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Cerebral Fat Embolism in Hemoglobin SC Disease
Accepted Manuscript Cerebral fat embolism in hemoglobin SC disease Carole Scheifer, MD, François Lionnet, MD, Claude Bachmeyer, MD, Katia StankovicStojanovic, MD, Sophie Georgin-Lavialle, MD-PhD, Sonia Alamowitch, MD-PhD, Beatrice Marro, MD, Sarah Mattioni, MD PII:
S0002-9343(17)30120-1
DOI:
10.1016/j.amjmed.2017.01.020
Reference:
AJM 13907
To appear in:
The American Journal of Medicine
Received Date: 29 September 2016 Revised Date:
6 January 2017
Accepted Date: 7 January 2017
Please cite this article as: Scheifer C, Lionnet F, Bachmeyer C, Stankovic-Stojanovic K, Georgin-Lavialle S, Alamowitch S, Marro B, Mattioni S, Cerebral fat embolism in hemoglobin SC disease, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.01.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Cerebral fat embolism in hemoglobin SC disease
RI PT
Carole Scheifer , MD, a François Lionnet, MD, a Claude Bachmeyer, MD, a Katia Stankovic-Stojanovic, MD, a Sophie Georgin-Lavialle MD-PhD, a Sonia Alamowitch, MD-PhD, c Beatrice Marro, MD, b Sarah Mattioni, MD, a a
Service de médecine interne, Hôpital Tenon (AP-HP), Paris, France Service de radiologie, Hôpital Tenon (AP-HP), Paris, France c Service de neurologie, Hôpital Saint Antoine (AP-HP), Paris France
SC
b
M AN U
Funding sources : none Conflict of interest : none (cf attached document)
Author contributions: all authors had access to the data and a role in writing this manuscript Running head:Fat embolism in sickle cell disease
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Keywords: fat embolism, bone marrow embolism, sickle cell disease, magnetic resonance imaging
1
ACCEPTED MANUSCRIPT PRESENTATION A 63-year-old Caribbean male was admitted to the hospital for low back and pelvic pain. His medical history included sickle cell hemoglobin C (HbSC) disease with no vaso-occlusive crisis within the last 20 years, chronic obstructive pulmonary disease treated with inhaled corticosteroids for the last four
RI PT
years.
A few hours after admission respiratory distress with polypnea occured requiring an oxygen flow rate of 12 liters per minute. At that time, a thrombocytopenia was detected in peripheral blood with a
SC
platelet count of 112 000/ mm3 as well as increased hemolysis (LDH 4990 IU/L normal range: 125250). He was transferred to intensive care unit (ICU). The patient’s neurological and respiratory status
M AN U
got worst in the ICU with agitation, confusion and hypercapnic acidosis leading to his intubation. Disseminated intravascular coagulation, thrombocytopenia and leucopenia developed. Chest CT scan showed lung bilateral alveolar condensation in the posterior basal segment and bilateral pleural effusions. A bone marrow smear was performed and showed bone marrow necrosis. The diagnosis of pulmonary infection without bacterial identification was made, the patient required antibiotic therapy
TE D
combination and blood transfusion. The wake-up after initial sedation was delayed and no real
ASSESSMENT
EP
consciousness after 4 days without sedation was detected, therefore leading to further investigations.
