatric records, the family history, the more recent history preceding the acute presentation, the details of the acute event itself, the resuscitation, and the subsequent management, all of which may contribute to the clinical and imaging findings. An incomplete medical evaluation may result in unnecessary cost-shifting to the child protection and criminal justice systems and have further adverse effects regarding transplantation organ donation in brain death cases and custody / adoptive dispositions for the surviving child and siblings.
Sirotnak’s recent review, along with others, extensively catalogues the many conditions that may mimic NAI [23,31,109,121]. These include perinatal conditions (birth trauma and congenital conditions), accidental trauma (including dysphagic choking ALTE), genetic and metabolic disorders, hematologic diseases and coagulopathies, infectious diseases, autoimmune and vasculitic conditions, oncologic disease (e.g. neuroblastoma, leukemia), toxins, poisons, and nutritional deficiencies, and medical and surgical complications. A partial summary is provided below.
Birth Trauma and Neonatal Conditions. Manifestations of birth trauma, including fracture, SDH, and RH may persist beyond the neonatal period. Other examples are the sequelae of extracorporeal membrane oxygenation (ECMO) therapy, at-risk prematurity, and congenital heart disease. When evaluating a young infant with apparent NAI, it is important to consider that the clinical and imaging findings may actually stem from parturitional and neonatal issues [93-108]. This includes hemorrhage, or re-hemorrhage, into collections existing from birth. Developmental anomalies and Congenital Conditions. Vascular malformations are rarely reported causes for the triad, but may be underdiagnosed. BECC and arachnoid cysts are also known to be associated with SDH and RH, spontaneously and with trauma [85-94]. Genetic and Metabolic Disorders. A number of conditions in this category may present with intracranial hemorrhage (e.g. SDH) or RH. These include osteogenesis imperfecta, glutaric aciduria type I, Menkes kinky hair disease, Ehlers-Danlos and Marfan syndromes, homocystinuria, and others [23,109,121,154-158 ].Hematologic Disease and Coagulopathy. Conditions in this category predispose to intracranial hemorrhage and RH. The bleeding or clotting disorder may be primary or secondary. A more extensive workup beyond the usual “screening” tests is needed, including a hematology consultation. This includes the anemias, hemorrhagic disease of the newborn (vitamin K deficiency), the hemophilias, thrombophilias, disseminated intravascular coagulation and consumption coagulopathy, liver or kidney disease, hemophagocytic lymphohistiocytosis, and anticoagulant therapy [23, 109, 121, 159-161].
Venous thrombosis includes dural venous sinus thrombosis (DVST) and cerebral venous thrombosis (CVT). DVST or CVT may be associated with primary or secondary hematologic or coagulopathic states [23,109,121,161-167]. Risk factors include acute systemic illness, dehydration, fluid-electrolyte imbalance, sepsis, perinatal complications, chronic systemic disease, cardiac disease, connective tissue disorder, hematologic disorder, oncologic disease and therapy, head and neck infection, and hypercoagulable states. Infarction, SAH, SDH, or RH may be seen, especially in infants. High densities on CT may be present along the dural venous sinuses, tentorium, falx, or the cortical, subependymal, or medullary veins and be associated with SAH, SDH, or intracerebral hemorrhage. There may be focal infarctions, hemorrhagic or nonhemorrhagic, intraventricular hemorrhage, and massive, focal or diffuse edema. Orbit, paranasal sinus, or otomastoid disease may be present. The thromboses and associated hemorrhages have variable MRI appearance depending upon their age. CTV or MRV may readily detect DVST but not CVT. The latter may be better detected as abnormal hypointensities on susceptibility-weighted sequences, but difficult to distinguish from hemorrhage (SDH, SAH) or small hemorrhagic infarctions.
Infectious and Post-infectious Conditions. Meningitis, encephalitis, or sepsis may involve the vasculature resulting in vasculitis, arterial or venous thrombosis, mycotic aneurysm, infarction, and hemorrhage [23, 109, 121]. SDH and RH may also be seen. Post-infectious illnesses may also be associated with these findings. Included in this category are the “encephalopathies of infancy and childhood”, “hemorrhagic shock and encephalopathy syndrome,” and post-vaccinial encephalopathy [23,109,121,168-173]. Toxins, Poisons, and Nutritional Deficiencies. This category includes lead poisoning, cocaine, anticoagulants, over-the-counter cold medications, prescription drugs, and vitamin deficiencies or depletions (e.g. K, C, D) [23,109,121,159, 170-175].Preterm neonates, and other chronically ill infants, are particularly vulnerable to nutritional deficiencies and complications of prolonged immobilization that often primarily effect bone development. Furthermore, the national and international epidemic of vitamin D deficiency and insufficiency in pregnant and breast-feeding mothers, their fetuses, and their neonates predisposes them to rickets. Such infants may have skeletal imaging findings (e.g. multiple healing fractures or pseudofractures) that are misinterpreted as NAI, especially in the presence of the triad .
