Lesions in the Splenium of the Corpus Callosum on MRI in Children: A Review Marinos Kontzialis, Bruno P. Soares, Thierry A.G.M. Huisman From the Section of Neuroradiology, Department of Radiology, Rush University Medical Center, Chicago, IL (MK); and Pediatric Radiology, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD (BPS, TAGMH).

ABSTRACT A wide variety of conditions may involve the splenium of the corpus callosum on magnetic resonance imaging in children. A single cause may present with different patterns of splenial involvement, and multiple diseases may have similar imaging findings. Keeping this limitation in mind, the goal of this text is to assist in the diagnostic process of pediatric neurological diseases that are characterized by prominent involvement of the splenium of the corpus callosum on imaging. The various pathologies will be reviewed and categorized based on etiology, reversibility, and pattern of additional or associated findings. Transient splenial lesions in children are an uncommon radiologic finding of unknown etiology in a long list of conditions that may present with altered consciousness, and it usually carries a favorable prognosis. The discussion continues with the presentation of diseases inflicting irreversible damage on the splenium. Familiarity with the various causes implicated in splenial injury may assist in the formulation of differential diagnosis in the appropriate clinical setting using an easily recognizable imaging finding. Keywords: Splenium, corpus callosum, children, MRI. Acceptance: Received May 9, 2017, and in revised form May 31, 2017. Accepted for publication June 2, 2017. Correspondence: Address correspondence to Thierry A.G.M. Huisman, MD, Pediatric Radiology and Pediatric Neuroradiology, Charlotte Bloomberg Children’s Center, Johns Hopkins Hospital, 1800 Orleans Street, Suite 4174, Baltimore, MD 21287, USA. E-mail: [email protected] Acknowledgement and Disclosures: We dedicate this manuscript to the memory of Andrea Poretti, MD. The authors declare no conflicts of interest. J Neuroimaging 2017;00:1-13. DOI: 10.1111/jon.12455

Introduction The corpus callosum (CC) is the largest telencephalic commissure composed of white matter tracts responsible for interhemispheric communication and coordination. It is divided into four parts: the rostrum, the genu, the body, and the splenium.1 The region between the body and the splenium is known as the isthmus. The majority of the fibers of the splenium extend posteriorly into the occipital lobes as the forceps major.2 In this review, we present and discuss the various pathologies that may present with lesions involving the splenium of the CC on magnetic resonance imaging (MRI). This discussion should narrow down the differential diagnosis for a variety of pediatric neurological diseases that may present with prominent involvement of the splenium of the CC. Based upon this often-obvious MRI finding, we categorize a wide variety of splenial lesions in correlation with the etiology, reversibility, and pattern of additional or associated findings. We acknowledge that a single disease may present with different patterns of injury, and that multiple diseases may present with similar imaging findings. With this limitation in mind, this manuscript should serve as a practical guide for pediatric neuroradiologists and neurologists to formulate a differential diagnosis based upon an easily identifiable imaging finding. Splenial lesions are divided by etiology into usually reversible and irreversible lesions (Tables 1 and 2).

Reversible Splenial Lesions Transient splenial lesions of the CC in children are uncommon radiologic findings in a variety of clinical conditions,3 and are often linked to a favorable prognosis.4 Awareness of the

reversibility and the clinical entities associated with these lesions is crucial for diagnostic purposes and to prevent further invasive investigation and intervention.3 The most common acronyms used in the literature are reversible splenial lesion syndrome (RESLES),4 and clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS).5 The clinical component of MERS is defined as an acute onset disturbance in consciousness lasting more than 12 hours.6 However, reversible splenial lesions have also been described in patients with clear consciousness or altered mental status lasting less than 12 hours.6 The typical transient lesion is ovalshaped, centered in the median aspect of the splenium, and it has been termed MERS type I when isolated to this site.3,7 Less commonly, the signal abnormality is more extensive involving the entire splenium, and possibly extending into the forceps major with additional reversible hemispheric white matter lesions, which is then referred to as MERS type II.3,7–10 The most characteristic imaging finding is reversible restricted diffusion.3 There is no clinical difference between MERS types I and II, and, in fact, it has been suggested that they may represent a continuum with a more extensive MERS type II lesion resolving through a more focal type I lesion.9 MERS type I lesions might have additional hemispheric white matter involvement, which could be beyond the resolution of conventional MRI when mild.9 Lesions in MERS typically disappear within a week with no residual signal or atrophy;10,11 however, there are cases in the literature of recurrent reversible splenial lesions, slow recovery, and irreversible damage.8,10,12 MERS is likely a postinfectious syndrome with most cases falling in the milder end of the spectrum.