An electroencephalogram (EEG), a lumbar puncture and a cerebral magnetic resonance imaging
AC C
(MRI) were performed: EEG showed neither pathognomonic sign of encephalopathy, nor localized abnormality, nor epileptic sign. The lumbar puncture was normal. The MRI findings were more conclusive:
DIAGNOSIS Indeed diffusion-weighted images (DWI) showed multiples areas of increased intensity in periventricular, splenium of corpus callosum, deep and the subcortical white matter corresponding to ischemic lesions (figure 1 a and b). Because the MRI was performed 14 days after admission, ADC (apparent diffusion coefficient) map was normal (data not shown). They give the characteristic
2
ACCEPTED MANUSCRIPT starfield pattern2 with several diffuse punctate foci of restricted diffusion in the bilateral white matter, predominantly in the splenium of the corpus callosum and the corticomedullary junction. These lesions were also detected with axial FLAIR (fluid-attenuated inversion recovery) images (figure 2). This reflects small parenchymal infarcts caused by cerebral fat embolism1. Figure 3 is axial gradient
RI PT
echo T2 weighted images. These punctate foci of low signal intensity are petechial hemorrhages1,2,3. Based on clinical presentation involving lungs and brain in a patient with bone marrow necrosis and characteristic “starfield pattern” on MRI a diagnosis of cerebral fat embolism syndrome was made. Fat embolism syndrome is a classic complication of long-bone fractures, but it may also be associated
SC
with many non traumatic conditions including sickle cell disease4. Fat embolism syndrome associated with sickle cell disease follows bone marrow necrosis4 and has usually a fatal outcome. A recent
M AN U
review identified 58 cases in the literature5. According to previous publications, fat embolism syndrome occurs preferentially among sickle cell disease patients displaying genotype other than HbSS and revealed the hemoglobinopathy in 33% of the cases6-8.
The classical triad of this syndrome consists of respiratory distress, unspecific neurological signs such
TE D
as confusion or a comatose state, and cutaneous petechiae9-12.
The most common presenting sign of fat embolism syndrome is an acute respiratory distress
10
and it
was possibly the first clinical feature in our patient. Thrombocytopenia often occurs5,3. In another case
EP
report disseminated intravascular coagulation was also detected14. Neurologic complications are common, occurring in up to 85% of cases4,12 but only few cases of cerebral embolism have been
AC C
described suggesting that this entity is underdiagnosed, especially as cerebral CT scans are usually normal
4
. MRI shows multiple, punctate, scattered hypointensities on T1-weighted images,
hyperintensities on T2-weighted images, primarily in the cortical white matter and brainstem3,4,13, Diffusion-weighted MRI (showing hypersignal) and susceptibility-weighted MRI enhance the specificity and sensitivity2,3,15. Gibbs et al performed a necropsy on a similar case showing diffuse microhemorrhages and microinfarcts involving both gray and white-matter structures of the brain, most likely corresponding to the « starfield » pattern16.
MANAGEMENT The only available and effective treatment for cerebral fat embolism is repeated transfusion6,13.
3
ACCEPTED MANUSCRIPT Due to the gravity of the clinical feature, the patient received several transfusions until achieve a 61 % Hb A level. After 28 days of mechanical ventilation the patient regained consciousness and has become progressively more self-sufficient. However after a three-month hospital stay, the patient had persistent neurologic deficits. In conclusion fat embolism syndrome is a rare but potentially lethal
RI PT
complication of sickle cell disease. Diagnosis of fat embolism syndrome should to be considered in case of unexplained multi-organ failure, especially in patients with mild forms of sickle cell disease.
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EP
TE D
M AN U
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Rapid institution of exchange transfusion may improve the outcome5,7,8,11.
