Pediatric Neurology 51 (2014) 576e579
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Leukoencephalopathy, Cerebral Calcifications, and Cysts in Two Sisters Richard L. Ogles MD a, *, Christopher L. Joshi MD a, Douglas C. Miller MD, PhD b, N. Scott Litofsky MD c, Mark D. Travis MD, PhD a a
Department of Diagnostic Radiology, University of Missouri School of Medicine, Columbia, Missouri Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri c Division of Neurological Surgery, Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri b
abstract BACKGROUND: The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. PATIENT DESCRIPTION: We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. CONCLUSION: In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance. Keywords: Labrune syndrome, leukoencephalopathy, cerebral calcifications, cysts, LCC, siblings, autosomal recessive, Coats plus
Pediatr Neurol 2014; 51: 576-579 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Patient Descriptions
The triad of leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare syndrome consisting of these three radiographic findings first described by Labrune et al.1 in 1996. At this time, the inheritance pattern and genetic mutation responsible for this syndrome have not been determined; indeed, it is not known for certain that this is a genetic disorder. We describe two siblings who presented with LCC diagnosed approximately 10 years apart.
Patient 1
Article History: Received May 6, 2014; Accepted in final form June 13, 2014 * Communications should be addressed to: Dr. Ogles; Department of Diagnostic Radiology; University of Missouri School of Medicine; 1 Hospital Drive; Columbia, Missouri 65212. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.06.007
A 25-year-old previously healthy Caucasian woman, born of nonconsanguineous parents, presented 10 days postpartum to the emergency department after 1 week of headaches and sudden onset of progressive left upper and lower extremity weakness. Her pregnancy was unremarkable other than adequately controlled gestational diabetes, and she delivered a healthy infant at term via a cesarean section. She denied nausea, vomiting, visual changes, seizures, or fever. At presentation she had left upper and lower extremity weakness and mild sensory loss, but otherwise, her general physical and ophthalmologic examinations were unremarkable. Laboratory evaluation including a complete blood count, standard metabolic panel, and toxicology screen were unremarkable. She had no prior history of seizures, neurological deficits, gastrointestinal hemorrhage, or osteopenia.
R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579 Computed tomography (CT) demonstrated bifrontal centrum semiovale cysts and dense calcification in both thalami and in the left basal ganglia (Fig 1A). The left frontal cyst contained a layered hemorrhage. Magnetic resonance imaging (MRI; Fig 1B,C) demonstrated the bifrontal cysts with thin uniformly enhancing walls and also extensive bilateral white matter increased T2 signal with sparing of the gray matter (not illustrated). There was no cerebral atrophy. She underwent open resection of a right frontal lobe cystic “mass” because of its hemorrhagic nature. Sections of the resected tissue (Fig 2A-E) had extensive gliosis with Rosenthal fibers, abnormal thickwalled blood vessels, rarefied microcystic foci, and a larger cyst with abundant hemosiderin along the wall. The abnormal blood vessels were Congo red negative and had smooth, evenly distributed periodic acidSchiff positivity (not illustrated).
Patient 2 An older sister, with the same nonconsanguineous parents, had been managed at an outside institution for long-standing epilepsy which began at age 3 months. She received phenobarbital until age 18 months she had no additional seizures for several years. At 11 years of age, she again developed generalized tonic-clonic seizures, and she continued to have breakthrough seizures every 2-3 months through age 18 years. Our records indicate that the patient had an MRI performed at an outside facility at age 16 years, which led to a possible diagnosis of tuberous sclerosis versus leukoencephalopathy. She underwent extensive evaluation for leukoencephalopathy and metabolic disorders at that time, which were reportedly negative. She presented to our institution in 2001 at age 18 years after multiple episodes of medically refractory generalized tonic-clonic seizures. During the course of her hospital stay, it was observed that she had baseline slow speech and an established learning disability, which caused her to have to repeat 11th grade. Otherwise, her physical, neurological, and ophthalmologic examination were unremarkable. There was no documented gastrointestinal hemorrhage or osteopenia. CT revealed numerous bilateral foci of calcification in the supratentorial subcortical and deep white matter, both thalami, and the left basal ganglia (Fig 3A,B), as well as cysts in the right frontal and left temporal lobes. MRI demonstrated right frontal and left temporal lobes cysts with thin uniformly enhancing walls (Fig 3C). There was increased T2 signal bilaterally in the white matter with sparing of the gray matter. However, there was no cerebral atrophy. She underwent a CT-guided stereotactic biopsy of a right frontal lobe cystic mass in 2002. Histopathologic findings (Fig 2F) had similarities to those of Patient 1, with the additional features of extensive calcifications and the absence of any abnormal blood vessels.
