Case Report Reversible Corpus Callosum Splenial Lesion Due to Steroid Therapy Banu Aksu, MD, Serpil Kurtcan, MD, Alpay Alkan, MD, Ayse Aralasmak, MD, Faruk Oktem, MD From the Department of Radiology (BA, SK, AA, AA); and Pediatric Nephrology Radiology (FO), School of Medicine, Bezmialem Vakif University, ˙Istanbul, Turkey
ABSTRACT Reversible corpus callosum splenial (CCS) lesions are rare findings and usually detected incidentally. We presented a case of 15-year-old boy with a diagnoses of nephrotic syndrome. He was referred for neuropsychiatric symptoms following dose reduction on steroid treatment. Brain magnetic resonance imaging (MRI) revealed a focal lesion in the CCS, hyperintense on T2 and FLAIR and hypointense on T1 images with diffusion restriction on apparent diffusion coefficient map. Follow-up MRI 3 weeks later showed complete resolution of the lesion. It was probably result of focal intramyelinic edema due to excytotoxic mechanisms and/or arginine-vasopressin release.
Keywords: Corpus callosum splenial lesion, diffusion weighted imaging, steroid. Acceptance: Received December 13, 2013, and in revised form February 7, 2014. Accepted for publication March 2, 2014. Correspondence: Address correspondence to Banu Aksu, MD, Department of Radiology, School of Medicine, Bezmialem Vakif University, Vatan Street, Aksaray, ˙Istanbul, Turkey. E-mail: [email protected]. J Neuroimaging 2014;00:1-4. DOI: 10.1111/jon.12128
Transient corpus callosum splenial (CCS) lesions are rare imaging findings and have been described in several different conditions.1 The most common causes of reversible CCS lesions are viral encephalitis, antiepileptic drug toxicity/withdrawal, and hypoglycemic encephalopathy.2,3 The typical magnetic resonance imaging (MRI) features are focal hyperintensity on T2 and FLAIR images in the splenium of corpus callosum. On diffusion weighted imaging, splenial lesions are hyperintense in b1000 images and hypointense in ADC maps, reflecting restricted diffusion. Resolution of imaging abnormalities on follow up studies is the most important features of these lesions. The pathophysiological mechanisms underlying transient CCS lesions remain controversial. However, exocytotoxic edema is suspected cause of diffusion restriction in focal CCS lesion.2 To our knowledge, reversible CCS lesion following oral corticosteroid therapy is reported in one case so far.4 Here in, we present a reversible CCS lesion due to steroid therapy in a child with nephrotic syndrome.
Case Report A 15-year-old boy with a 7-year history of nephrotic syndrome was referred to our emergency room with massive edema of extremities and face and abdominal pain. Laboratory examination showed decreased serum albumin (1 mg/dL) and total protein (3.5 mg/dL) level with high urine protein (4+). His serum electrolytes was within normal limits (Na: 138 mmol/L
[136-145 mmol/L], K: 3.9 mmol/L [3.5-5 mmol/L], Cl: 103 mmol/L [98-107 mmol/L], Ca: 8.6 mg/dL [8.4-10.2 mg/dL], Mg: 1.86 mg/dL [1.6-2.3 mg/dL], Fo: 3 mg/dL [2.4-5.1 mg/dL]). He was hospitalized with a diagnosis of nephrotic syndrome upsurge. Pulse corticosteroid treatment was applied for three days (methyl prednisolone 30 mg/kg/day). After clinical recovery and improvement of serum and urine protein values, he was discharged with oral corticosteroid treatment (methyl prednisolone 2 mg/kg/day). He was admitted to the hospital for the second time with psychotic attack (behavioral alterations and paranoid delusions) 1 week after discharge. No neurological focal deficit and meningeal irritation signs was found. There was no abnormality in his laboratory tests including hemogram, renal functions, serum electrolytes. Cerebrospinal fluid (CSF) examinations revealed normal cell counts, and protein and glucose levels. CSF culture and viral serology was negative. Brain MRI revealed a focal lesion in the splenium of corpus callosum, hyperintense on T2, and FLAIR images and hypointense on T1 images, without contrast enhancement. On DWI, the lesion was hyperintense in b1000 images and hypointense in ADC maps, reflecting restricted diffusion. A follow-up MRI performed 3 weeks later showed complete resolution of the splenial lesion with no residual diffusion abnormality (Figs 1, 2).