4
ACCEPTED MANUSCRIPT
References
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1. Stoeger A, Daniaux M, Felber S, Stockhammer G, Aichner F, zur Nedden D. MRI findings in cerebral fat embolism. European Radiology. 1998;8(9):1590-3. PubMed PMID: WOS:000077355800009. English. 2. Zaitsu Y, Terae S, Kudo K, Tha KK, Hayakawa M, Fujima N, et al. SusceptibilityWeighted Imaging of Cerebral Fat Embolism. Journal of Computer Assisted Tomography. 2010 Jan-Feb;34(1):107-12. PubMed PMID: WOS:000274272300020. 3. Parizel PM, Demey HE, Veeckmans G, Verstreken F, Cras P, Jorens PG, et al. Early diagnosis of cerebral fat embolism syndrome by diffusion-weighted MRI (starfield pattern). Stroke. 2001 Dec;32(12):2942-4. PubMed PMID: WOS:000172599500043. 4. Horton DP, Ferriero DM, Mentzer WC.Non traumatic fat embolism syndrome in sickle cell anemia . Pediatric Neurology. 1995 Jan;12(1):77-80. PubMed PMID: WOS:A1995QH31700012. English. 5. Tsitsikas DA, Gallinella G, Patel S, Seligman H, Greaves P, Amos RJ. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. Blood reviews. 2014 2014 Jan (Epub 2014 Jan;28(1):23-30. PubMed PMID: MEDLINE:24468004. English. 6. Zaidi Y, Sivakumaran M, Graham C, Hutchinson RM. Fatal bone marrow embolism in a patient with sickle cell beta(+) thalassaemia. Journal of Clinical Pathology. 1996 Sep;49(9):774-5. PubMed PMID: WOS:A1996VG65900021. 7. Johnson K, Stastny JF, Rucknagel DL. Fat embolism syndrome associated with asthma and sickle cell beta+thalassemia. American Journal of Hematology. 1994 Aug;46(4):354-7. PubMed PMID: WOS:A1994NX21000017. 8. Ober WB, Bruno MS, Simon RM, Weiner L.Hemoglobin S C disease with fat embolism - report of a patient dying in crisis-autopsy finding. . American Journal of Medicine. 1959 1959;27(4):647-58. PubMed PMID: WOS:A1959WC16700012. 9. Mossa-Basha M, Izbudak I, Gurda GT, Aygun N. Cerebral fat embolism syndrome in sickle cell anaemia/beta-thalassemia: Importance of susceptibility-weighted MRI. Clinical radiology. 2012 2012 Oct (Epub 2012 May;67(10):1023-6. PubMed PMID: MEDLINE:22608248. 10. Girodeau A, Hauret L, Vincenti-Rouquette I, Cordoliani YS. Cerebral fat embolism and drepanocytosis. Journal de radiologie. 2003 2003;84(2 Pt 1):164-5. PubMed PMID: MEDLINE:12717292. 11. Bachmeyer C, Lionnet F, Stojanovic KS, Moguelet P, Aractingi S. Unusual cutaneous lesions indicating fat embolism syndrome in homozygous sickle cell disease. American Journal of Hematology. 2014 Feb;89(2):233-. PubMed PMID: WOS:000331334200019. English. 12. Alobeidi F, Inusa BPD, Singh RR, U-King-Im JM. Cerebral microhaemorrhages secondary to fat embolus syndrome in sickle cell disease. Postgraduate Medical Journal. 2015 Jan;91(1071):55-6. PubMed PMID: WOS:000347920000011. 13. Dang NC, Johnson C, Eslami-Farsani M, Haywood LJ. Bone marrow embolism in sickle cell disease: A review. American Journal of Hematology. 2005 May;79(1):61-7. PubMed PMID: WOS:000228843000012. 14. Hutchins.Rm, Merrick MV, White JM. Fat embolism in sickle cell disease. Journal of Clinical Pathology. 1973 1973;26(8):620-2. PubMed PMID: WOS:A1973Q796400011. 5
ACCEPTED MANUSCRIPT
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15. Medina FJ, Marquez JC, Castillo M. Cerebral fat embolism detection with susceptibility-weighted images in sickle cell disease. The neuroradiology journal. 2012 2012-Sep;25(4):411-4. PubMed PMID: MEDLINE:24029033. 16. Gibbs WN, Opatowsky MJ, Burton EC. AIRP best cases in radiologic-pathologic correlation: cerebral fat embolism syndrome in sickle cell beta-thalassemia. Radiographics : a review publication of the Radiological Society of North America, Inc. 2012 2012;32(5):1301-6. PubMed PMID: MEDLINE:22977019.
6
ACCEPTED MANUSCRIPT Figure legends:
Figure 1 a and b: Axial DWI showed multiple areas of increased signal intensity in
RI PT
splenium of corpus callosum, periventricular and sub cortical white matter. ADC map is not shown but was normal.
Figure 2: Axial flair image showed multiple areas of increased signal intensity in
SC
splenium of corpus callosum, periventricular and subcortical white matter.
