HHS Public Access Author manuscript Author Manuscript Pediatr Neurol. Author manuscript; available in PMC 2018 May 12. Published in final edited form as: Pediatr Neurol. 2017 June ; 71: 56–59. doi:10.1016/j.pediatrneurol.2017.03.008. Treatment of Leukoencephalopathy With Calcifications and Cysts With Bevacizumab Alex J. Fay, MD, PhDa,*, Allison A. King, MD, MPH, PhDb, Joshua S. Shimony, MD, PhDc, Yanick J. Crow, MBBS, MRCP, PhDd,e, and Jan E. Brunstrom-Hernandez, MDf aDepartment of Neurology, University of California, San Francisco, San Francisco, California Author Manuscript bProgram in Occupational Therapy, Division of Hematology-Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri cMallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri dFaculty of Biology, Medicine and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, UK eINSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Hôpital Necker, Paris Descartes—Sorbonne Paris Cité University, Paris, France f1 CP Place, PLLC, Plano, Texas Abstract Author Manuscript BACKGROUND—Leukoencephalopathy with calcifications and cysts is a rare, autosomal recessive cerebral microangiopathy that causes progressive white matter disease, calcifications, and cysts within the brain. It is typically associated with slowly progressive psychomotor regression, seizures, and movement disorders. Although leukoencephalopathy with calcifications and cysts affects only the central nervous system, it demonstrates remarkable neuropathologic and radiologic overlap with Coats plus, a disorder of small vessels of the brain, eyes, gastrointestinal tract, and bone. Coats disease without extraocular involvement, a genetically distinct disorder from Coats plus, is characterized by retinal telangiectasias and exudative retinopathy, accompanied by neovascularization. Inhibition of vascular endothelial growth factor (VEGF) signaling with the monoclonal anti-VEGF antibody bevacizumab can improve retinal edema and exudates in Coats disease. Given these observations, we reasoned that VEGF inhibition might also be effective in treating leukoencephalopathy with calcifications and cysts and Coats plus, neither of which has any known therapy. Author Manuscript METHODS—We treated an 18-year-old man with leukoencephalopathy with calcifications and cysts using biweekly infusions of the VEGF inhibitor bevacizumab for more than one year and performed clinical examinations and brain imaging at three month intervals. * Communications should be addressed to: Dr. Fay; Department of Neurology; University of California, San Francisco; 1550 4th Street; RH 546; MB 2922; San Francisco, CA 94107. Alexander.fay@ucsf.edu. Author Disclosures: All authors report no disclosures. Author Contributions: A.J.F. drafted the manuscript and interpreted data. A.A.K., and J.E.B.-H. conceptualized the study and edited the manuscript. Y.J.C. coordinated genetic testing and edited the manuscript. J.S.S. assisted with interpretation of MRI data and preparation of images. Fay et al. Page 2 Author Manuscript RESULTS—After treatment for more than one year, the patient showed improved bradykinesia and range of motion, and brain magnetic resonance imaging demonstrated a marked reduction in cyst volume and white matter lesions. CONCLUSIONS—Further studies in a cohort of patients are warranted to investigate the efficacy of VEGF inhibition as a treatment for leukoencephalopathy with calcifications and cysts. Keywords cerebrovascular disease; developmental disorders; genetics; movement disorders; leukodystrophy Introduction Author Manuscript Among the many causes of progressive cerebral white matter disease is a group of disorders that affect the microvasculature of the brain and sometimes other organs. These diseases include Coats plus and leukoencephalopathy with calcifications and cysts (LCC), both of which cause white matter disease and cerebral calcifications.1 These diseases are frequently associated with psychomotor regression, epilepsy, dystonia, and spastic quadriparesis. Although Coats plus is caused by mutations in the conserved telomere maintenance component CTC1,2 the genetic basis of LCC was only recently discovered to be because of autosomal recessive mutations in the box C/D small nucleolar RNA SNORD118.3 LCC is a rare disease, with unknown frequency, and more than 70 patients have been reported in two large studies (with some patients described in both studies).1,4 Author Manuscript Coats plus and LCC share similar pathology and imaging findings of white matter disease, calcifications, and cysts, but the clinical phenotype of LCC is apparently restricted to the brain, whereas Coats plus can involve other organs, including the eyes, gastrointestinal tract, and bones.5 Coats plus is named for its shared ocular pathology with Coats disease, which combines retinal telangiectasias with exudative retinopathy and retinal neovascularization. Coats disease and the related familial exudative vitreoretinopathies have been treated successfully with inhibitors of vascular endothelial growth factor (VEGF) such as bevacizumab, which reduce retinal edema and exudates.6–9 LCC and Coats plus currently have no established therapies, but given the similar microvascular pathology of Coats disease, Coats plus and LCC, we considered that VEGF inhibition might be helpful in treating LCC. This report describes the treatment of a single patient with genetically confirmed LCC with bevacizumab over the course of one year and his clinical and radiographic response. Author Manuscript Patient Description The patient was born at an estimated gestational age of 29 weeks, weighing 1.62 kg, after a pregnancy complicated by premature rupture of membranes. After