CASE REPORT Cerebroretinal Microangiopathy With Calcifications and Cysts: Demonstration of Radiological Progression Melissa J. Armstrong, MD,* Lotfi Hacein-Bey, MD,Þ and Henry Brown, MDþ Abstract: Cerebroretinal microangiopathy with calcifications and cysts is a rare entity with progressive calcifications, enhancing subcortical cysts, and leukoencephalopathy. We present the oldest reported woman with this disorder, with 10 years of imaging documenting progression. This reveals (1) more profound white matter involvement than that previously reported and (2) growth and shrinkage of cysts over time, which may suggest a more complex pathogenesis than that previously theorized. Key Words: CMRCC, leukoencephalopathy, LCC, Labrune syndrome, Coats plus syndrome, cerebral cysts, cerebral calcifications, MRI (J Comput Assist Tomogr 2009;33: 571Y572) C erebroretinal microangiopathy with calcifications and cysts (CRMCC) is a rare disease that encompasses leukoencephalopathy with calcifications and cysts (LCC) and Coats plus syndromes. Neuroimaging reveals a characteristic combination of progressive LCC. Histopathologic findings show a microangiopathy with calcifications and secondary gliosis. We described the oldest known patient with CRMCC. The leukoencephalopathy in our patient is more advanced than that previously described with variable cyst progression and regression, which may suggest a new pathogenetic mechanism. CASE REPORT A 32-year-old woman presented to our clinic for continuing care. Her parents were nonconsanguineous, but her birth history was otherwise unknown. She experienced global developmental delay and had generalized seizures, which resolved spontaneously 30 months after birth. There was no family history of neurological disease. Near her 21st birthday, she experienced a generalized tonic-clonic seizure. Result of her examination was normal, but imaging showed right temporal and intraventricular masses. Pathological findings from a right temporal biopsy suggested an astrocytoma. Result of the biopsy of the growing intraventricular tumor 2 months later was read as pilocytic astrocytoma. Her hospitalization was complicated by transient postoperative left hemiparesis and a left fibular fracture and ankle syndesmosis disruption in a fall. Five years after initial presentation, recurrent seizures prompted reimaging, showing a new left temporal cyst. Resection showed fibrinoid wall degeneration, hemosiderosis, and reactive gliosis, all of unclear etiology. From the Departments of *Neurology, †Neuroradiology, and ‡Pathology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL. Received for publication August 5, 2008; accepted August 18, 2008. Reprints: Lotfi Hacein-Bey, MD, Radiological Associates of Sacramento Medical Group Inc, 1500 Expo Parkway, Sacramento, CA 95815 (e-mail: lhaceinbey@yahoo.com). Dr Armstrong is now with Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario, Canada. Copyright * 2009 by Lippincott Williams & Wilkins J Comput Assist Tomogr & Volume 33, Number 4, July/August 2009 Serial patient examinations showed cognitive impairment and mild left leg weakness. The patient’s sister reported dramatic personality changes, from cheerful to unhappy and irritable. At 29 years of age, the patient underwent left total hip arthroplasty for avascular necrosis of the femoral head. Our examination 11 years after initial presentation showed impaired cognition, labile affect, and mild dysarthria. She exhibited decreased visual acuity and left central facial weakness. She had mild left-side weakness and dysmetria with mild hyperreflexia and bilateral Hoffman and Babinski signs. Her gait was spastic on the left. Review of 10 years of neuroimaging (Fig. 1) revealed (1) asymmetric progressive bilateral white matter disease, posteriorly predominant at onset with late U-fiber involvement and sparing of the basal ganglia, thalami, anterior parts of the internal capsule, and cerebellum; (2) coarse calcifications in the thalamic and periventricular regions extending into the subcortical white matter; and (3) enhancing cystic lesions in the thalami, ventricles, and subcortical white matter, which fluctuated in size. There was no restricted diffusion. Further review of 2 available biopsy results revealed a telangiecticlike proliferative pattern with thick small-vessel walls, perivascular calcifications, and extensive reactive gliosis with prominent Rosenthal fibers. DISCUSSION White matter changes, brain calcifications, and parenchymal cysts have a limited differential diagnosis. This triad was first described in 1996 by Labrune et al1 in children and was later reported in a young adult.2 Recent series have described overlap with Coats plus syndrome, prompting the more inclusive nomenclature of CRMCC.3Y5 Our patient exhibited the LCC spectrum of CRMCC and had none of the features described in Coats plus syndrome. She did not have retinal abnormalities, sparse hair, and skin or nail changes.4Y6 She had no laboratory evidence of anemia or liver dysfunction and no history of intestinal bleeding.4Y6 Although she required 2 orthopedic surgeries, radiographs showed no skeletal changes.4Y6 It is unclear whether she experienced intrauterine and postnatal growth retardation.4Y6 Although she had developmental delay and infantile seizures of unknown etiology, our patient may have had late disease onset. At 32 years