M AN U
Figure 3: Axial gradient echo T2 weighted images showed multiple, small, scattered,
AC C
EP
TE D
non confluent hypointense intracerebral lesions.
7
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
S0002-9343(17)30120-1
DOI:
10.1016/j.amjmed.2017.01.020
Reference:
AJM 13907
To appear in:
The American Journal of Medicine
Received Date: 29 September 2016 Revised Date:
6 January 2017
Accepted Date: 7 January 2017
Please cite this article as: Scheifer C, Lionnet F, Bachmeyer C, Stankovic-Stojanovic K, Georgin-Lavialle S, Alamowitch S, Marro B, Mattioni S, Cerebral fat embolism in hemoglobin SC disease, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.01.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Cerebral fat embolism in hemoglobin SC disease
RI PT
Carole Scheifer , MD, a François Lionnet, MD, a Claude Bachmeyer, MD, a Katia Stankovic-Stojanovic, MD, a Sophie Georgin-Lavialle MD-PhD, a Sonia Alamowitch, MD-PhD, c Beatrice Marro, MD, b Sarah Mattioni, MD, a a
Service de médecine interne, Hôpital Tenon (AP-HP), Paris, France Service de radiologie, Hôpital Tenon (AP-HP), Paris, France c Service de neurologie, Hôpital Saint Antoine (AP-HP), Paris France
SC
b
M AN U
Funding sources : none Conflict of interest : none (cf attached document)
Author contributions: all authors had access to the data and a role in writing this manuscript Running head:Fat embolism in sickle cell disease
AC C
EP
TE D
Keywords: fat embolism, bone marrow embolism, sickle cell disease, magnetic resonance imaging
1
ACCEPTED MANUSCRIPT PRESENTATION A 63-year-old Caribbean male was admitted to the hospital for low back and pelvic pain. His medical history included sickle cell hemoglobin C (HbSC) disease with no vaso-occlusive crisis within the last 20 years, chronic obstructive pulmonary disease treated with inhaled corticosteroids for the last four
RI PT
years.
A few hours after admission respiratory distress with polypnea occured requiring an oxygen flow rate of 12 liters per minute. At that time, a thrombocytopenia was detected in peripheral blood with a
SC
platelet count of 112 000/ mm3 as well as increased hemolysis (LDH 4990 IU/L normal range: 125250). He was transferred to intensive care unit (ICU). The patient’s neurological and respiratory status
M AN U
got worst in the ICU with agitation, confusion and hypercapnic acidosis leading to his intubation. Disseminated intravascular coagulation, thrombocytopenia and leucopenia developed. Chest CT scan showed lung bilateral alveolar condensation in the posterior basal segment and bilateral pleural effusions. A bone marrow smear was performed and showed bone marrow necrosis. The diagnosis of pulmonary infection without bacterial identification was made, the patient required antibiotic therapy
TE D
combination and blood transfusion. The wake-up after initial sedation was delayed and no real
ASSESSMENT
EP
consciousness after 4 days without sedation was detected, therefore leading to further investigations.
An electroencephalogram (EEG), a lumbar puncture and a cerebral magnetic resonance imaging
AC C
(MRI) were performed: EEG showed neither pathognomonic sign of encephalopathy, nor localized abnormality, nor epileptic sign. The lumbar puncture was normal. The MRI findings were more conclusive:
DIAGNOSIS Indeed diffusion-weighted images (DWI) showed multiples areas of increased intensity in periventricular, splenium of corpus callosum, deep and the subcortical white matter corresponding to ischemic lesions (figure 1 a and b). Because the MRI was performed 14 days after admission, ADC (apparent diffusion coefficient) map was normal (data not shown). They give the characteristic
2
ACCEPTED MANUSCRIPT starfield pattern2 with several diffuse punctate foci of restricted diffusion in the bilateral white matter, predominantly in the splenium of the corpus callosum and the corticomedullary junction. These lesions were also detected with axial FLAIR (fluid-attenuated inversion recovery) images (figure 2). This reflects small parenchymal infarcts caused by cerebral fat embolism1. Figure 3 is axial gradient
RI PT
echo T2 weighted images. These punctate foci of low signal intensity are petechial hemorrhages1,2,3. Based on clinical presentation involving lungs and brain in a patient with bone marrow necrosis and characteristic “starfield pattern” on MRI a diagnosis of cerebral fat embolism syndrome was made. Fat embolism syndrome is a classic complication of long-bone fractures, but it may also be associated
SC
with many non traumatic conditions including sickle cell disease4. Fat embolism syndrome associated with sickle cell disease follows bone marrow necrosis4 and has usually a fatal outcome. A recent
M AN U
review identified 58 cases in the literature5. According to previous publications, fat embolism syndrome occurs preferentially among sickle cell disease patients displaying genotype other than HbSS and revealed the hemoglobinopathy in 33% of the cases6-8.