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Table 1. Causes of Reversible Splenial Involvement Infection

Seizurerelated Systemic and congenital illnesses Malnutrition Toxic Mountain sickness

– Viral: Influenza (most common), Rotavirus, Mumps, Measles, Human herpesvirus 6, Varicella zoster virus, Epstein-Barr virus, Cytomegalovirus, Adenovirus, Respiratory syncytial virus, Hepatitis A virus, Parvovirus B19, Enterovirus – Bacterial: Streptococcus, E. coli, Mycoplasma pneumonia, Klebsiella pneumonia, Enterococcus faecalis, Rickettsial encephalitis – Parasitic: Malaria, Neurocysticercosis Benign partial epilepsy of infancy, Neonatal seizures, Acute seizure activity, Antiepileptic drug withdrawal Kawasaki disease, SLE, X-linked Charcot-Marie-Tooth disease Anorexia nervosa, Gastric bypass surgery – CO poisoning – Medications: Metronidazole, Corticosteroids, 5-FU, IVIG, Tetracycline

SLE = systemic lupus erythematosus; CO = carbon monoxide; 5-FU = 5fluorouracil; IVIG = intravenous immunoglobulin.

The clinical significance of transient splenial lesions is unclear, and it might represent nonspecific brain injury. The imaging appearance is not specific for a cause, and additional clinical and imaging findings can point toward the right direction (Fig 1).13 A causative infectious agent or underlying condition is sometimes identified, but this will not necessarily

Table 2. Causes of Irreversible Splenial Involvement Neurometabolic

Neurocutaneous Acquired demyelination Traumatic/ischemic Metabolic/toxic Infection Neoplastic

X-linked adrenoleukodystrophy, Metachromatic leukodystrophy, Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, Krabbe disease, Leigh syndrome, Mucopolysaccharidoses NF-1 MS, Lyme disease, PML, Osmotic demyelination, Marchiafava-Bignami disease DAI, Hypoxic ischemic encephalopathy, Splenium infarction Neonatal hypoglycemia, PRES Malaria Glioblastoma, Gliomatosis cerebri

NF-1 = neurofibromatosis type 1; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; DAI = diffuse axonal injury; PRES = posterior reversible encephalopathy syndrome.

add to management because splenial involvement is usually self-limiting.14 There are multiple potential causes for a reversible splenial lesion and the list would expand further if adult cases were to be included. Infection related to MERS is the most common cause in childhood.15,16

Infection In a series of 54 Japanese patients with splenial lesions, the pathogen was unknown in 41%.5 Nine patients had additional CC and symmetric white matter involvement.5 In the largest series to date that included 153 cases with MERS, the most common associated pathogens were influenza virus (34.4%)

Fig 1. Pattern recognition approach for a reversible splenial lesion in children. AED = antiepileptic drug; GI = gastrointestinal; E. coli = Escherichia coli; HHV-6 = human herpesvirus 6; SLE = systemic lupus erythematosus; CMT = Charcot-Marie-Tooth disease; HACE = high-altitude cerebral edema; CO = carbon monoxide; 5-FU = 5-fluorouracil; IVIG = intravenous immunoglobulin; ADEM = acute disseminated encephalomyelitis.