Discussion Reversible CCS lesions were first described in patients with epilepsy in 1990s.5 These lesions are usually detected
Copyright
◦ 2014 by the American Society of Neuroimaging C
1
Fig 1. Sagittal T2W (A) and axial FLAIR (B) images show a focal, well-defined hyperintense lesion in the central part of the corpus callosum splenium (thin arrow). The lesion is hyperintense on DWI (C) and hypointense in ADC map (D) (arrow head), reflecting restricted diffusion. Axial postcontrast T1 image (E) shows absence of enhancement (open arrow).
incidentally upon MRI performed for encephalopathy, encephalitis, and seizures. Although the patients are usually asymptomatic, the most common symptoms that may accompany with focal reversible CCS lesions are headache, drowsiness, confusion, ataxia, seizures, delirium, and coma.2 A wide variety of diseases can be associated with CCS lesions, which include: brain infarction, multiple sclerosis, neoplasms, acute axonal injury, neoplasms, aids, dementia complex, adrenoleukodystrophy, Marchiafava-bignami disease, renal failure, hemolytic uremic syndrome, and metabolic disorders.2,6 In patients presenting as encephalitis/encephalopathy with focal lesions in the white matter on MRI, acute disseminated encephalomyelitis (ADEM) should be considered in differential diagnosis. In ADEM, MRI reveals bilateral, asymmetric multiple foci with T1 and T2 prolongation in subcortical white matter, and show punctate, ring, and arc enhancement after contrast treatment, which is not compatible with isolated CCS lesion mimicking acute infarction in our case. Also there was
2
Journal of Neuroimaging Vol 00 No 0 XXX 2014
not viral infection or vaccination history and his CSF analysis was also normal in our patient. Therefore, we clinically and radiologically excluded ADEM in differential diagnosis. A new entity called reversible splenium lesion syndrome (RESLES) was identified by Garcia et al.7 Lesions involving the CCS, which disappeared or significantly improved on follow-up studies defined as RESLES. If the main lesion centered on SCC, the presence of additional brain lesions apart from CC included in RESLES. Therefore, patients with ADEM or other demyelinating disorders involving CCS were excluded from this definition. In addition, an another clinic-radiological syndrome, clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) have been described.8 Takanashi et al. defined it as MERS spectrum in which MERS is described in two types. Type 1 associated with isolated CCS lesion and type 2 with a reversible diffusion restriction of extensive white matter and/or entire callosal involvement. They showed complete disappearance of associated white matter and corpus callosum lesions in MERS type 2 on follow-up studies (60 hours). It has
Fig 2. Control MRI acquired 3 weeks later on sagittal T2W (A) and axial FLAIR image (B), the lesion is no longer visible (thin arrow). Axial view of DWI (C) and ADC map (D) show complete reversal of diffusion restriction (arrow head).