The classical triad of this syndrome consists of respiratory distress, unspecific neurological signs such
TE D
as confusion or a comatose state, and cutaneous petechiae9-12.
The most common presenting sign of fat embolism syndrome is an acute respiratory distress
10
and it
was possibly the first clinical feature in our patient. Thrombocytopenia often occurs5,3. In another case
EP
report disseminated intravascular coagulation was also detected14. Neurologic complications are common, occurring in up to 85% of cases4,12 but only few cases of cerebral embolism have been
AC C
described suggesting that this entity is underdiagnosed, especially as cerebral CT scans are usually normal
4
. MRI shows multiple, punctate, scattered hypointensities on T1-weighted images,
hyperintensities on T2-weighted images, primarily in the cortical white matter and brainstem3,4,13, Diffusion-weighted MRI (showing hypersignal) and susceptibility-weighted MRI enhance the specificity and sensitivity2,3,15. Gibbs et al performed a necropsy on a similar case showing diffuse microhemorrhages and microinfarcts involving both gray and white-matter structures of the brain, most likely corresponding to the « starfield » pattern16.
MANAGEMENT The only available and effective treatment for cerebral fat embolism is repeated transfusion6,13.
3
ACCEPTED MANUSCRIPT Due to the gravity of the clinical feature, the patient received several transfusions until achieve a 61 % Hb A level. After 28 days of mechanical ventilation the patient regained consciousness and has become progressively more self-sufficient. However after a three-month hospital stay, the patient had persistent neurologic deficits. In conclusion fat embolism syndrome is a rare but potentially lethal
RI PT
complication of sickle cell disease. Diagnosis of fat embolism syndrome should to be considered in case of unexplained multi-organ failure, especially in patients with mild forms of sickle cell disease.
AC C
EP
TE D
M AN U
SC
Rapid institution of exchange transfusion may improve the outcome5,7,8,11.
4
ACCEPTED MANUSCRIPT
References
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EP
TE D
M AN U
SC
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1. Stoeger A, Daniaux M, Felber S, Stockhammer G, Aichner F, zur Nedden D. MRI findings in cerebral fat embolism. European Radiology. 1998;8(9):1590-3. PubMed PMID: WOS:000077355800009. English. 2. Zaitsu Y, Terae S, Kudo K, Tha KK, Hayakawa M, Fujima N, et al. SusceptibilityWeighted Imaging of Cerebral Fat Embolism. Journal of Computer Assisted Tomography. 2010 Jan-Feb;34(1):107-12. PubMed PMID: WOS:000274272300020. 3. Parizel PM, Demey HE, Veeckmans G, Verstreken F, Cras P, Jorens PG, et al. Early diagnosis of cerebral fat embolism syndrome by diffusion-weighted MRI (starfield pattern). Stroke. 2001 Dec;32(12):2942-4. PubMed PMID: WOS:000172599500043. 4. Horton DP, Ferriero DM, Mentzer WC.Non traumatic fat embolism syndrome in sickle cell anemia . Pediatric Neurology. 1995 Jan;12(1):77-80. PubMed PMID: WOS:A1995QH31700012. English. 5. Tsitsikas DA, Gallinella G, Patel S, Seligman H, Greaves P, Amos RJ. Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. Blood reviews. 