Dysphagic Choking ALTE as a Mimic of NAI. Apnea is an important and common form of ALTE in infancy whose origin may be central, obstructive, or combined . The obstructive and mixed forms may present with choking, gasping, coughing, or gagging due to mechanical obstruction. When paroxysmal or sustained, the result may be severe brain injury or death due to a combination of central venous hypertension and hypoxia-ischemia. It is this synergism that produces cerebral edema and dural vascular plexus hemorrhage with SDH, SAH, and RH. Examples include dysphagic choking (e.g. aspiration of a feed, gastroesophageal reflux), viral airway infection (e.g. RSV), and pertussis, and particularly when occurring in a predisposed child (e.g. prematurity, Pierre-Robin syndrome, SIDS) [31,176-182].
Imaging Challenges and the Importance of a Differential Diagnosis.
Computed Tomography (CT). Because of the evidence-based challenges to NAI, imaging protocols should be designed to evaluate not only NAI vs. AI, but also the medical mimics. Non-contrast CT has been the primary modality for brain imaging because of its access, speed, and ability to show lesions (e.g. hemorrhage and edema) requiring immediate neurosurgical or medical intervention [23,123,124,128,184-202]. Cervical spinal CT may also be needed. CT angiography or venography (CTA, CTV) may be helpful to evaluate the cause of hemorrhage (e.g. vascular malformation, aneurysm) or infarction (e.g. dissection, venous thrombosis). A radiographic or scintigraphic skeletal survery should also be obtained according to established guidelines (201,202).
Magnetic Resonance Imaging (MRI). Brain and cervical spinal MRI should be done as soon as possible because of its sensitivity and specificity regarding pattern of injury and timing parameters [23,124,128,203-216]. Brain MRI should include T1, T2, T2*, FLAIR, and diffusion imaging (DWI / ADC). Gadolinium-enhanced T1 images should probably be used along with MRA and MRV. T1 and T2 are necessary for estimating the timing of hemorrhage, thrombosis, and other collections using published criteria [23,215,216]. T2* techniques are most sensitive for detecting hemorrhage or thromboses, but may not distinguish new (e.g. deoxyhemoglobin) from old (e.g. hemosiderin). DWI plus ADC can be quickly obtained to show hypoxia-ischemia or vascular occlusive ischemia [23,169,216,217]. However, restricted, or reduced, diffusion may be seen with other processes including encephalitis, seizures, or metabolic disorders, and with suppurative collections and some tumors [23,169,216,217]. Gadolinium-enhanced sequences and MRS can be used to evaluate for these other processes. Additionally, MRA and MRV are important to evaluate for arterial occlusive disease (e.g. dissection) or venous thrombosis, although they cannot rule out small vessel disease. The STIR technique is particularly important for cervical spine imaging.
Scalp and Skull Abnormalities.Scalp injuries (e.g. edema, hemorrhage, laceration) are difficult to precisely time on imaging studies and depend upon the nature and number of traumatic events or other factors (e.g. circulatory compromise, coagulopathy, medical interventions, etc) [7,23]. Skull abnormalities may include fracture and suture splitting. Fracture may not be distinguished from sutures, synchondroses, their normal variants, or from wormian bones (e.g. osteogenesis imperfecta) on CT or skull films. 3DCT surface reconstructions may be needed. In general, the morphology of a fracture cannot differentiate NAI from AI, and must be correlated with the trauma scenario (e.g. biomechanically). Skull fractures are also difficult to time because of the lack of periosteal reaction [7,23]. Suture diastasis may be traumatic or a reflection of increased intracranial pressure, but must be distinguished from pseudodiastasis due to a metabolic or dysplastic bone disorder (e.g. rickets) [7,23,175,219-221]. The “growing fracture” (e.g. leptomeningeal cyst” is not specific for NAI and may follow any diastatic fracture in a young infant, including birth-related [7,9,23]. Nondetection of scalp or skull abnormalities on imaging should not be interpreted as the absence of impact injury.