been found that MERS type 2 resolve through a period to MERS type 1 (isolated CCS) lesion, which also finally shows complete resolution.9 The pathophysiological mechanism of transient CCS lesions is not well known.10 . In literature, there are several theories in the development of the transient CCS lesions: transient breakdown of the blood-brain barrier, reversible demyelination, intramyelinic edema, exocytotoxic edema, and argininevasopressin release (AVP).2,4,5,11 Edema with diffusion restriction in focal reversible CCS lesions has been attributed to exocytotoxic mechanisms without brain ischemia. Excytotoxic edema, a form of cytotoxic edema, is due to increased glutamate concentration in the extracellular space, which results in Na and Ca entrance to glial cells and myelin sheaths along with water diffusion. So in the early phase of the injury, excytotoxic edema results in separation of myelin layers and edema formation in the intramyelinic clefts. This could explain why this kind of edema is reversible; the edema of glial cells and myelin sheaths protect axons from intracellular
edema and permanent damage. Therefore, MRI signal abnormalities normalize totally with time or following removal of the causative pathological factors.2,12 Renald et al.4 have described another hypothesis that AVP, which regulates regional cerebral blood flow and brain water content, may play a role in the development of transient CCS lesions. AVP release is seen after corticosteroid withdrawal, which results in destabilization of brain water balance.4 It is not clear yet why the transient corpus callosum lesions particularly involve the splenium. Anatomical studies showed the same fiber composition in the splenium compared with other parts of the corpus callosum.5 There are some theories, which state that the vulnerability of the corpus callosum splenium is due to its close functional relationship with temporal lobes and limbic system, which has an important role in spread of excitation in seizures. However, other conditions such as encephalitis or hypoglycemia in which splenium are also involved, cannot be explained by this relationship. It has been suggested that the specific affinity of viral antigens or induced
Aksu et al: Reversible CCS Lesion
3
antibodies to the splenial axonal receptors is responsible for the splenial involvement in viral encephalitis.1 Despite all of these theories, a common pathophysiological mechanism that explains splenial predilection in different disease processes has not been found. In our case, transient stroke like splenial lesion was noted incidentally. The patient had a diagnosis of nephrotic syndrome and presented with neuropsychiatric symptoms after abrupt dose reduction of steroid treatment. The lesion showed diffusion restriction on DWI and corresponding ADC map. Follow-up MRI performed 3 weeks later showed complete resolution of the lesion. Totally reversible MRI findings support that transient CCS lesion was related to high-dose corticosteroid usage and/or withdrawal. It was probably the result of focal intramyelinic edema due to exocytotoxic mechanisms and/or AVP release. Patients with reversible CCS lesions are usually asymptomatic and incidentally noted in brain imaging performed for other reasons. Therefore, the actual incidence of steroid-related splenial lesions is not known. The abrupt dose reduction of high-dose corticosteroids may result in focal transient splenial lesions. As a conclusion, when neuropsychiatric symptoms are detected in children with nephrotic syndrome on steroid treatment, MRI and DTI should be performed to assess and follow up any CCS lesions.
References 1. Doherty MJ, Jayadev S, Watson NF, et al. Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol 2005;62(3):433-437.
4
Journal of Neuroimaging Vol 00 No 0 XXX 2014
2. Galllucci M, Limbucci N, Paonessa A, et al. Reversible focal spleniallesions. Neuroradiology 2007;49(7):541-544. 3. Liu WM, Lin CH. A reversible stroke-like splenial lesion in viral encephalopathy. Acta Neurol Taiwan 2013;22(3): 117-121. 4. Renard D, Bonafe A, Heroum C. Transient lesion in the splenium of the corpus callosum after oral corticoid therapy. Eur J Neurol 2007;14(8):19-20. 5. Kim SS, Chang KH, Kim ST, et al. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? Am J Neuroradiol 1999;20(1):125129. 6. Da Rocha AJ, Reis F, Gama HP, et al. Focal transient lesion in the splenium of the corpus callosum in three non-epileptic patients. Neuroradiology 2006;48(10):731-735. 7. Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 2011;21(2):1-14. 8. Takanashi J. Two newly proposed encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521-528. 9. Takanashi J, Imamura A, Hayakawa F, et al. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci 2010;292(1–2):24-27. 10. Singh P, Gogoi D, Vyas S, et al. Transient splenial lesion: further experience with two cases. Indian J Radiol Imaging 2010;20(4):254257. 11. Cohen-Gadol AA, Britton JW, Jack CR Jr, et al. Transient postictal magnetic resonance imaging abnormality of the corpus callosum in a patient with epilepsy: case report and review of the literature. J Neurosurg 2002;9(3):714-717. 12. Moritani T, Smoker WR, Sato Y, et al. Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 2005;26(2):216228.
