Accepted Manuscript A pediatric case of reversible cerebral vasoconstriction syndrome with similar radiographical findings to posterior reversible encephalopathy syndrome Tomoya Kamide, Taishi Tsutsui, Kouichi Misaki, Hiroki Sano, Masanao Mohri, Naoyuki Uchiyama, Mitsutoshi Nakada PII: S0887-8994(16)30725-1 DOI: 10.1016/j.pediatrneurol.2017.02.008 Reference: PNU 9089 To appear in: Pediatric Neurology Received Date: 24 September 2016 Revised Date: 8 February 2017 Accepted Date: 12 February 2017 Please cite this article as: Kamide T, Tsutsui T, Misaki K, Sano H, Mohri M, Uchiyama N, Nakada M, A pediatric case of reversible cerebral vasoconstriction syndrome with similar radiographical findings to posterior reversible encephalopathy syndrome, Pediatric Neurology (2017), doi: 10.1016/ j.pediatrneurol.2017.02.008. 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. 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ACCEPTED MANUSCRIPT A pediatric case of reversible cerebral vasoconstriction syndrome with similar RI PT radiographical findings to posterior reversible encephalopathy syndrome Tomoya Kamidea, Taishi Tsutsuia, Kouichi Misakia, Hiroki Sanob, Masanao Mohria, M AN U a SC Naoyuki Uchiyamaa, Mitsutoshi Nakadaa Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan b Department of Neurosurgery, Kanazawa Municipal Hospital, Kanazawa, Ishikawa, TE D Japan EP Corresponding author: Tomoya Kamide AC C Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan Phone: +81-76-265-2384, Fax: +81-76-234-4262 E-mail: kamide@med.kanazawa-u.ac.jp 1 ACCEPTED MANUSCRIPT Word count: 2,013 AC C EP TE D M AN U SC RI PT Running title: Pediatric thunderclap headache 2 ACCEPTED MANUSCRIPT Abstract RI PT Background: Reversible cerebral vasoconstriction syndrome predominantly occurs in middle-aged women. Only 9 pediatric cases of this syndrome have ever been reported. SC Case report: Here we present a pediatric case of reversible cerebral vasoconstriction M AN U syndrome (RCVS) with similar radiographical findings to posterior reversible encephalopathy syndrome (PRES). A 10-year-old healthy boy developed thunderclap headache with no neurological deficit. Brain magnetic resonance angiography (MRA) revealed multifocal narrowing of the cerebral arteries, while magnetic resonance TE D imaging (MRI) with diffusion-weighted imaging and fluid-attenuated inversion recovery demonstrated hyperintense lesions in the bilateral occipital lobes and the left EP cerebellum. The patient’s clinical symptoms resolved spontaneously after a few hours AC C and no recurrence was reported thereafter. MRA on the 2nd day showed a complete normalization of the affected arteries and MRI after 1 month demonstrated a significant improvement in the abnormal findings, leading to a diagnosis of RCVS with similar radiographical findings to PRES. Conclusions: This report suggests that, although rare, RCVS with or without PRES, should be considered in pediatric patients if they present with a thunderclap headache. 3 ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC syndrome, posterior reversible encephalopathy syndrome RI PT Key words: pediatric, thunderclap headache, reversible cerebral vasoconstriction 4 ACCEPTED MANUSCRIPT Introduction RI PT Reversible cerebral vasoconstriction syndrome (RCVS) is a clinico-radiological condition characterized by severe, often thunderclap, headaches with or without SC concomitant neurological signs and symptoms, in the context of reversible M AN U vasoconstriction of the cerebral arteries [1]. RCVS may occur spontaneously or may be provoked by various precipitating factors, such as pregnancy-related factors, drugs, headache disorders, medical problems, surgical procedures, and blood product transfusions [2]. The clinical features of RCVS are also common to posterior reversible TE D encephalopathy syndrome (PRES), which is characterized by symmetrical areas of vasogenic edema of the white matter predominantly localized to the territories of the EP posterior circulation in patients with acute neurological symptoms (e.g., seizures, AC C encephalopathy, headache, and visual disorders). PRES is diagnosed in the settings of renal failure, blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia, but has also been reported to occur in individuals with RCVS [3]. RCVS