577
Discussion
The intracranial radiographic findings of leukoencephalopathy, cysts, and calcifications have been described with both LCC and Coats plus syndrome. Based on the radiographic findings, additional considerations in the differential diagnosis might include neurocysticercosis, cryptococcosis, or Fahr disease; however, none of these conditions would present with the triad of radiographic findings specific for LCC and Coats plus syndrome. Coats plus syndrome has additional non-neurological features which distinguish it from LCC including retinal telangiectasia and exudates, increased incidence of osteopenia and recurrent fractures, and a risk of gastrointestinal bleeding and portal hypertension.2,3 These two entities have been collectively referred to as cerebroretinal microangiopathy with calcifications and cysts, and it has previously been proposed that they may share a common genetic mutation.3 A 2012 report by Polvi et al.4 demonstrated that patients with childhood-onset cerebroretinal microangiopathy with calcifications and cysts had a compound heterozygous CTC1 mutation and that CTC1 is not responsible for the adolescent or adult-onset LCC phenotype. They were not able to conclude that this would also apply to childhood-onset LCC because patients with this phenotype were not encountered in their study. A study by Anderson et al.2 in 2012 also concluded that Coats plus and Labrune syndrome are not allelic. Our patients were referred for genetic testing in 2012 but transferred their care to an outside institution and were lost to follow-up. For this reason, no follow-up imaging was obtained on the younger patient after her open biopsy. Two-year follow-up imaging in Patient 2 from 2001-2003 demonstrated unchanged MRI findings, and there was no significant change clinically with persistent intermittent seizure activity. This is consistent with the expected slow disease progression which has been described in prior reports.5,6 The initial patients with LCC described by Labrune et al.,1 along with several subsequent case reports,5,7,8 have indicated common histopathologic findings of gliosis, Rosenthal fibers, abundant angiomatous changes, and microcalcifi-
FIGURE 1. (A) Computed tomography demonstrating left caudate and thalamic calcifications, left frontal lobe cyst, and diffuse bilateral white matter hypodensity. (B) Gradient-echo magnetic resonance image demonstrating hemorrhage within a left frontal lobe cyst and small foci of blooming artifact in the white matter and within the walls of a right frontoparietal cyst. (C) Contrast-enhanced T1-weighted magnetic resonance image revealing thin, uniform enhancement within the cyst walls.
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R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579
FIGURE 2. Histopathology. (A) A hematoxylin and eosin (H-E) stained section of the open biopsy specimen from the younger sister depicts gliotic white matter with hemosiderin in macrophages with scattered Rosenthal fibers, with an associated cluster of thick-walled abnormal blood vessels. 400 original magnification. (B) The white matter contains rarefied areas with microcysts. H-E, 200 original magnification. (C) There is severe but subtotal loss of myelin. Luxol fast blue and H-E combination stain, 100 original magnification. (D) A narrow larger cyst is lined by astrocytes and by hemosiderin-filled macrophages. H-E, 100 original magnification. (E) Higher magnification of the cyst wall reveals the mixture of macrophages with hemosiderin and astrocytes. H-E, 400 original magnification. (F) The stereotactic biopsy from the other sister demonstrated extensive calcification in gliotic white matter. H-E, 400 original magnification.
cations. With the exceptions of absent microcalcifications in the surgical specimen from the younger sister (although they were clearly present in the CT images), and a lack of angiomatous changes in the needle biopsies from the older one, the histopathologic findings in these two siblings were
concordant with previously described cases of LCC. Nagae-Poetscher et al.9 previously presented a patient with LCC whose histopathologic findings revealed no definite angiomatous changes. They attributed this finding to small sample size, which could also be the case in the older of the
R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579
579
FIGURE 3. (A-B) Computed tomography images depicting calcifications within the subcortical and deep white matter, left basal ganglia, and thalamus; a right frontal cyst and extensive bilateral white matter hypodensity. (C) Contrast-enhanced T1-weighted magnetic resonance imaging revealing thin uniform enhancement within the walls of a right frontal cyst.
