Accepted Manuscript Reversible Cerebral Vasoconstriction Syndrome: A novel mechanism for neurologic complications in Schimke Immuno-osseous Dysplasia Darrah N. Haffner, MD, MHS, Nancy K. Rollins, MD, Michael M. Dowling, MD, PhD, MSCS PII: S0887-8994(18)30795-1 DOI: https://doi.org/10.1016/j.pediatrneurol.2018.10.022 Reference: PNU 9453 To appear in: Pediatric Neurology Received Date: 11 July 2018 Revised Date: 25 October 2018 Accepted Date: 30 October 2018 Please cite this article as: Haffner DN, Rollins NK, Dowling MM, Reversible Cerebral Vasoconstriction Syndrome: A novel mechanism for neurologic complications in Schimke Immuno-osseous Dysplasia, Pediatric Neurology (2018), doi: https://doi.org/10.1016/j.pediatrneurol.2018.10.022. 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 Haffner, et al. 1 Title: Reversible Cerebral Vasoconstriction Syndrome: A novel mechanism for neurologic complications in Schimke Immuno-osseous Dysplasia. RI PT Authors: Darrah N. Haffner, MD, MHS1 Nancy K. Rollins, MD2 SC Michael M. Dowling, MD, PhD, MSCS1 1 M AN U Affiliations: Department of Pediatrics and Neurology and Neurotherapeutics; Division of Pediatric Neurology; University of Texas Southwestern Medical Center Dallas, and Children’s Health System of Texas, Dallas, TX USA 2 Department of Radiology; University of Texas Southwestern Medical Center Dallas, and Corresponding author: EP Darrah Haffner, MD, MHS TE D Children’s Health System of Texas, Dallas, TX USA 1 Department of Pediatrics and Neurology and Neurotherapeutics; Division of Pediatric AC C Neurology; University of Texas Southwestern Medical Center Dallas, and Children’s Health System of Texas 1935 Medical District Drive Dallas, TX USA 75235 214-456-7000 Darrah.haffner@utsouthwestern.edu ACCEPTED MANUSCRIPT Haffner, et al. 2 Number of text pages: 5 Number of words in text: 1032 (not counting abstract) Number of words in abstract: 145 RI PT Number of figures: 4 (1a/b, 2, 3) Number of tables: 0 AC C EP TE D M AN U SC Number of references: 21 ACCEPTED MANUSCRIPT Haffner, et al. 3 Abstract Background: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disease secondary to biallelic SMARCAL1 mutations, characterized by short stature, nephropathy and RI PT immunodeficiency, presenting in early childhood. Approximately 50% of those affected have neurological complications including migraines, transient ischemic attacks, and strokes. Case: We present a six-year-old SIOD patient without evidence of atherosclerotic disease with SC recurrent episodes of severe headache, fluctuating hemiparesis and aphasia. Magnetic resonance imaging/angiography were normal during the initial episode; multiple areas of M AN U reversible restricted diffusion with decreased perfusion and arterial stenosis were seen with subsequent attacks. Conclusions: This constellation of symptoms and imaging findings is suggestive of reversible cerebral vasoconstriction syndrome, which we propose as a mechanism for the transient ischemic attacks and infarcts seen in some patients with SIOD, as opposed to accelerated this rare disorder. TE D atherosclerosis alone. This new insight may provide a basis for novel preventative therapy in EP Key Words: stroke, pediatrics, Schimke immuno-osseous dysplasia, transient ischemic attack, AC C reversible cerebral vasoconstriction syndrome Introduction Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disease with an estimated prevalence of 1:1-3,000,000 live births1,characterized by a triad of short stature, nephropathy, and immunodeficiency. SIOD is complicated by transient ischemic attacks (TIA) of uncertain pathophysiology, previously hypothesized to be secondary to accelerated atherosclerosis in combination with systemic hypertension1-3. Kilic, proposed that SMARCAL1 mutations are associated with disruptions in immunologic homeostasis, leading to inflammation ACCEPTED MANUSCRIPT Haffner, et al. 4 and vascular reactivity4, as SMARCAL1, which is responsible for chromatin remodeling, is highly expressed in human and mouse neuro-progenitor cells and