ABSTRACT Reversible corpus callosum splenial (CCS) lesions are rare findings and usually detected incidentally. We presented a case of 15-year-old boy with a diagnoses of nephrotic syndrome. He was referred for neuropsychiatric symptoms following dose reduction on steroid treatment. Brain magnetic resonance imaging (MRI) revealed a focal lesion in the CCS, hyperintense on T2 and FLAIR and hypointense on T1 images with diffusion restriction on apparent diffusion coefficient map. Follow-up MRI 3 weeks later showed complete resolution of the lesion. It was probably result of focal intramyelinic edema due to excytotoxic mechanisms and/or arginine-vasopressin release.
Keywords: Corpus callosum splenial lesion, diffusion weighted imaging, steroid. Acceptance: Received December 13, 2013, and in revised form February 7, 2014. Accepted for publication March 2, 2014. Correspondence: Address correspondence to Banu Aksu, MD, Department of Radiology, School of Medicine, Bezmialem Vakif University, Vatan Street, Aksaray, ˙Istanbul, Turkey. E-mail: [email protected]. J Neuroimaging 2014;00:1-4. DOI: 10.1111/jon.12128
Transient corpus callosum splenial (CCS) lesions are rare imaging findings and have been described in several different conditions.1 The most common causes of reversible CCS lesions are viral encephalitis, antiepileptic drug toxicity/withdrawal, and hypoglycemic encephalopathy.2,3 The typical magnetic resonance imaging (MRI) features are focal hyperintensity on T2 and FLAIR images in the splenium of corpus callosum. On diffusion weighted imaging, splenial lesions are hyperintense in b1000 images and hypointense in ADC maps, reflecting restricted diffusion. Resolution of imaging abnormalities on follow up studies is the most important features of these lesions. The pathophysiological mechanisms underlying transient CCS lesions remain controversial. However, exocytotoxic edema is suspected cause of diffusion restriction in focal CCS lesion.2 To our knowledge, reversible CCS lesion following oral corticosteroid therapy is reported in one case so far.4 Here in, we present a reversible CCS lesion due to steroid therapy in a child with nephrotic syndrome.
Case Report A 15-year-old boy with a 7-year history of nephrotic syndrome was referred to our emergency room with massive edema of extremities and face and abdominal pain. Laboratory examination showed decreased serum albumin (1 mg/dL) and total protein (3.5 mg/dL) level with high urine protein (4+). His serum electrolytes was within normal limits (Na: 138 mmol/L
[136-145 mmol/L], K: 3.9 mmol/L [3.5-5 mmol/L], Cl: 103 mmol/L [98-107 mmol/L], Ca: 8.6 mg/dL [8.4-10.2 mg/dL], Mg: 1.86 mg/dL [1.6-2.3 mg/dL], Fo: 3 mg/dL [2.4-5.1 mg/dL]). He was hospitalized with a diagnosis of nephrotic syndrome upsurge. Pulse corticosteroid treatment was applied for three days (methyl prednisolone 30 mg/kg/day). After clinical recovery and improvement of serum and urine protein values, he was discharged with oral corticosteroid treatment (methyl prednisolone 2 mg/kg/day). He was admitted to the hospital for the second time with psychotic attack (behavioral alterations and paranoid delusions) 1 week after discharge. No neurological focal deficit and meningeal irritation signs was found. There was no abnormality in his laboratory tests including hemogram, renal functions, serum electrolytes. Cerebrospinal fluid (CSF) examinations revealed normal cell counts, and protein and glucose levels. CSF culture and viral serology was negative. Brain MRI revealed a focal lesion in the splenium of corpus callosum, hyperintense on T2, and FLAIR images and hypointense on T1 images, without contrast enhancement. On DWI, the lesion was hyperintense in b1000 images and hypointense in ADC maps, reflecting restricted diffusion. A follow-up MRI performed 3 weeks later showed complete resolution of the splenial lesion with no residual diffusion abnormality (Figs 1, 2).