sisters we have described, because her biopsy was only a stereotactic needle biopsy. In these siblings, the triad of radiological findings, aforementioned histopathologic findings, and normal ophthalmologic examinations are consistent with familial LCC. The genetic basis for LCC has not been definitively established. The presence of this rare syndrome in two sisters strongly suggests autosomal recessive inheritance and excludes the possibility of an X-linked recessive disorder. Genetic testing in patients like these could potentially provide the key for unlocking the mutation responsible for this rare syndrome. References 1. Labrune P, Lacroix C, Goutieres F, et al. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology. 1996;46:1297-1301. 2. Anderson BH, Kasher PR, Mayer J, et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012;44:338-342.
3. Briggs T, Abdel-Salam G, Balicki M, et al. Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Am J Med Genet A. 2008;146A:182-190. 4. Polvi A, Linnankivi T, Kivela T, et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet. 2012; 90:540-549. 5. Gulati A, Singh P, Ramanathan S, Khandelwal N. A case of leukoencephalopathy, cerebral calcifications, and cysts. Ann Indian Acad Neurol. 2011;14:310-312. 6. Santos Pessoa AL, do Vale Menteiro A, Fonseca de Queiroz R, Malveira GL, Kok F. Leukoencephalopathy with cerebral calcifications and cyst: Labrune syndrome. Arq. Neuro-Psiquiatr. 2012;70: 230-231. 7. Berry-Candelario J, Kasper E, Eskandar E, Chen C. Neurosurgical management of leukoencephalopathy, cerebral calcifications, and cysts: a case report and review of literature. Surg Neurol Int. 2011;2:160. 8. Senor U, Zorlu Y, Men S, Bayol U, Zanapalioglu U. Leukoencephalopathy, cerebral calcifications, and cysts. Am J Neuroradiol. 2006;27: 200-203. 9. Nagae-Poetscher LM, Bibat G, Philippart M, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology. 2004;62:1206-1209.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
Leukoencephalopathy, Cerebral Calcifications, and Cysts in Two Sisters Richard L. Ogles MD a, *, Christopher L. Joshi MD a, Douglas C. Miller MD, PhD b, N. Scott Litofsky MD c, Mark D. Travis MD, PhD a a
Department of Diagnostic Radiology, University of Missouri School of Medicine, Columbia, Missouri Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri c Division of Neurological Surgery, Department of Surgery, University of Missouri School of Medicine, Columbia, Missouri b
abstract BACKGROUND: The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. PATIENT DESCRIPTION: We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. CONCLUSION: In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance. Keywords: Labrune syndrome, leukoencephalopathy, cerebral calcifications, cysts, LCC, siblings, autosomal recessive, Coats plus
Pediatr Neurol 2014; 51: 576-579 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Patient Descriptions
The triad of leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare syndrome consisting of these three radiographic findings first described by Labrune et al.1 in 1996. At this time, the inheritance pattern and genetic mutation responsible for this syndrome have not been determined; indeed, it is not known for certain that this is a genetic disorder. We describe two siblings who presented with LCC diagnosed approximately 10 years apart.
Patient 1
Article History: Received May 6, 2014; Accepted in final form June 13, 2014 * Communications should be addressed to: Dr. Ogles; Department of Diagnostic Radiology; University of Missouri School of Medicine; 1 Hospital Drive; Columbia, Missouri 65212. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.06.007
A 25-year-old previously healthy Caucasian woman, born of nonconsanguineous parents, presented 10 days postpartum to the emergency department after 1 week of headaches and sudden onset of progressive left upper and lower extremity weakness. Her pregnancy was unremarkable other than adequately controlled gestational diabetes, and she delivered a healthy infant at term via a cesarean section. She denied nausea, vomiting, visual changes, seizures, or fever. At presentation she had left upper and lower extremity weakness and mild sensory loss, but otherwise, her general physical and ophthalmologic examinations were unremarkable. Laboratory evaluation including a complete blood count, standard metabolic panel, and toxicology screen were unremarkable. She had no prior history of seizures, neurological deficits, gastrointestinal hemorrhage, or osteopenia.
