Treatment of Leukoencephalopathy with Calcifications and Cysts with Bevacizumab Running Title: Treatment of LCC with Bevacizumab Fay, A.J.,* King, A.A.,^ Shimony, J.S., % Crow, Y.J., a, b and Brunstrom- Hernandez, J.E. # * Dept. of Neurology, University of California, San Francisco, 1550 4 th St., RH 546 MB 2922, San Francisco, CA 94143, USA. ^ Program in Occupational Therapy, Dept. of Pediatrics, Division of Hematology-Oncology, Washington University School of Medicine, Campus Box 8505, St. Louis, MO 63108, USA. % Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. a Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, UK. b INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes – Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France. # Director, 1 CP Place, PLLC, 7709 San Jacinto Place, Suite 203, Plano, TX 75024, USA. Title Character Count: 71 Number of References: 12 Number of Figures: 1 Word Count Abstract: 218 Word Count Paper: 1693 Corresponding Author:
Transcript
Treatment of Leukoencephalopathy with Calcifications and Cysts with Bevacizumab
Running Title: Treatment of LCC with Bevacizumab
Fay, A.J.,* King, A.A.,^ Shimony, J.S.,% Crow, Y.J.,a, b and Brunstrom-Hernandez, J.E.#
* Dept. of Neurology, University of California, San Francisco, 1550 4th St., RH 546 MB 2922, San Francisco, CA 94143, USA.
^ Program in Occupational Therapy, Dept. of Pediatrics, Division of Hematology-Oncology, Washington University School of Medicine, Campus Box 8505, St. Louis, MO 63108, USA.
% Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
a Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, UK.
b INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes – Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France.
# Director, 1 CP Place, PLLC, 7709 San Jacinto Place, Suite 203, Plano, TX 75024, USA.
Title Character Count: 71
Number of References: 12
Number of Figures: 1
Word Count Abstract: 218
Word Count Paper: 1693
Corresponding Author:
Alex Fay MD,PhD
Dept. of Neurology, University of California, San Francisco
Key Words: Cerebrovascular Disease, Developmental Disorders, Genetics, Movement Disorders, Leukodystrophy
Author Contributions: AJF drafted the manuscript and interpreted data. AA King and JEB-H conceptualized the study and edited the manuscript. YJC coordinated genetic testing and edited the manuscript. JSS assisted with interpretation of MRI data and preparation of images.
Acknowledgements
The authors wish to acknowledge the Genentech Access to Care Foundation for partial coverage of the costs of bevacizumab.
Author Disclosures
Alex Fay reports no disclosures.
Allison King reports no disclosures.
Yanick Crow reports no disclosures.
Joshua Shimony reports no disclosures.
Janice Brunstrom-Hernandez reports no disclosures.
Study Funding
YJC 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). JSS acknowledges support from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University.
Background: Leukoencephalopathy with Calcifications and Cysts (LCC) is a rare, autosomal recessive cerebral microangiopathy that causes progressive white matter disease, calcifications and cysts within the brain, typically associated with slowly progressive psychomotor regression, seizures, and movement disorders. While LCC affects only the central nervous system, it demonstrates remarkable neuropathological and radiological 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 LCC and Coats plus, neither of which has any known therapy. Methods: We treated an 18-year-old man with LCC using biweekly infusions of the VEGF inhibitor bevacizumab over one year, and performed clinical examinations and brain imaging at three monthly intervals. Results: Over one year of treatment, the patient showed improved bradykinesia and range of motion, and brain magnetic resonance imaging (MRI) 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 LCC.
Introduction
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. While 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 due to 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
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, while 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.
Case
The patient was born at 29 weeks estimated gestational age, weighing 1.62 kg, after a pregnancy complicated by premature rupture of membranes. Following six weeks in the intensive care unit, he was discharged home and at 11 weeks of age developed seizures, which were easily treated. Developmental milestones were delayed: he sat independently at age 11 months (uncorrected), walked at 21 months, and at 5 years of age his language was estimated to be at the level of a 3-year old.
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 seven years of age he was becoming progressively bradykinetic, for which he was started on levodopa-carbidopa, leading to some mild improvement. He began to have difficulty ambulating at age 10 years, and by 13 years of age he was falling repeatedly and had worsening dysarthria. He had a single, non-convulsive, 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 15 years of age, 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.
Brain MRI at six years of age, his first recorded cranial imaging, revealed calcifications in the bilateral hemispheres, without cysts or white matter changes. By thirteen years of age, 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, and increased T2/FLAIR (fluid-attenuated inversion recovery) signal changes in periventricular and subventricular white matter. Repeat brain MRI at 18 years of age demonstrated a further progression of his imaging abnormalities, with increased calcifications in the periventricular white matter, basal ganglia, thalami and dentate nuclei, associated with cysts in the bilateral 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.
At age 18 years of age our patient began treatment with bevacizumab, 5 mg/kg biweekly. Prior to initiation of therapy, his neurological examination was notable for bradyphrenia and the ability to answer questions with single words, though with increased latency. Cranial nerves were otherwise normal. He was not able to lift the right arm above the shoulder, and had minimal abduction of the left arm, with bradykinesia and spasticity in both upper extremities. In his lower extremities, he had spasticity in both legs, more pronounced on the left, and 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 in the upper limbs compared to prior examinations. Following 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 to pre-treatment 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 reviously. The clinical improvements in range of motion and bradykinesia plateaued after six months of bevacizumab, but he showed none of the decline in mobility he had experienced over the years preceding treatment.
A follow-up MRI after 3 months of treatment showed a slight interval decrease in the size of the cystic lesions, most notably in the right corona radiata (Fig. 1, E-F), reduced FLAIR hyperintensity within the left cerebellar hemisphere, and interval resolution of FLAIR abnormality within the left cerebral peduncle. MRI after 6 months of treatment showed a further decrease in white matter FLAIR hyperintensity, with a marked reduction in the size of several thin-walled cysts (Fig. 1, I-J) and unchanged multifocal calcifications (Fig. 1I). Imaging demonstrated continued reduction of cysts and white matter abnormalities between six months and one year of treatment.
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, but 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 due to 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
We present the first reported 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 in the patient’s speech, dystonia and gait, he experienced no further obvious decline in his clinical state over the twelve-month period of therapy with bevacizumab; indeed, 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 over the twelve months of treatment. LCC is a progressive disease associated with severe neurological deficits and premature death in a majority of patients, and with no recognized treatments at the present time. We could not find any reports in the literature of spontaneous remission of white matter lesions, and while cysts have been reported to grow and shrink over time,10 we did not observe any cyst growth while our patient was undergoing treatment.
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 due to antagonism of VEGF-mediated increases in vascular permeability, as has been described in diabetic retinopathy.12 In our patient, there was reversal of 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. As such, the data presented here indicate that further studies of VEGF inhibition are warranted in the context of LCC, and possibly also Coats plus.
References
1. Livingston JH, Mayer J, Jenkinson E, et al. Leukoencephalopathy with calcifications and cysts: a purely neurological disorder distinct from coats plus. Neuropediatrics. 2014 Jun;45(3):175-82.
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Figure 1. Brain MRI scans 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, N), hypothalamus (C, G, K, O), and cerebellum (D, H, L, P). Note that the patient’s head tilt in the MRI scanner was different in the 12 month images (M-P) compared to the other images, resulting in less consistent alignment when compared to the pre-treatment, three month, and six month images.