Intracranial Collections.It should not be assumed that such collections are always traumatic in origin. A differential diagnosis is always necessary and includes NAI, AI, coagulopathy (hemophilic and thrombophilic conditions), infectious and post-infectious conditions, metabolic disorders, and so forth [9,23,29,37,109,110,121,126-130]. It may not be possible to specify with any precision the components, or age, of an extracerebral collection because of meningeal disruptions (e.g. acute or subacute subdural hygroma [SDHG] vs. chronic SDH, or subarachnoid vs. thin subdural hemorrhage) [7,23,123,124,186,193,197,200]. Subarachnoid and subdural collections, hemorrhagic or nonhemorrhagic, may be localized or extensive, and may occur about the convexities, interhemispheric (along the falx), and along the tentorium. With time and gravity, these collections may redistribute to other areas, including into, or out of, the spinal canal and cause confusion [23, 199,222]. For example, a convexity SDH may migrate to the peritentorial and posterior interhemispheric regions, or into the intraspinal spaces. SDH migration may lead to a misinterpretation that there are hemorrhages of different timing. The distribution, or migration, of the sediment portion of a hemorrhage with blood levels (i.e. hematocrit effect) may cause further confusion since density / intensity differences between the sediment and supernatant may be misinterpreted as hemorrhages (and trauma) of differing age and location [23,124,200]. Prominent subarachnoid cerebrospinal fluid (CSF) spaces are commonly present in infants (i.e. benign extracerebral collections – BECC). This entity predisposes infants to SDH which may be spontaneous or associated with trauma of any type (e.g. dysphagic choking ALTE) [23,85-93]. A hemorrhagic collection may continually change, or evolve, with regard to size, extent, location, and density / intensity characteristics. Rapid spontaneous resolution and redistribution of acute SDH over a few hours to 1 - 2 days has been reported [23,199,220]. A tear in the arachnoid may allow SDH washout into the subarachnoid space or CSF dilution of the subdural space.
For apparent CT high densities, it may be difficult to differentiate cerebral hemorrhage from subarachnoid hemorrhage or from venous thrombosis . According to the literature, hemorrhage or thromboses that are high density (i.e. clotted) on CT (i.e. acute to subacute) have a wide timing range of 0-3 hours up to 7-10 days [23,124,200]. Hemorrhage that is iso-hypodense on CT (i.e. nonclotted) may be hyperacute (< 3 hrs.) or chronic (> 10 days). The low density may also represent pre-existing wide CSF-containing subarachnoid spaces (e.g. BECC) or SDHG (i.e. CSF-containing) that may be acute or chronic [23, 123,124,197]. Blood levels are unusual in the acute stage unless there is coagulopathy [23,124,215,216]. CT cannot distinguish acute hemorrhage from re-hemorrhage upon existing chronic collections (BECC or chronic SDHG) [23,86,92,99,112-124,193,200]. Traditionally, the interhemispheric SDH as well as mixed density SDH were considered characteristic, if not pathognomonic, of SBS/NAI [7-9,184,190,193]. This has been proven unreliable. In fact, interhemispheric SDH may be seen with AI or with nontraumatic conditions (e.g. HIE, venous thrombosis, venous hypertension, dysphagic choking ALTE). Mixed density SDH also occurs in AI as well as in other conditions. Furthermore, SDH may occur in BECC either spontaneously or result from minor trauma (i.e. AI), and rehemorrhage within SDH may occur spontaneously or with minor AI [19,23,54,62,82,110,124,200].
Only MRI may provide more precise information regarding pattern of injury and timing, particularly with regard to (a) hemorrhage vs. thromboses (see Table) and (b) brain injury [23,124,128,203-217]. As a result, MRI has become the standard and should be done as soon as possible. Mixed intensity collections, however, are problematic regarding timing. Matching the MRI findings with the CT findings may help along with followup MRI. Blood levels may indicate subacute hemorrhage vs. coagulopathy. The timing guidelines are better applied to the sediment than to the supernatant. With mixed intensity collections, MRI cannot reliably differentiate BECC with acute SDH from acute SDHG / SDH, from hyperacute SDH, or from chronic SDH or chronic SDHG with re-hemorrhage [23,124]. T2* hypointensities are iron-sensitive but may not differentiate hemorrhages from venous thromboses that are not detected by MRV (e.g. cortical, medullary, subependymal).