Discussion Reversible CCS lesions were first described in patients with epilepsy in 1990s.5 These lesions are usually detected
Copyright
◦ 2014 by the American Society of Neuroimaging C
1
Fig 1. Sagittal T2W (A) and axial FLAIR (B) images show a focal, well-defined hyperintense lesion in the central part of the corpus callosum splenium (thin arrow). The lesion is hyperintense on DWI (C) and hypointense in ADC map (D) (arrow head), reflecting restricted diffusion. Axial postcontrast T1 image (E) shows absence of enhancement (open arrow).
incidentally upon MRI performed for encephalopathy, encephalitis, and seizures. Although the patients are usually asymptomatic, the most common symptoms that may accompany with focal reversible CCS lesions are headache, drowsiness, confusion, ataxia, seizures, delirium, and coma.2 A wide variety of diseases can be associated with CCS lesions, which include: brain infarction, multiple sclerosis, neoplasms, acute axonal injury, neoplasms, aids, dementia complex, adrenoleukodystrophy, Marchiafava-bignami disease, renal failure, hemolytic uremic syndrome, and metabolic disorders.2,6 In patients presenting as encephalitis/encephalopathy with focal lesions in the white matter on MRI, acute disseminated encephalomyelitis (ADEM) should be considered in differential diagnosis. In ADEM, MRI reveals bilateral, asymmetric multiple foci with T1 and T2 prolongation in subcortical white matter, and show punctate, ring, and arc enhancement after contrast treatment, which is not compatible with isolated CCS lesion mimicking acute infarction in our case. Also there was
2
Journal of Neuroimaging Vol 00 No 0 XXX 2014
not viral infection or vaccination history and his CSF analysis was also normal in our patient. Therefore, we clinically and radiologically excluded ADEM in differential diagnosis. A new entity called reversible splenium lesion syndrome (RESLES) was identified by Garcia et al.7 Lesions involving the CCS, which disappeared or significantly improved on follow-up studies defined as RESLES. If the main lesion centered on SCC, the presence of additional brain lesions apart from CC included in RESLES. Therefore, patients with ADEM or other demyelinating disorders involving CCS were excluded from this definition. In addition, an another clinic-radiological syndrome, clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) have been described.8 Takanashi et al. defined it as MERS spectrum in which MERS is described in two types. Type 1 associated with isolated CCS lesion and type 2 with a reversible diffusion restriction of extensive white matter and/or entire callosal involvement. They showed complete disappearance of associated white matter and corpus callosum lesions in MERS type 2 on follow-up studies (60 hours). It has
Fig 2. Control MRI acquired 3 weeks later on sagittal T2W (A) and axial FLAIR image (B), the lesion is no longer visible (thin arrow). Axial view of DWI (C) and ADC map (D) show complete reversal of diffusion restriction (arrow head).