old, she is the oldest reported patient with CRMCC, with 2 individuals aged 25 and 26 years5 and 1 aged 30 years,8 all reported in 2008. Our patient’s neuroimaging features are consistent with CRMCC. Posterior white matter changes’ predominance at onset has been reported,1,5,6 but late U-fiber involvement has not.2,3 Also, cyst regression and progression over time have not been previously described. On review, our patient’s pathological finding was also consistent with CRMCC. The originally diagnosed glial tumors likely reflected the secondary gliosis with Rosenthal fibers seen in CRMCC. www.jcat.org | 571 Copyright @ 2009 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Armstrong et al FIGURE 1. Radiological progression of leukoencephalopathy sparing the cerebellum and brainstem and associated lesions over a 10-year period. AYD, MRI findings in 1998. A, Axial T2-weighted imaging at the level of the thalami shows posterior leukoencephalopathy sparing the U-fibers and bilateral thalamic lesions, the right one with increased susceptibility. B, Axial fluid attenuated inversion recovery (FLAIR) imaging at the midlateral ventricle level shows diffuse white matter disease involving the periventricular and lobar regions and sparing the U-fibers and periventricular cysts. C and D, PostYcontrast axial T1 imaging at the level of the lateral ventricles and the corona radiata shows bilateral confluent microcystic enhancing lesions. EYH, Computed tomography findings in 2004: Axial nonYcontrast computed tomography imaging from the level of the thalami through the corona radiata shows marked interval progression of leukoencephalopathy to the periventricular and lobar white matter to involve the U-fibers in the right frontal and left posterior parietal regions; the posterior limbs of the internal capsules are also involved, whereas the basal ganglia are spared. There are coarse bilateral thalamic and periventricular calcifications and large cysts in the left frontal and occipital white matter. IYL, Magnetic resonance imaging findings in 2008: There has been further significant progression of leukoencephalopathy. I, Axial T2 imaging at the level of the thalami shows further progression of white matter disease involving the U-fibers and the posterior limbs of the internal capsules and bilateral thalamic lesions. A large cyst is present adjacent to the occipital horn of the left lateral ventricle; the larger left frontal cyst has disappeared in the interval. J, Axial FLAIR imaging at the level of the lateral ventricles shows extensive white matter disease. K, PostYcontrast axial T1 imaging at the level of the thalami shows significant enhancement of cystic and microcystic lesions. L, Axial gradient-echo imaging shows extensive susceptibility effect in the corona radiata bilaterally indicative of diffuse microcalcifications, microhemorrhages, or both. Cerebroretinal microangiopathy with calcifications and cysts is likely autosomal recessive,3Y6 with onset from infancy to young adulthood.1Y6 Clinical progression is slow. In 8 patients 572 | www.jcat.org J Comput Assist Tomogr & Volume 33, Number 4, July/August 2009 with prolonged follow-up, progression to loss of speech, bulbar symptoms, and severe spasticity occurred over 11 to 20 years.4 One adult patient with LCC has been reported with a small lacunar infarct, and it has been suggested that this condition may belong to hereditary ischemic neuropathies such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukeoncephalopathy (CADASIL)7; however, sequential imaging in our patient never showed restricted diffusion. The primary pathogenetic process is an obliterative cerebral microangiopathy leading to disruption of the blood-brain barrier, necrosis, and gliosis.1,2,4,5 Calcifications and increased white matter water content are felt to be secondary.1,4 Progressive fluid accumulation has been a proposed mechanism for cyst formation,1Y3 with fusion of microcysts causing macrocyst formation.2 Our patient’s neuroimaging, however, shows both growth and shrinkage in cysts over time. This finding may be more consistent with recent reports of megalencephalic leukoencephalopathy with subcortical cysts, where interactions of proteins that are expressed in astrocytic end-feet at the blood-brain and cerebrospinal fluidYbrain barriers are felt to explain cyst formation and increased myelin water content.8 In conclusion, we report the oldest known case of CRMCC, with presentation, neuroimaging, and pathological finding consistent with this diagnosis. Our case demonstrates the 10year radiological progression of CRMCC with more extensive white matter changes than those previously reported. The fact that some cysts decrease in size over time may suggest a more complex pathological finding than has been previously theorized. 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. 1996:46:1297Y1301. 2. Sener U, Zorlu Y, Men S, et al. Leukoencephalopathy, cerebral calcifications, and cysts. AJNR Am J Neuroradiol. 2006:27:200Y203. 3. Nagae-Poetscher LM, Bibat G, Philippart M, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology. 2004: 62:1206Y1209. 4. Linnankivi T, Valanne L, Paetau A, et al. Cerebroretinal microangiopathy with calcifications and cysts. Neurology. 2006:67:1437Y1443. 5. Briggs TA, Abdel-Salam GMH, Balicki M, et al. 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