Brain Injury. Edema or swelling in pediatric head trauma may represent primary injury or secondary injury and be acute-hyperacute (e.g. minutes to a few hours) or delayed (e.g. several hours to a few days) including association with short falls and lucid interval [23,52-55,74-82]. The edema or swelling may be further subtyped as traumatic, malignant, hypoxic-ischemic, or related to (or combined with) other factors. Traumatic edema is related to areas of primary brain trauma (i.e. contusion or shear) or to traumatic vascular injury with infarction (e.g. dissection, herniation). Traumatic edema is usually focal or multifocal, whether hemorrhagic or not. However, CT may not distinguish focal or multifocal cerebral high densities as hemorrhagic contusion, hemorrhagic shear, or hemorrhagic infarction (23). Focal or multifocal low density edema may also be seen with infarction (e.g. arterial or venous occlusive), encephalitis, demyelination (e.g. ADEM), or seizure edema [23,109,161-169]. Also, MRI often shows shear and contusional injury as focal / multifocal restricted diffusion, GRE hypointensities, and/or T2 / FLAIR high intensities (23). Focal / multifocal ischemic findings may also be due to traumatic arterial injury (e.g. dissection) or venous injury (e.g. tear, thrombosis), arterial spasm (as with any cause of hemorrhage), herniation, or edema with secondary perfusion deficit or seizures (e.g. status epilepticus) [23,84,169,217,218]. However, these may not be reliably differentiated from focal / mutlifocal ischemic or hemorrhagic infarction from nontraumtic causation (e.g. dissection, vasculitis, venous, embolic) even without supportive MRA, CTA, MRV, or angiography. Also, similar cortical or subcortical intensity abnormalities (including restricted diffusion) may also be observed with encephalitis, seizures, and metabolic disorders. Therefore, a differential diagnosis is always required [23,169,217,218].
Malignant brain edema, a term used for severe cerebral swelling following head trauma, may lead to rapid deterioration [7,23,75,82]. The edema is usually bilateral and may be related to cerebrovascular congestion (i.e. hyperemia) as a vasoreactive rather than an autoregulatory phenomenon and associated with global ischemia. A unilateral form may also occur in association with an ipsilateral SDH that progresses to bilateral edema . There may be rapid or delayed onset (i.e. lucid interval). Predisposing factors are not well-established, but likely include a genetic basis. Hyperemic edema may appear early as accentuated gray-white matter differentiation on CT, then progresses to loss of differentiation.
Global hypoxia (e.g. apnea, respiratory failure) or ischemia (e.g. cardiovascular failure or hypoperfusion) is likely a major cause of, or contributor to, brain edema in the child with head trauma (e.g. malignant edema) [23,52-55,62,75,82]. HIE, depending on its severity and duration, may have a diffuse appearance acutely (i.e. diffuse or “vascular” axonal injury) with decreased gray-white differentiation throughout the cerebrum on CT (e.g. white cerebellum sign), and then evolve to a more specific pattern on CT or MRI (e.g. borderzone or watershed, basal ganglia / thalamic, cerebral white matter necrosis, reversal sign) (23,217) . It is typically bilateral but may not be symmetric. This more diffuse pattern may distinguish HIE from the multifocal pattern of primary traumatic injury, although they may coexist. Hypoxia-ischemic brain injury due to apnea / respiratory arrest may occur with head trauma or with neck / cervical spine / cord injuries (e.g. SCIWORA) whether AI or NAI [23,51-53]. It may also occur with any nontraumatic cause (e.g. choking, paroxysmal coughing, aspiration, etc.) [23, 31,176-182]. In addition to the diffuse brain injury, there may be associated subarachnoid and subdural hemorrhage without mass effect [23,51-53,62]. MRI shows hypoxic-ischemic injury, depending upon timing, as diffuse restricted diffusion on DWI / ADC plus matching T1/T2 abnormalities as the injury evolves [23,217]. Other important contributors to edema or swelling include such complicating factors as seizures (e.g. status epilepticus), fluid-electrolyte imbalance, other systemic or metabolic derangements (e.g. hypoglycemia, hyperglycemia, hyperthermia), or hydrocephalus . It is well known that many of these may also be associated with restricted diffusion along with other nontraumatic processes (encephalitis, seizures, and metabolic disorders) [23,169,214,215,217]. Once again, a differential diagnosis is required.