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and rotavirus (11.7%).11 A transient splenial lesion along with the clinical and laboratory findings is usually sufficient to point toward an infectious agent, and to exclude other differential considerations.17

Viral Infections Influenza A and B virus are considered the most common cause of MERS, and patients tend to present more often with delirious behavior.5,18 The splenial lesion is usually focal and isolated, and additional genu and hemispheric white matter involvement have been reported.6,14,16,19,20 Similarly, isolated focal and diffuse splenial lesions with additional callosal and symmetric white matter involvement have been described in influenza A (H1N1) infection.21,22 A Caucasian girl with positive nasopharyngeal swab for influenza A and encephalopathy presented with a focal lesion in the splenium, and additional involvement of the right dentate nucleus.23 Rotavirus is a major pathogen of gastroenteritis in infants and young children,24–26 and is occasionally accompanied by encephalitis/encephalopathy.26,27 The pattern of involvement in rotavirus can range from focal to diffuse splenial lesions with or without cerebellitis.24–33 In a series of 11 children with rotavirus gastroenteritis and cerebellitis, the gastroenteric symptoms were followed by disturbance of consciousness, mutism, and neurologic sequelae. There was a reversible splenial lesion in the acute stage in six children. The abnormal signal in the posterior fossa progressed from the cerebellar white matter and nuclei in the acute to subacute stage to cerebellar cortex involvement and to cerebellar atrophy in the chronic phase, indicating that cerebellar lesions in rotavirus infection might not be reversible.26,33 Focal and diffuse splenial lesions have also been described in children with mumps,19,20,34 and MERS has been reported in an 8-year-old following mumps vaccination (diffuse splenium and periventricular white matter involvement).35 Furthermore, a focal splenial lesion has been described in measles,36 and another child with measles developed a diffuse reversible splenial lesion and bilateral substantia nigra involvement, which persisted on follow-up imaging; the presumptive diagnosis was postinfectious parkinsonism.37 Human herpesvirus 6 (HHV-6) is more frequently associated with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD),11 and mild AESD can coexist with MERS.38 HHV-6 has been implicated

in a 2.5-year-old girl presenting with focal splenial lesion and acute cerebellitis.39 Reversible splenial involvement has been described in varicella zoster virus.20 Diffuse reversible splenial lesions with additional symmetric white matter involvement have been described in Epstein-Barr virus,8,40 and in cytomegalovirus infection.15 Reversible diffuse splenial lesions without and with extensive white matter involvement have been described in adenovirus infection.5,20,41 Additional viral agents associated with reversible splenial involvement include respiratory syncytial virus (the patient had additional genu and subcortical white matter involvement),6 hepatitis A virus (focal isolated lesion in the splenium),42 parvovirus B19 in siblings with hereditary spherocytosis (focal isolated splenial lesions),43 and enterovirus (Fig 2).

Bacterial Infections Bacterial infections, such as streptococcus (Fig 3) and Escherichia coli,5 are less commonly associated with MERS (3.3%).11 Salmonella enteritis has been linked to focal and diffuse splenial lesions without and with additional white matter involvement.15,44,45 Mycoplasma pneumonia can cause focal splenium involvement.6,44 Another patient with mycoplasma infection and positive nasopharyngeal swab for influenza type B presented with MERS type 2 with diffuse splenium, genu, and bilateral centrum semiovale involvement.46 Recovery was slow, cerebrospinal fluid (CSF) abnormal (pleocytosis and increased protein), and the hemispheric signal changes persisted following resolution of the splenium lesion, which means type 2 lesions do not always resolve through a type 1 lesion.46 The authors suggested that the slow recovery and the abnormal CSF imply an overlap between MERS and acute disseminated encephalomyelitis (ADEM). A reversible focal splenial lesion has been described in a teenager with febrile urinary tract infection caused by Klebsiella pneumonia.47 MERS has been described in 2 pediatric patients with acute focal bacterial nephritis caused by Enterococcus faecalis.48 The patients had marked elevation of interleukin (IL)-6 in CSF and serum, and exhibited hyponatremia and delirium. One patient had diffuse splenial and white matter involvement, and the other patient had a focal splenial lesion. The authors suggested that the inflammatory response associated with the nephritis likely accounted for the splenial lesion. Rickettsial encephalitis in a 17-year-old has presented with diffuse splenial

Fig 2. Callosal involvement in neonatal enterovirus infection. Diffuse restricted diffusion in the splenium and genu of the corpus callosum ((A) diffusion-weighted imaging, (B) apparent diffusion coefficient, and (C) axial T2-weighted). Small foci of cystic white matter injury are present in the deep anterior frontal white matter bilaterally.