neurons5. We present a six-yearold boy with severe SIOD with progression from migraines to TIAs, infarcts, and seizures in RI PT whom imaging showed reversible cerebral vasoconstriction syndrome (RCVS). Case SC The patient presented at 21 months for failure to thrive and was subsequently diagnosed with focal segmental glomerular sclerosis progressing rapidly to end stage renal disease. The M AN U diagnosis of SIOD was made at 3.5 years with two pathogenic mutations in SMARCAL1 (c.2291G>A and c.1910T>C). At 5 years, the patient presented with right sided hemiplegia and dysarthria following a severe headache; blood pressure on arrival was at the 50% for age and habitus though later in admission became elevated. Limited magnetic resonance imaging and angiography (MRI and MRA) of the head and neck were normal; no perfusion imaging was TE D performed. Electroencephalogram showed left temporo-parieto-occipital slowing, perhaps suggestive of left hemispheric dysfunction related to decreased perfusion. Echocardiogram and hypercoagulable work up were normal. Diagnosis on discharge was TIA and aspirin was started EP for secondary prevention. Daily valproic acid was also initiated for headache prophylaxis given intermittent mild headaches in the preceding year, however was tapered off shortly thereafter for AC C behavioral side effects Six months later, the patient presented with left sided weakness, aphasia, and disabling headache in the setting of hypertension. MRI initially demonstrated multi-focal restricted diffusion in the right hemisphere along with corresponding diminished relative cerebral blood flow on arterial spin labeling (ASL) imaging; MRA showed peripheral branch narrowing of right anterior, middle, and posterior cerebral arteries (Figure 1a/b). Imaging the next day demonstrated increased areas of restricted diffusion within the right hemisphere but improved visualization of distal middle cerebral and posterior cerebral branches (Figure 2). Given the ACCEPTED MANUSCRIPT Haffner, et al. 5 potential for RCVS, verapamil was introduced to target vasospasm, in addition to his current aspirin. Over the next week, there was complete resolution of symptoms with improved perfusion imaging on discharge (Figure 3). RI PT In the following months, he presented with increasing frequency of severe headaches and alternating hemiplegia. With milder episodes of less severe weakness and more rapid return to baseline, imaging did not show diffusion changes, and only subtle vasoconstriction SC correlating to the side of hemiplegia. Blood pressures were moderately elevated to 90-95% for age and habitus. His most recent presentation was the most severe, consisting of right M AN U hemiplegia, aphasia and hemi-clonic seizures, progressing to status epilepticus. On presentation, blood pressure was elevated and the patient was febrile. MRI showed multifocal bilateral non-confluent patchy restricted diffusion, predominantly posteriorly, left more than right, which progressed to the entire left hemisphere days later. MRA and ASL imaging could not be obtained due to the severity of illness. He was discharged to home hospice with persistent TE D symptoms. Overall, these findings of reductions in cerebral blood flow with corresponding multifocal reversible branch vessel narrowing with headaches, fluctuating hemiparesis, and syndrome. AC C Discussion EP seizures suggest RCVS perhaps on a background of posterior reversible encephalopathy SIOD was first described by Schimke in 1971,6 and later named by Spranger in 19917. Virtually all individuals have short stature and progressive nephropathy with 75% displaying spondyloepiphyseal dysplasia and T-cell immunodeficiencies. Other features include growth failure, characteristic facies, hyperpigmented macules,8,9 and in 50% neurologic complications1,3,4. Presentation ranges from early-onset with death within four to eight years from diagnosis to the later-onset form with individuals surviving to adulthood with renal ACCEPTED MANUSCRIPT Haffner, et al. 6 transplantation1,9. The