R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579 Computed tomography (CT) demonstrated bifrontal centrum semiovale cysts and dense calcification in both thalami and in the left basal ganglia (Fig 1A). The left frontal cyst contained a layered hemorrhage. Magnetic resonance imaging (MRI; Fig 1B,C) demonstrated the bifrontal cysts with thin uniformly enhancing walls and also extensive bilateral white matter increased T2 signal with sparing of the gray matter (not illustrated). There was no cerebral atrophy. She underwent open resection of a right frontal lobe cystic “mass” because of its hemorrhagic nature. Sections of the resected tissue (Fig 2A-E) had extensive gliosis with Rosenthal fibers, abnormal thickwalled blood vessels, rarefied microcystic foci, and a larger cyst with abundant hemosiderin along the wall. The abnormal blood vessels were Congo red negative and had smooth, evenly distributed periodic acidSchiff positivity (not illustrated).
Patient 2 An older sister, with the same nonconsanguineous parents, had been managed at an outside institution for long-standing epilepsy which began at age 3 months. She received phenobarbital until age 18 months she had no additional seizures for several years. At 11 years of age, she again developed generalized tonic-clonic seizures, and she continued to have breakthrough seizures every 2-3 months through age 18 years. Our records indicate that the patient had an MRI performed at an outside facility at age 16 years, which led to a possible diagnosis of tuberous sclerosis versus leukoencephalopathy. She underwent extensive evaluation for leukoencephalopathy and metabolic disorders at that time, which were reportedly negative. She presented to our institution in 2001 at age 18 years after multiple episodes of medically refractory generalized tonic-clonic seizures. During the course of her hospital stay, it was observed that she had baseline slow speech and an established learning disability, which caused her to have to repeat 11th grade. Otherwise, her physical, neurological, and ophthalmologic examination were unremarkable. There was no documented gastrointestinal hemorrhage or osteopenia. CT revealed numerous bilateral foci of calcification in the supratentorial subcortical and deep white matter, both thalami, and the left basal ganglia (Fig 3A,B), as well as cysts in the right frontal and left temporal lobes. MRI demonstrated right frontal and left temporal lobes cysts with thin uniformly enhancing walls (Fig 3C). There was increased T2 signal bilaterally in the white matter with sparing of the gray matter. However, there was no cerebral atrophy. She underwent a CT-guided stereotactic biopsy of a right frontal lobe cystic mass in 2002. Histopathologic findings (Fig 2F) had similarities to those of Patient 1, with the additional features of extensive calcifications and the absence of any abnormal blood vessels.
577
Discussion
The intracranial radiographic findings of leukoencephalopathy, cysts, and calcifications have been described with both LCC and Coats plus syndrome. Based on the radiographic findings, additional considerations in the differential diagnosis might include neurocysticercosis, cryptococcosis, or Fahr disease; however, none of these conditions would present with the triad of radiographic findings specific for LCC and Coats plus syndrome. Coats plus syndrome has additional non-neurological features which distinguish it from LCC including retinal telangiectasia and exudates, increased incidence of osteopenia and recurrent fractures, and a risk of gastrointestinal bleeding and portal hypertension.2,3 These two entities have been collectively referred to as cerebroretinal microangiopathy with calcifications and cysts, and it has previously been proposed that they may share a common genetic mutation.3 A 2012 report by Polvi et al.4 demonstrated that patients with childhood-onset cerebroretinal microangiopathy with calcifications and cysts had a compound heterozygous CTC1 mutation and that CTC1 is not responsible for the adolescent or adult-onset LCC phenotype. They were not able to conclude that this would also apply to childhood-onset LCC because patients with this phenotype were not encountered in their study. A study by Anderson et al.2 in 2012 also concluded that Coats plus and Labrune syndrome are not allelic. Our patients were referred for genetic testing in 2012 but transferred their care to an outside institution and were lost to follow-up. For this reason, no follow-up imaging was obtained on the younger patient after her open biopsy. Two-year follow-up imaging in Patient 2 from 2001-2003 demonstrated unchanged MRI findings, and there was no significant change clinically with persistent intermittent seizure activity. This is consistent with the expected slow disease progression which has been described in prior reports.5,6 The initial patients with LCC described by Labrune et al.,1 along with several subsequent case reports,5,7,8 have indicated common histopathologic findings of gliosis, Rosenthal fibers, abundant angiomatous changes, and microcalcifi-
FIGURE 1. (A) Computed tomography demonstrating left caudate and thalamic calcifications, left frontal lobe cyst, and diffuse bilateral white matter hypodensity. (B) Gradient-echo magnetic resonance image demonstrating hemorrhage within a left frontal lobe cyst and small foci of blooming artifact in the white matter and within the walls of a right frontoparietal cyst. (C) Contrast-enhanced T1-weighted magnetic resonance image revealing thin, uniform enhancement within the cyst walls.