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Fig 3. Ten-year-old boy with pneumococcus meningitis complicating sinusitis. Axial diffusion tensor imaging (DTI) (A), axial apparent diffusion coefficient map (B), and sagittal DTI (C) demonstrate focal lesion in the splenium. Note the pus with restricted diffusion in the right frontal sinus (arrow in C).

and genu involvement.13 A reversible splenial lesion has been reported in a 7-year-old with hemolytic uremic syndrome caused by O-157 E. coli enteritis and mild encephalopathy.49

Parasitic Infections Reversible diffuse splenium involvement with hyperintense signal on T2 and on diffusion-weighted imaging (DWI) has been described in cerebral malaria.50 However, cerebral malaria usually causes more extensive involvement including callosal lesions leading to eventual splenial volume loss.51 A reversible splenial lesion has been reported in a 15-year-old patient with Neurocysticercosis presenting with obstructive hydrocephalus.52

Seizure-Related Focal and diffuse reversible lesions of the splenium of the CC have been described in benign partial epilepsy in infancy and in neonatal seizures with additional genu and white matter signal changes.53,54 Transient focal-isolated splenial lesion in epileptic patients has been associated with acute seizure activity and antiepileptic drugs (AEDs), most often with rapid changes in medication serum levels, such as abrupt withdrawal for presurgical evaluation (Fig 4).4,55–60 This is supported by multiple cases of reversible splenial lesions in patients using or discontinuing AED for various conditions not related to seizures.58,61–63 In large series of presurgical seizure workup and AED withdrawal, the incidence of splenial lesions was between .7% and 5%.58,59

Lesions associated with AED withdrawal have been described 1–7 days following medication cessation and seizure-related splenial lesions without medication cessation are usually described 3 weeks following the last seizure, most likely reflecting the timing of imaging rather than a specific pattern.4 The lesions are likely secondary to abrupt fluctuations in AED serum levels,59,61 rather than drug toxicity or sensitivity.64 The most frequently implicated medications are carbamazepine, phenytoin, lamotrigine, and vigabatrin.4,61,65 The focal splenial lesions associated with AEDs have a stereotypical focal ovoid appearance on imaging, develop during intake or shortly after withdrawal, present with normal or unchanged neurological examination, and typically resolve completely over the course of several weeks.4,55,58 The effect could be mediated through the influence of such medications on the arginine-vasopressin system and fluid balance,56,58,59 and excitotoxic injury might be implicated.58 It has been speculated that abrupt cessation of phenytoin could lead to syndrome of inappropriate antidiuretic hormone secretion (SIADH) contributing to brain edema.57

Systemic and Congenital Illness MERS types 1 and 2 have been described in Kawasaki disease, a systemic vasculitis of unknown etiology.6,15,66–68 In a case report by Sato et al, while MRI showed only focal splenial-restricted diffusion (MERS type 1), SPECT showed more diffuse hypoperfusion in the cingulate gyri, thalami, basal ganglia, brainstem, and frontal cortices, which overlapped with MERS type 2.66 Diffusion abnormalities in the hemispheres where there is low

Fig 4. Child presenting with seizures. Axial diffusion tensor imaging (A) and apparent diffusion coefficient map (B) demonstrate diffuse restricted diffusion in the splenium.

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density of fibers may result in subthreshold effects, whereas fibers in the CC are tightly packed and subtle diffusion abnormalities might become apparent.19 MERS type 1 or RESLES has been described in pediatric systemic lupus erythematosus associated with encephalopathy and septic shock, and with nephritis and photosensitivity.69,70 Symptomatic and asymptomatic transient focal lesion of the splenium of the CC has been described in X-linked Charcot-Marie-Tooth disease without and with associated symmetric transient posterior cerebral white matter abnormalities.71,72

Malnutrition Transient focal lesion in the CC has been described in a pediatric patient with anorexia nervosa.73 The patient had no neurologic symptomatology and was treated with vitamin B supplements leading to resolution of the splenial signal.73 The authors hypothesized that severe malnutrition precipitated the splenial signal changes.73 Similar splenial lesion in a young patient following gastric bypass surgery was attributed to nutritional deficiency as well.16