diagnosis is confirmed by genetic testing, demonstrating biallelic pathogenic mutations in SMARCAL110. The neurological complications were first described by Ehrich in 19953. Despite RI PT subsequent advances, the neuro-pathophysiology is still poorly understood. We suggest RCVS as a contributing factor in this syndrome, given the severe recurrent headaches and alternating hemiplegia with MRI showing corresponding areas of patchy reversible restricted diffusion, SC diminished perfusion, and reversible arteriopathy in our patient. RCVS is a clinico-radiologic syndrome characterized by “thunderclap” headaches with or without neurological symptoms, in the setting of diffuse segmental constriction of cerebral arteries, which typically resolves within 3 M AN U months 11-14. RCVS may be complicated by subarachnoid hemorrhage, posterior reversible encephalopathy syndrome, and hemorrhagic or ischemic infarcts11. It is rare in children 12,15-17 and has not been reported in SIOD. Ehrich described three children with SIOD and TIAs with shifting areas of decreased TE D perfusion on positron emission tomography; no MRI or vascular imaging was included3. Sigurdardottir described a teenager with step-wise developmental regression and worsening seizures, where MRI showed biparietal encephalomalacia and narrowing of middle cerebral EP artery branches18. Subsequent studies reported patients with narrowing and irregularity of intracranial vessels, suggestive of diffuse atherosclerosis and Moyamoya disease2,9,19. In AC C 2005, Kilic published a series, where 13 of 29 patients had severe, recurrent migraine-like headaches without mention of neurologic findings. Six had abnormal MRIs4. One of five children with abnormal angiography had reversible vascular stenosis during cerebral attacks4. Our case, with reversible perfusion deficits and vascular changes along with these prior observations, suggest that the severe migraine-like headaches, TIAs, and infarcts are more of a spectrum rather than two distinct phenomena in SIOD patients. We posit that RCVS may act as a bridge between the two, either independently or in in conjunction with atherosclerosis. ACCEPTED MANUSCRIPT Haffner, et al. 7 Based on review of the literature and this experience, we recommend early MRI with vessel imaging and perfusion studies, prior to neurological symptoms, for all SIOD patients. Revascularization procedures have been performed in asymptomatic SIOD patients with silent RI PT infarcts and intracranial atherosclerosis21. Risk factor management of hyperlipidemia, hypertension, prophylactic anti-platelet/thrombotic medication is indicated5,19. Given the possible etiology of RCVS, the use of calcium channel blockers may be beneficial though did not seem particularly helpful for our patient. In prior cases, the vasodilatory agents minoxidil and SC pentoxyphillin were temporarily effective in preventing attacks3,4. More research is needed M AN U regarding the connection between RCVS and SIOD in order to discover new treatments and slow disease progression. AC C EP TE D Conflicts of Interest: The authors declare no conflicts of interest. ACCEPTED MANUSCRIPT Haffner, et al. 8 References AC C EP TE D M AN U SC RI PT 1. Morimoto M, Lewis DB, Lucke T, Boerkoel CF. Schimke Immunoosseous Dysplasia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. 2. Boerkoel CF, Nowaczyk MJ, Blaser SI, Meschino WS, Weksberg R. Schimke immunoosseous dysplasia complicated by moyamoya phenomenon. American journal of medical genetics 1998;78:118-22. 3. Ehrich JH, Burchert W, Schirg E, et al. Steroid resistant nephrotic syndrome associated with spondyloepiphyseal dysplasia, transient ischemic attacks and lymphopenia. Clinical nephrology 1995;43:89-95. 4. Kilic SS, Donmez O, Sloan EA, et al. Association of migraine-like headaches with Schimke immuno-osseous dysplasia. American journal of medical genetics Part A 2005;135:206-10. 5. Deguchi K, Clewing JM, Elizondo LI, et al. Neurologic phenotype of Schimke immunoosseous dysplasia and neurodevelopmental expression of SMARCAL1. Journal of neuropathology and experimental neurology 2008;67:565-77. 