been found that MERS type 2 resolve through a period to MERS type 1 (isolated CCS) lesion, which also finally shows complete resolution.9 The pathophysiological mechanism of transient CCS lesions is not well known.10 . In literature, there are several theories in the development of the transient CCS lesions: transient breakdown of the blood-brain barrier, reversible demyelination, intramyelinic edema, exocytotoxic edema, and argininevasopressin release (AVP).2,4,5,11 Edema with diffusion restriction in focal reversible CCS lesions has been attributed to exocytotoxic mechanisms without brain ischemia. Excytotoxic edema, a form of cytotoxic edema, is due to increased glutamate concentration in the extracellular space, which results in Na and Ca entrance to glial cells and myelin sheaths along with water diffusion. So in the early phase of the injury, excytotoxic edema results in separation of myelin layers and edema formation in the intramyelinic clefts. This could explain why this kind of edema is reversible; the edema of glial cells and myelin sheaths protect axons from intracellular
edema and permanent damage. Therefore, MRI signal abnormalities normalize totally with time or following removal of the causative pathological factors.2,12 Renald et al.4 have described another hypothesis that AVP, which regulates regional cerebral blood flow and brain water content, may play a role in the development of transient CCS lesions. AVP release is seen after corticosteroid withdrawal, which results in destabilization of brain water balance.4 It is not clear yet why the transient corpus callosum lesions particularly involve the splenium. Anatomical studies showed the same fiber composition in the splenium compared with other parts of the corpus callosum.5 There are some theories, which state that the vulnerability of the corpus callosum splenium is due to its close functional relationship with temporal lobes and limbic system, which has an important role in spread of excitation in seizures. However, other conditions such as encephalitis or hypoglycemia in which splenium are also involved, cannot be explained by this relationship. It has been suggested that the specific affinity of viral antigens or induced
Aksu et al: Reversible CCS Lesion
3
antibodies to the splenial axonal receptors is responsible for the splenial involvement in viral encephalitis.1 Despite all of these theories, a common pathophysiological mechanism that explains splenial predilection in different disease processes has not been found. In our case, transient stroke like splenial lesion was noted incidentally. The patient had a diagnosis of nephrotic syndrome and presented with neuropsychiatric symptoms after abrupt dose reduction of steroid treatment. The lesion showed diffusion restriction on DWI and corresponding ADC map. Follow-up MRI performed 3 weeks later showed complete resolution of the lesion. Totally reversible MRI findings support that transient CCS lesion was related to high-dose corticosteroid usage and/or withdrawal. It was probably the result of focal intramyelinic edema due to exocytotoxic mechanisms and/or AVP release. Patients with reversible CCS lesions are usually asymptomatic and incidentally noted in brain imaging performed for other reasons. Therefore, the actual incidence of steroid-related splenial lesions is not known. The abrupt dose reduction of high-dose corticosteroids may result in focal transient splenial lesions. As a conclusion, when neuropsychiatric symptoms are detected in children with nephrotic syndrome on steroid treatment, MRI and DTI should be performed to assess and follow up any CCS lesions.
References 1. Doherty MJ, Jayadev S, Watson NF, et al. Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol 2005;62(3):433-437.
4
Journal of Neuroimaging Vol 00 No 0 XXX 2014
2. Galllucci M, Limbucci N, Paonessa A, et al. Reversible focal spleniallesions. Neuroradiology 2007;49(7):541-544. 3. Liu WM, Lin CH. A reversible stroke-like splenial lesion in viral encephalopathy. Acta Neurol Taiwan 2013;22(3): 117-121. 4. Renard D, Bonafe A, Heroum C. Transient lesion in the splenium of the corpus callosum after oral corticoid therapy. Eur J Neurol 2007;14(8):19-20. 5. Kim SS, Chang KH, Kim ST, et al. Focal lesion in the splenium of the corpus callosum in epileptic patients: antiepileptic drug toxicity? Am J Neuroradiol 1999;20(1):125129. 6. Da Rocha AJ, Reis F, Gama HP, et al. Focal transient lesion in the splenium of the corpus callosum in three non-epileptic patients. Neuroradiology 2006;48(10):731-735. 7. Garcia-Monco JC, Cortina IE, Ferreira E, et al. Reversible splenial lesion syndrome (RESLES): what’s in a name? J Neuroimaging 2011;21(2):1-14. 8. Takanashi J. Two newly proposed encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521-528. 9. Takanashi J, Imamura A, Hayakawa F, et al. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci 2010;292(1–2):24-27. 10. Singh P, Gogoi D, Vyas S, et al. Transient splenial lesion: further experience with two cases. Indian J Radiol Imaging 2010;20(4):254257. 11. Cohen-Gadol AA, Britton JW, Jack CR Jr, et al. Transient postictal magnetic resonance imaging abnormality of the corpus callosum in a patient with epilepsy: case report and review of the literature. J Neurosurg 2002;9(3):714-717. 12. Moritani T, Smoker WR, Sato Y, et al. Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 2005;26(2):216228.