Toxic Focal isolated lesion of the splenium has been demonstrated in carbon monoxide (CO) poisoning.3 Metronidazole-induced encephalopathy may also show associated signal abnormalities in the cerebellar dentate nuclei and brainstem in addition to the splenial involvement.74 Focal reversible splenial lesion has been reported in a 15-year-old patient presenting with neuropsychiatric symptoms after abrupt dose reduction of corticosteroid therapy for nephrotic syndrome.75 Reversible splenial lesion has been associated with 5-fluorouracil, intravenous immunoglobulin, and tetracycline.28,76 A focal reversible splenial lesion has been reported in a child with acute lymphocytic leukemia.77 The patient had received antineoplastic medications, which could have been responsible for the signal, but the authors did not disclose which medications had been administered.77

Mountain Sickness High-altitude cerebral edema (HACE) is characterized by white matter vasogenic edema with a predilection for the splenium,78 which could be secondary to hemodynamic factors such as sustained vasodilatation, impaired autoregulation, elevated capillary pressure, and hypoxia-induced alteration of the blood-brain barrier.4,57,78,79 In HACE and pregabalin withdrawal-induced encephalopathy, the edema is vasogenic, in contrast to the various other associated conditions presenting with restricted diffusion.4,59 In any patient with encephalitis/encephalopathy and white matter lesions, ADEM should be considered in the differential.20 ADEM is a postinfectious or postvaccinal inflammatory disorder, which is pathologically characterized by acute perivenular lymphocytic infiltration with confluent demyelination.20,80 Impaired consciousness is helpful to discriminate it from other demyelinating diseases such as multiple sclerosis (MS).81 ADEM usually presents with multifocal and typically monophasic involvement, in contrast to MS that presents with multiple episodes disseminated in space and time.28 ADEM lesions tend to resolve completely or partially.28 ADEM lesions are ill-defined, T2 hyperintense, and involve gray and white matter.15,28 In contrast to MERS, ADEM

presents with asymmetric callosal involvement with or without contrast enhancement, which depends on the stage and severity of inflammation.28 ADEM lesions might resolve partially or completely.81 In contrast to ADEM, MS lesions are usually more well defined, complete resolution of lesions in MS is rare, and development of new lesions is common.81 The etiology of reversible splenial lesions remains unknown, and the lack of pathologic correlation does not allow formal confirmation of the hypotheses.23 The similar imaging presentation is suggestive of a final common pathway induced by various insults.3 The rapid resolution of lesions is not consistent with demyelination, and additional lesions in the same vascular territory would be expected if the cause were ischemia.81 Proposed explanations for the transient restricted diffusion include intramyelinic edema due to separation of myelin layers,20 interstitial edema in the extracellular space between tightly packed fibers, a transient inflammatory infiltrate,5 or a myelinspecific toxin released in the instance of infection.15 Reversible splenial lesion has been reported in a newborn with mild asphyxia, and therefore the splenial lesions might not be related to myelin since myelination in the CC is not present until 2 months of age.19 Hyponatremia is common and is possibly a contributing factor in MERS, which could be secondary to SIADH.15,35,57 Reversible splenial lesions have also been described in adult patients with hypernatremia.4 It has been suggested that IL-6 in inflammation results in nonosmotic release of vasopressin, which leads to hyponatremia.48 Hypotonic hyponatremia results in entry of water into the brain cells, resulting in cerebral edema.27 High titers of IL-6 have been described in the CSF in rotavirus MERS and in cases of nephritis caused by E. faecalis, which are suggestive of central nervous system (CNS) inflammation and increased vascular permeability.27,48 This is supported by raised concentrations of IL-6, TNF-a, and their receptors in influenza-associated encephalopathy.23 This cytokine storm could eventually lead to blood-brain barrier disruption causing cytotoxic edema.23 Genetic factors might be implicated in the pathogenesis since reversible splenial lesions have been repeatedly reported in patients from Southeast Asia,82 although this could be at least partly due to lower threshold for obtaining an MRI.6 Encephalopathy with reversible splenial and more extensive white matter involvement has been described in Japanese siblings, which could be suggestive of underlying familial/genetic predisposition.41,43 On diffusion tensor imaging, only slight change on diffusion anisotropy has been demonstrated.44 On MRS, normal/near normal spectrum with normal N-acetyl-aspartate (NAA) further supports transient intramyelinic edema over neuroaxonal damage or severe demyelination.83 It is unclear why there is increased vulnerability of the splenium of the CC, and there is no definite difference in fiber composition of the splenium when compared with the remainder of the CC.17 It has been suggested that the splenium might have special affinity for infectious antigens or the antibodies induced by the antigens.17 Nevertheless, it is difficult to prove a theory in the absence of histopathologic correlation.17