six weeks in the intensive care unit, he was discharged home and at age 11 weeks he developed seizures, which were easily treated. Developmental milestones were delayed: he sat independently at age 11 months (uncorrected), walked at 21 months, and at five years of age his language was estimated to be at the level of a three-year old. Pediatr Neurol. Author manuscript; available in PMC 2018 May 12. Fay et al. Page 3 Author Manuscript The first focal motor deficit noted was at age six years, when the patient was found to have left-sided weakness and left ankle dystonia. By age seven years he was becoming progressively bradykinetic; he began levodopa-carbidopa and experienced mild improvement. He began to have difficulty ambulating at age ten years, and by age 13 years, he was falling repeatedly and had worsening dysarthria. He had a single, nonconvulsive, seizure at age 14 years and started using a cane to walk at home and a wheelchair for longer distances. He underwent scoliosis surgery at age 15 years, at which time he was diagnosed with depression and anxiety and treated with escitalopram. Gabapentin and baclofen were initiated because of worsening muscle spasms, and he continued to show progressive spastic quadriparesis. Author Manuscript Author Manuscript Brain magnetic resonance imaging (MRI) at age six years, his first recorded cranial imaging, revealed calcifications in both cerebral hemispheres, without cysts or white matter changes. By age 13 years, when he had worsening dysarthria and falls, MRI demonstrated bilateral calcifications and cysts, some with contrast enhancement, in the periventricular regions, basal ganglia, and thalami, along with increased T2/FLAIR (fluid-attenuated inversion recovery) signal changes in periventricular and subventricular white matter. Repeat brain MRI at age 18 years demonstrated further progression of his imaging abnormalities, with increased calcifications in the periventricular white matter, basal ganglia, thalami, and dentate nuclei, associated with cysts in both hemispheres and subcortical white matter, without mass effect, and extensive cerebral and cerebellar white matter FLAIR hyperintensity. These clinical and radiological features were consistent with a diagnosis of either Coats plus or LCC. Genetic testing was negative for mutations in CTC1, whilst he was found to be compound heterozygous for two rare variants in SNORD118, n.*5C>G and n. 81G>A, discovered as part of a genetic study to identify the cause of LCC.2 His similarly affected brother carried the same two variants, with each parent being heterozygous for a single mutation. Author Manuscript At age 18 years our patient began treatment with bevacizumab, 5 mg/kg biweekly. Before initiation of therapy, his neurological examination was notable for bradyphrenia and the ability to answer questions with single words, with increased latency. Cranial nerves were otherwise normal. He was not able to lift the right arm above his shoulder and had minimal abduction of the left arm, with bradykinesia and spasticity in both upper extremities. He exhibited spasticity in both legs, more pronounced on the left, and he required maximal assistance in moving from the floor to standing or from supine to sitting. He required assistance to stand from a chair and moderate assistance for ambulation, with dystonic posturing and crouching gait. After 14 weeks of treatment, he demonstrated less bradykinesia and a greater range of motion of the arms compared with prior examinations. After six months of treatment, he could lift both arms above his head. In addition, range of motion measurements showed improvement in the hamstrings, hip abductors, and ankle dorsiflexors (other muscles were not measured) compared with pretreatment measurements. He stood from a chair without assistance and required only moderate assistance to transition from floor to standing and supine to sitting. He continued to require moderate help with ambulation, but initiated steps more quickly than he had six months previously. The clinical improvements in range of motion and bradykinesia plateaued after six months of Pediatr Neurol. Author manuscript; available in PMC 2018 May 12. Fay et al. Page 4 Author Manuscript bevacizumab, but he showed none of the decline in mobility that he had experienced over the years preceding treatment. A follow-up MRI after three months of treatment showed a slight interval decrease in the size of the cystic lesions, most notably in the right corona radiata (Figure, E–F versus A–B), reduced FLAIR hyperintensity within the left cerebellar hemisphere (Figure H versus E), and interval resolution of FLAIR abnormality within the left cerebral peduncle. MRI after six months of treatment showed a further decrease in white matter FLAIR hyperintensity, with a marked reduction in the size of several thin-walled cysts (Figure I, J) and unchanged multifocal calcifications (Figure I). Imaging demonstrated continued reduction of cysts and white matter abnormalities between six months and one year of treatment (Figure M–P). Author Manuscript Throughout the course of his infusions he experienced a single nosebleed that was easily controlled, and none of the thromboembolic, hemorrhagic, or gastrointestinal adverse effects that have been reported for bevacizumab. His complete blood counts, electrolytes, creatinine, transaminases, and urine protein were monitored every two weeks while he was undergoing infusions and showed no abnormalities. Treatment was not continued beyond one year, given the plateau in clinical response after six months of bevacizumab, and the patient has remained clinically stable since his last infusion. The patient’s brother