2014 2014 Jan (Epub 2014 Jan;28(1):23-30. PubMed PMID: MEDLINE:24468004. English. 6. Zaidi Y, Sivakumaran M, Graham C, Hutchinson RM. Fatal bone marrow embolism in a patient with sickle cell beta(+) thalassaemia. Journal of Clinical Pathology. 1996 Sep;49(9):774-5. PubMed PMID: WOS:A1996VG65900021. 7. Johnson K, Stastny JF, Rucknagel DL. Fat embolism syndrome associated with asthma and sickle cell beta+thalassemia. American Journal of Hematology. 1994 Aug;46(4):354-7. PubMed PMID: WOS:A1994NX21000017. 8. Ober WB, Bruno MS, Simon RM, Weiner L.Hemoglobin S C disease with fat embolism - report of a patient dying in crisis-autopsy finding. . American Journal of Medicine. 1959 1959;27(4):647-58. PubMed PMID: WOS:A1959WC16700012. 9. Mossa-Basha M, Izbudak I, Gurda GT, Aygun N. Cerebral fat embolism syndrome in sickle cell anaemia/beta-thalassemia: Importance of susceptibility-weighted MRI. Clinical radiology. 2012 2012 Oct (Epub 2012 May;67(10):1023-6. PubMed PMID: MEDLINE:22608248. 10. Girodeau A, Hauret L, Vincenti-Rouquette I, Cordoliani YS. Cerebral fat embolism and drepanocytosis. Journal de radiologie. 2003 2003;84(2 Pt 1):164-5. PubMed PMID: MEDLINE:12717292. 11. Bachmeyer C, Lionnet F, Stojanovic KS, Moguelet P, Aractingi S. Unusual cutaneous lesions indicating fat embolism syndrome in homozygous sickle cell disease. American Journal of Hematology. 2014 Feb;89(2):233-. PubMed PMID: WOS:000331334200019. English. 12. Alobeidi F, Inusa BPD, Singh RR, U-King-Im JM. Cerebral microhaemorrhages secondary to fat embolus syndrome in sickle cell disease. Postgraduate Medical Journal. 2015 Jan;91(1071):55-6. PubMed PMID: WOS:000347920000011. 13. Dang NC, Johnson C, Eslami-Farsani M, Haywood LJ. Bone marrow embolism in sickle cell disease: A review. American Journal of Hematology. 2005 May;79(1):61-7. PubMed PMID: WOS:000228843000012. 14. Hutchins.Rm, Merrick MV, White JM. Fat embolism in sickle cell disease. Journal of Clinical Pathology. 1973 1973;26(8):620-2. PubMed PMID: WOS:A1973Q796400011. 5
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15. Medina FJ, Marquez JC, Castillo M. Cerebral fat embolism detection with susceptibility-weighted images in sickle cell disease. The neuroradiology journal. 2012 2012-Sep;25(4):411-4. PubMed PMID: MEDLINE:24029033. 16. Gibbs WN, Opatowsky MJ, Burton EC. AIRP best cases in radiologic-pathologic correlation: cerebral fat embolism syndrome in sickle cell beta-thalassemia. Radiographics : a review publication of the Radiological Society of North America, Inc. 2012 2012;32(5):1301-6. PubMed PMID: MEDLINE:22977019.
6
ACCEPTED MANUSCRIPT Figure legends:
Figure 1 a and b: Axial DWI showed multiple areas of increased signal intensity in
RI PT
splenium of corpus callosum, periventricular and sub cortical white matter. ADC map is not shown but was normal.
Figure 2: Axial flair image showed multiple areas of increased signal intensity in
SC
splenium of corpus callosum, periventricular and subcortical white matter.
M AN U
Figure 3: Axial gradient echo T2 weighted images showed multiple, small, scattered,
AC C
EP
TE D
non confluent hypointense intracerebral lesions.
7
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