Irreversible Splenial Lesions Neurometabolic X-linked adrenoleukodystrophy is caused by acyl-CoA synthetase deficiency, which is a peroxisomal enzyme.84 The defect causes impaired capacity to degrade very long-chain fatty Kontzialis et al: Splenial Lesions in Children

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acids leading to demyelination in the CNS.84 The splenium is usually affected first followed by posterior periventricular and peritrigonal white matter involvement (Fig 5).2,84,85 The lesions are symmetric and show variable contrast enhancement.86 Enhancing peritrigonal demyelination is the most important imaging feature,84 and the demyelination progresses usually from posterior to anterior.87 Metachromatic leukodystrophy is caused by a deficiency in the lysosomal enzyme arysulfatase A, and typical imaging findings include symmetric confluent T2 hyperintensities in the periventricular white matter with sparing of the subcortical U fibers and “tigroid” pattern of demyelination (Fig 6).88 The CC, the internal capsules, the corticospinal tracts, and cerebellar white matter are additional sites of frequent involvement.88 Leukoencephalopa-

thy with brainstem and spinal cord involvement and lactate elevation (LBSL) can present with signal abnormalities in the splenium (Fig 7).89 Krabbe disease is caused by abnormal accumulation of galactocerebroside. It is characterized by callosal, periventricular, and posterior fossa white matter involvement (Fig 8).85,90 Symmetric hyperdensities on CT in the thalami and basal ganglia and cranial nerve enlargement are characteristic. Mitochondrial disorders typically involve the deep gray nuclei.86 MRI findings in Leigh syndrome include bilateral symmetric T2 hyperintensities in the basal ganglia, brainstem, and the cerebellar nuclei, and splenial involvement has been reported.91 Dilated perivascular Virchow-Robin spaces in the CC might be an incidental finding.92 Mucopolysaccharidoses lead to the accumulation of glycosaminoglycans

Fig 5. X-linked adrenoleukodystrophy. Axial T2-weighted (A) and T2-weighted fluid attenuated inversion recovery (B) images demonstrate characteristic peritrigonal and splenium demyelination.

Fig 6. Metachromatic leukodystrophy. Axial T2-weighted images demonstrate typical confluent pattern of demyelination in the deep and periventricular supratentorial white matter including the splenium.

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Fig 7. Sixteen-year-old patient with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. Axial T2-weighted images demonstrate abnormal signal in the bilateral centrum semiovale with relative sparing of the subcortical white matter (A), in the periventricular white matter and the splenium (arrow; B), in the cerebellum and the pons including the intraparenchymal tract of the trigeminal nerves (arrow; C), and in the medulla including the inferior cerebellar peduncles (arrow; D).

Fig 8. Nine-month-old with Krabbe disease. Axial T2-weighted (A and B) and sagittal T1-weighted (C) images demonstrate abnormal signal in the left cerebellum (arrow in A) and in the splenium (arrow in B). Note the enlarged optic chiasm (arrow in C).