was considered for treatment, but he had previously experienced multiple episodes of gastrointestinal bleeding because of recurrent vomiting, and his parents felt that he would not tolerate the frequent travel required for regular infusions. Thus, he did not receive bevacizumab, and his symptoms continued to progress during the period of his brother’s treatment. Discussion Author Manuscript We describe the first use of anti-VEGF therapy in a patient with LCC, demonstrating apparent clinical and radiological improvement over a one year period of treatment with no adverse events. Indeed, after many years of progressive deterioration his speech, dystonia, and gait, he experienced no further decline in his clinical state during more than a 12-months of bevacizumab therapy, whereas his bradykinesia and range of motion improved. The improvement in his brain MRI scans was particularly striking, with a dramatic decrease in the size of several cerebral cysts, and diminished extent of FLAIR white matter involvement during treatment. LCC is a progressive disease associated with severe neurological deficits and premature death in most patients, and with no recognized treatments at the present time. We found no reports of spontaneous remission of white matter lesions in individuals with LCC, and although cysts have been reported to grow and shrink over time,10 we did not observe any cyst growth while our patient was undergoing treatment. Author Manuscript VEGF is recognized as a promoter of neovascularization and vascular permeability, and VEGF inhibition has been reported to reduce exudates and cysts in ocular disorders such as macular edema and Coats disease.11 This effect is presumed to occur because of antagonism of VEGF-mediated increases in vascular permeability, as has been described in diabetic retinopathy.12 Our patient exhibited reversal of his white matter lesions and shrinkage of cysts. It would be interesting to know if earlier treatment might prevent the accumulation of calcifications, which was the first imaging abnormality noted in our patient. The data Pediatr Neurol. Author manuscript; available in PMC 2018 May 12. Fay et al. Page 5 Author Manuscript presented here suggest that further studies of VEGF inhibition are warranted in individuals with LCC and possibly those with Coats plus. Acknowledgments Funding: Y.J.C. acknowledges funding from the Newlife Foundation (14-15/15), the Great Ormond Street Hospital Children’s Charity (V1212), and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future” (ANR-10-IAHU-01). J.S.S. acknowledges support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University. The authors acknowledge the Genentech Access to Care Foundation for partial coverage of the costs of bevacizumab. References Author Manuscript Author Manuscript Author Manuscript 1. Livingston JH, Mayer J, Jenkinson E, et al. Leukoencephalopathy with calcifications and cysts: a purely neurological disorder distinct from coats plus. Neuropediatrics. 2014; 45:175–182. [PubMed: 24407470] 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. [PubMed: 22267198] 3. Jenkinson EM, Rodero MP, Kasher PR, et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet. 2016; 48:1185– 1192. [PubMed: 27571260] 4. Wang M, Zhang M, Wu L, et al. Leukoencephalopathy with cerebral calcification and cysts: cases report and literature review. J Neurol Sci. 2016; 370:173–179. [PubMed: 27772754] 5. Linnankivi T, Valanne L, Paetau A, et al. Cerebroretinal microangiopathy with calcifications and cysts. Neurology. 2006; 67:1437–1443. [PubMed: 16943371] 6. Venkatesh P, Mandal S, Garg S. Management of Coats disease with bevacizumab in 2 patients. Can J Ophthalmol. 2008; 43:245–246. [PubMed: 18347637] 7. Ray R, Barañano DE, Hubbard GB. Treatment of Coats’ disease with intravitreal bevacizumab. Br J Ophthalmol. 2013; 97:272–277. [PubMed: 23269680] 8. Sigler EJ, Randolph JC, Calzada JI, Wilson MW, Haik BG. Current management of Coats disease. Surv Ophthalmol. 2014; 59:30–46. [PubMed: 24138893] 9. Lin KL, Hirose T, Kroll AJ, Lou PL, Ryan EA. Prospects for treatment of pediatric vitreoretinal diseases with vascular endothelial growth factor inhibition. Semin Ophthalmol. 2009; 24:70–76. [PubMed: 19373689] 10. Armstrong MJ, Hacein-Bey L, Brown H. Cerebroretinal microangiopathy with calcifications and cysts: demonstration of radiological progression. J Comput Assist Tomogr. 2009; 33:571–572. [PubMed: 19638852] 11. Gunther JB, Altaweel MM. Bevacizumab (Avastin) for the treatment of ocular disease. Surv Ophthalmol. 2009; 54:372–400. [PubMed: 19422965] 12. Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H. Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res. 1995; 27:48– 52. [PubMed: 7596559] Pediatr Neurol. Author manuscript; available in PMC 2018 May 12. Fay et al. Page 6 Author Manuscript Author Manuscript Author Manuscript FIGURE. Brain magnetic resonance imaging before treatment with bevacizumab (A–D), after three months of treatment (E–H), after six months of treatment (I–L), and after 12 months of treatment (M–P). The first column (images A, E, I, and P) shows T2* images, and the second, third, and fourth columns show FLAIR images at the level of the cerebral hemispheres (B, F, J, and N), hypothalamus (C, G, K, and O), and cerebellum (D, H, L, and P). Note that the patient’s head tilt in the magnetic resonance imaging scanner was different in the 12 month images (M–P) compared with the other images, resulting in less consistent alignment when compared with the pretreatment, three month, and six month images. FLAIR, fluid-attenuated inversion recovery. Author Manuscript Pediatr Neurol. Author manuscript; available in PMC 2018 May 12.