6. Schimke RN, Horton WA, King CR. Chondroitin-6-sulphaturia, defective cellular immunity, and nephrotic syndrome. Lancet (London, England) 1971;2:1088-9. 7. Spranger J, Hinkel GK, Stoss H, Thoenes W, Wargowski D, Zepp F. Schimke immunoosseous dysplasia: a newly recognized multisystem disease. The Journal of pediatrics 1991;119:64-72. 8. Morimoto M, Yu Z, Stenzel P, et al. Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia? Orphanet journal of rare diseases 2012;7:70. 9. Boerkoel CF, O'Neill S, Andre JL, et al. Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature. European journal of pediatrics 2000;159:1-7. 10. Boerkoel CF, Takashima H, John J, et al. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nature genetics 2002;30:215-20. 11. Ducros A. Reversible cerebral vasoconstriction syndrome. The Lancet Neurology 2012;11:906-17. 12. Kamide T, Tsutsui T, Misaki K, et al. A Pediatric Case of Reversible Cerebral Vasoconstriction Syndrome With Similar Radiographic Findings to Posterior Reversible Encephalopathy Syndrome. Pediatric neurology 2017;71:73-6. 13. The International Classification of Headache Disorders: 2nd edition. Cephalalgia : an international journal of headache 2004;24 Suppl 1:9-160. 14. Chen S-P, Fuh J-L, Wang S-J. Reversible cerebral vasoconstriction syndrome: an underrecognized clinical emergency. Therapeutic Advances in Neurological Disorders 2010;3:161-71. 15. Oikawa Y, Okubo Y, Numata-Uematsu Y, et al. Initial vasodilatation in a child with reversible cerebral vasoconstriction syndrome. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2017;39:108-10. ACCEPTED MANUSCRIPT Haffner, et al. 9 AC C EP TE D M AN U SC RI PT 16. Ueki H, Sanayama Y, Miyajima A, Tsuchimochi T, Igarashi S, Sunami S. Reversible Cerebral Vasoconstriction Syndrome Promptly Diagnosed with Magnetic Resonance Imaging Including Magnetic Resonance Angiography During Immunosuppressive Therapy in a 16-YearOld Girl with Refractory Cytopenia of Childhood. Hematology reports 2016;8:6673. 17. Trolliet M, Sevely A, Albucher JF, et al. [Reversible cerebral vasoconstriction syndrome: A rare pediatric cause of thunderclap headaches]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 2016;23:1254-9. 18. Sigurdardottir S, Myers SM, Woodworth JM, Raymond GV. Mental retardation and seizure disorder in Schimke immunoosseous dysplasia. American journal of medical genetics 2000;90:294-8. 19. Samanta D, Ramakrishnaiah R. Diffuse Carotid Arteriosclerosis and Stroke in a Patient With Schimke Immuno-osseous Dysplasia. Pediatric neurology 2017;71:82-3. 20. Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D. Reversible Cerebral Vasoconstriction Syndrome, Part 2: Diagnostic Work-Up, Imaging Evaluation, and Differential Diagnosis. AJNR American journal of neuroradiology 2015;36:1580-8. 21. Westbroek EM, Mukerji N, Kalanithi P, Steinberg GK. Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia. Journal of neurosurgery Pediatrics 2015;15:189-91. ACCEPTED MANUSCRIPT Figure 1 1b. SC RI PT 1a. AC C EP Figure 3 TE D M AN U Figure 2 Figure 1: Magnetic resonance angiography and arterial spin labeling in a 6-year-old male with Schimke immuno-osseous dysplasia (SIOD). Images are from the day of presentation of his second lifetime attack, presenting with severe headache, left sided weakness and aphasia. ACCEPTED MANUSCRIPT Figure 1a. Magnetic resonance angiography demonstrating pruning of the right middle cerebral artery branches (see arrows). Figure 1b. Arterial spin labeling images with decreased relative cerebral blood flow in the right cerebral hemisphere. RI PT Figure 2: Magnetic resonance angiography. Images are from the day following Figure 1, demonstrating increased caliber fo the right hemispheric arteries with a new focal narrowing of the right middle cerebral artery bifurcation. AC C EP TE D M AN U SC Figure 3: Arterial spin labeling images with asymmetric blood flow, diminished on right, though improved from initial study from one week after Figure 1.