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Fig 9. Nine-year-old boy with neurofibromatosis type 1. Axial T2-weighted (A) and axial diffusion tensor imaging (B) demonstrate a small “unidentified bright object” in the right side of the splenium.

in many tissues, and can produce dilated VirchowRobin spaces involving the CC including the splenium.84,87

Neurocutaneous CNS manifestations of neurofibromatosis type I (NFI) include optic pathway gliomas, parenchymal gliomas, and scattered T2 hyperintensities, sometimes called “unidentified bright objects” (UBOs).93 UBOs are usually seen in the basal ganglia, the brainstem, and the cerebellum, but can occur in the CC, mainly in the splenium (Fig 9).92,94 Callosal UBOs and neoplasms occurred in 14% of patients in a series of 79 children.95 UBOs are rare before the age of 4 years, tend to increase in number and volume until the age of 10–12 years, and, although not transient, they tend to resolve thereafter.95

Acquired Demyelination The CC is frequently involved in MS. Typical findings in MS include hyperintense band along the undersurface of the CC, involvement of the callososeptal interface, and ovoid perivenular lesions radiating perpendicular from the ventricular surface known as Dawson’s fingers (Fig 10).80,81,84,96 Breakdown of the blood-brain barrier in acute demyelination is accompanied by contrast enhancement.97 Hyperacute demyelinating MS lesions can demonstrate cytotoxic edema on DWI, which mainly corresponds to intramyelinic edema pathologically.56 Lyme disease can present MS-like T2 hyperintensities involving the CC, and a high level of suspicion is needed in endemic areas.92 Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by the JC virus, a neurotropic polyomavirus.98 PML is rare in children and is associated with HIV infection, primary immunodeficiency, cancer, and solid organ transplant.98 Typical imaging findings include T2 hyperintense and T1 hypointense asymmetric subcortical white matter lesions without mass effect.98 CC involvement occurs in 10–15% of cases, enhancement is absent or peripheral and faint, and there is profound atrophy in the involved parenchyma in survivors.80 8

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Fig 10. Multiple sclerosis. Sagittal T2-weighted image demonstrates splenium involvement (arrow).

Osmotic demyelination is associated with rapid correction of hyponatremia, and in 10% of cases, there is extrapontine involvement, including the CC and especially the splenium.80,99 Conditions predisposing children to myelinolysis include diabetes mellitus, renal failure, malnutrition, cancer, and chemotherapy.80,99 Marchiafava-Bignami-like injury to the splenium of the CC has been described in an infant with associated involvement of the genu and the bifrontal white matter/forceps minor.86 Marchiafava-Bignami disease is thought to represent demyelination and necrosis of the CC usually associated with chronic alcoholism, malnutrition, and multiple vitamin deficiencies.80,87,100 It has been described in a wide age range (14-79 years).100 The splenium is most frequently involved, and lesions are often located across the entire CC in the acute and chronic phase.80,100 Isolated splenial involvement occurs in one third of cases, and is associated with better outcome.100 In the

chronic phase, the CC becomes atrophic and cavitary, although complete resolution of signal changes can occur.87,96,100

Traumatic/Ischemic Diffuse axonal injury (DAI) is a significant cause of morbidity in traumatic brain injury and it is caused by sudden acceleration, deceleration, and rotational forces.85 DAI is best demonstrated

on SWI and DWI as hypointense and hyperintense lesions, respectively (Fig 11). Smaller lesions tend to be unilateral and eccentric, and larger lesions can involve the entire CC.80 DAI is usually associated with additional findings of head trauma (epidural, subdural, subarachnoid, intraventricular, and/or intraparenchymal hemorrhage).80 Chronic lesions are associated with hemosiderin staining and encephalomalacia.87 The

Fig 11. Traumatic brain injury in a 15-year-old-boy. Axial T2-weighted fluid attenuated inversion recovery (A, C) and axial diffusion tensor imaging (B, D) demonstrate diffuse axonal injury involving the splenium and the posterior body of the corpus callosum.

Fig 12. Five-day-old neonate with hypoxic ischemic encephalopathy and hypoglycemia. Axial diffusion tensor imaging (A, C) and corresponding apparent diffusion coefficient maps (B, D) demonstrate restricted diffusion in the bilateral occipital lobes (arrowheads in A), the globi pallidi and thalami (arrows in B), and in the splenium diffusely (arrows in C and D).