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R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579
FIGURE 2. Histopathology. (A) A hematoxylin and eosin (H-E) stained section of the open biopsy specimen from the younger sister depicts gliotic white matter with hemosiderin in macrophages with scattered Rosenthal fibers, with an associated cluster of thick-walled abnormal blood vessels. 400 original magnification. (B) The white matter contains rarefied areas with microcysts. H-E, 200 original magnification. (C) There is severe but subtotal loss of myelin. Luxol fast blue and H-E combination stain, 100 original magnification. (D) A narrow larger cyst is lined by astrocytes and by hemosiderin-filled macrophages. H-E, 100 original magnification. (E) Higher magnification of the cyst wall reveals the mixture of macrophages with hemosiderin and astrocytes. H-E, 400 original magnification. (F) The stereotactic biopsy from the other sister demonstrated extensive calcification in gliotic white matter. H-E, 400 original magnification.
cations. With the exceptions of absent microcalcifications in the surgical specimen from the younger sister (although they were clearly present in the CT images), and a lack of angiomatous changes in the needle biopsies from the older one, the histopathologic findings in these two siblings were
concordant with previously described cases of LCC. Nagae-Poetscher et al.9 previously presented a patient with LCC whose histopathologic findings revealed no definite angiomatous changes. They attributed this finding to small sample size, which could also be the case in the older of the
R.L. Ogles et al. / Pediatric Neurology 51 (2014) 576e579
579
FIGURE 3. (A-B) Computed tomography images depicting calcifications within the subcortical and deep white matter, left basal ganglia, and thalamus; a right frontal cyst and extensive bilateral white matter hypodensity. (C) Contrast-enhanced T1-weighted magnetic resonance imaging revealing thin uniform enhancement within the walls of a right frontal cyst.
sisters we have described, because her biopsy was only a stereotactic needle biopsy. In these siblings, the triad of radiological findings, aforementioned histopathologic findings, and normal ophthalmologic examinations are consistent with familial LCC. The genetic basis for LCC has not been definitively established. The presence of this rare syndrome in two sisters strongly suggests autosomal recessive inheritance and excludes the possibility of an X-linked recessive disorder. Genetic testing in patients like these could potentially provide the key for unlocking the mutation responsible for this rare syndrome. References 1. Labrune P, Lacroix C, Goutieres F, et al. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology. 1996;46:1297-1301. 2. Anderson BH, Kasher PR, Mayer J, et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nat Genet. 2012;44:338-342.
3. Briggs T, Abdel-Salam G, Balicki M, et al. Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Am J Med Genet A. 2008;146A:182-190. 4. Polvi A, Linnankivi T, Kivela T, et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet. 2012; 90:540-549. 5. Gulati A, Singh P, Ramanathan S, Khandelwal N. A case of leukoencephalopathy, cerebral calcifications, and cysts. Ann Indian Acad Neurol. 2011;14:310-312. 6. Santos Pessoa AL, do Vale Menteiro A, Fonseca de Queiroz R, Malveira GL, Kok F. Leukoencephalopathy with cerebral calcifications and cyst: Labrune syndrome. Arq. Neuro-Psiquiatr. 2012;70: 230-231. 7. Berry-Candelario J, Kasper E, Eskandar E, Chen C. Neurosurgical management of leukoencephalopathy, cerebral calcifications, and cysts: a case report and review of literature. Surg Neurol Int. 2011;2:160. 8. Senor U, Zorlu Y, Men S, Bayol U, Zanapalioglu U. Leukoencephalopathy, cerebral calcifications, and cysts. Am J Neuroradiol. 2006;27: 200-203. 9. Nagae-Poetscher LM, Bibat G, Philippart M, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology. 2004;62:1206-1209.