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Fig 13. Child with gliomatosis cerebri. Axial T2-weighted (A) and T2-weighted fluid attenuated inversion recovery (B) demonstrate infiltrative signal and mild local mass effect and expansion in the left insula (arrow in A), the splenium (arrow in B), and the adjacent left parietal lobe. splenium and the posterior body of the CC are frequently involved due to their dural fixation, as are the gray/white matter interface, the fornix, and the dorsolateral upper brainstem including the cerebellar peduncles.56,80,85,99 Hypoxic ischemic encephalopathy (HIE) in the neonatal period can present as diffuse callosal involvement on DWI along with restricted diffusion in the basal ganglia, white matter, and corticospinal tracts, leading eventually to atrophy (Fig 12).56,85 In a series of 34 infants with HIE, restricted diffusion in the splenium was associated with extensive brain injury and a significantly higher incidence of death or severe developmental delay as it appears to be an early neuroradiologic marker of adverse neurologic outcomes.101 Changes in the splenium of the CC were also associated with lower birth weights, larger base deficits in cord arterial gas, and more severe encephalopathy during enrollment in selective head cooling. Periventricular leukomalacia affects premature infants and is thought to represent watershed infarction in the setting of slow flow or decreased oxygen state. Severe cases may involve the CC with cystic changes and hemorrhage.84,87 In Wallerian degeneration after hemispheric damage, the involved part of the CC becomes atrophic.96 Round, focal splenium infarction has been described in a 21-year-old patient with superior sagittal and right transverse sinus thrombosis.102 CC infarctions are rare because of its rich collateral supply from the posterior and anterior circulation.81,96 The most common location of CC infarction is the splenium, and there are usually additional infarctions in other brain areas supplied by the same artery.80,96 Associated conditions include vasculitis, emboli, major ischemic stroke, subfalcine herniation, and extracorporeal membrane oxygenation (ECMO).80,87 Petechial hemorrhages in the splenium might be seen in ECMO.80

Metabolic/Toxic Neonatal hypoglycemia is the most common metabolic derangement in the newborn infant, and is associated with restricted diffusion in the entire splenium and the parieto-occipital white matter leading to eventual volume loss and gliosis on follow-up.103,104 Associated spectroscopic findings included decreased NAA and increased lipid-lactate peak.103 On imaging 10

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the main differential consideration is hypoxic encephalopathy, and findings may coexist.105 Predilection for and prominent involvement of the parieto-occipital lobes is observed in neonatal hypoglycemia when compared to hypoxic-ischemic encephalopathy.103–106 The prognosis depends on prompt recognition and treatment.105 Less severe hypoglycemia that is treated promptly might result in transient abnormalities that resolve on follow-up.105 The diagnosis of posterior reversible encephalopathy syndrome (PRES) might be overlooked in children,107 despite the fact that all age groups are susceptible.108 Predisposing conditions in children are similar to adults and include hypertension, renal disease, immunosuppressive and cytotoxic agents, and metabolic abnormalities.80,108,109 Typical involvement includes the posterior parietal and occipital white matter, and the splenium is occasionally involved.80,107 Although complete resolution is the norm, encephalomalacia occasionally develops.

Infection Cerebral involvement by malaria in children includes the CC in approximately half of the cases.51 The splenium is most commonly affected and diffuse callosal involvement can occur.51 Additional neuroimaging findings include cerebral edema, focal cortical abnormalities, periventricular white matter changes, and abnormalities in the deep gray matter.51 Thinning and volume loss of the splenium has been associated with behavioral and cognitive abnormalities in malaria survivors.51

Neoplastic Brain neoplasms with propensity of splenial involvement are usually of high grade. Glioblastoma, although relatively rare in children, can extend across the CC to produce the classic butterfly appearance.87 Heterogeneous enhancement, central necrosis, and blood products are highly suggestive of glioblastoma.96 Gliomatosis cerebri describes a diffuse growth pattern of glioma that by definition involves two or more lobes; and CC, basal ganglia, and thalamic involvement are often observed (Fig 13).80,87

Conclusion In this manuscript, we present and summarize the major differential considerations for lesions involving the splenium in children. It is difficult to interpret splenial lesions in isolation, and associated abnormalities elsewhere in the brain and clinical presentation are essential to arrive at the correct diagnosis. However, the splenial lesions are often obvious on neuroimaging and a thorough familiarity with the various pathologies that may result in primary or secondary injury to the splenium of the CC may help to narrow down the differential diagnosis.

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