is mostly observed in middle-aged women. In fact, only 9 pediatric cases of RCVS have ever been reported [1, 4-9]. Among the pediatric cases, only 1 5 ACCEPTED MANUSCRIPT patient with Loeys-Dietz syndrome, which is an autosomal dominant connective tissue disease, exhibited RCVS together with PRES [1]. In this report, we describe an RI PT extremely rare case of a healthy pediatric patient diagnosed with RCVS with similar SC radiographical findings to PRES. M AN U Case report A 10-year-old boy presented with a sudden-onset, throbbing, severe, diffuse headache with a verbal numeric pain scale of 10/10 intensity without other neurological deficits TE D after mild exercise. He developed several moderate to severe headaches after karate, which is a traditional Japanese system of unarmed combat, in the two weeks prior to his EP visit. He was born through Caesarean section at 32 weeks’ gestation and weighed 1,600 AC C g, but his development was normal. He had no history of headache and his family history was negative for headache, migraine, or premature vascular disease, although his mother was diagnosed with antiphospholipid syndrome. He was not taking medication and denied alcohol, tobacco, or substance misuse. He went to the emergency department of another hospital and was referred to our hospital because his brain imaging results had abnormal findings. 6 ACCEPTED MANUSCRIPT Upon admission, the patient’s headache had completely disappeared and his neurological examination was unremarkable. His blood pressure was 140/92 mmHg and RI PT laboratory findings, including blood cell counts and chemistries, were normal. Serology demonstrated normal inflammatory markers, autoimmune profile, complement and SC immunoglobulin levels, and procoagulant screen results. Cerebrospinal fluid (CSF) M AN U examination indicated normal opening pressure and no abnormal findings. Brain magnetic resonance angiography (MRA) showed multiple, segmental, mild to moderate narrowings of the bilateral middle cerebral arteries (MCAs) and the right posterior cerebral artery (PCA) (Fig. 1a). Brain magnetic resonance imaging (MRI) revealed large bilateral hyperintense TE D relatively lesions of the occipital lobes on diffusion-weighted images (DWI, Fig. 2c) and fluid-attenuated inversion recovery EP (FLAIR, Fig. 2d), in addition to a lesion that was not visualized on DWI (Fig. 2a), but AC C was visible on the left cerebellum on FLAIR (Fig. 2b). This lesion corresponded to a cerebral infarction. After admission, the patient’s blood pressure returned to the normal range (90-100/60-70 mmHg) spontaneously and he was carefully observed without medication. A follow-up MRA on day 2 revealed a complete resolution of the vascular stenosis of the MCAs and the PCA (Fig. 1b), although DWI and FLAIR images 7 ACCEPTED MANUSCRIPT revealed maturation of the hyperintense lesions. Furthermore, contrast high-resolution MRI demonstrated no findings of vessel wall thickening or enhancement. No additional RI PT headaches occurred and the patient was discharged on day 9 without any neurological deficits. Follow-up MRI after 1 month showed notable improvement of the DWI and SC FLAIR hyperintense lesions (Figs. 2e-h). Further repeat MRI and MRA after 3 and 6 M AN U months remained unchanged and the patient remained headache-free for >6 months. Discussion TE D RCVS is characterized by thunderclap headaches with or without neurological deficits, benign CSF analysis, and multifocal segmental areas of cerebral arterial narrowing or EP vasoconstriction that usually resolve within weeks. We observed all of the above AC C characteristics in our case. Ischemic infarctions are the most common complicated lesions found in several cohort analyses, and occur in 6-39% of cases. These infarctions tend to occur in arterial watershed areas [2]. RCVS mainly occurs in middle-aged adults and only 9 pediatric cases have ever been reported (Table 1) [1, 4-9]. The majority of the pediatric cases are in boys, while adult cases mainly occur in women [1, 4]. Pediatric arterial ischemic stroke also occurs predominantly in boys. Normann et al. 8 ACCEPTED MANUSCRIPT have reported that testosterone levels above the 90th percentile for age and sex are documented in 16.7% of pediatric patients with stroke, when compared to 1.8% in RI PT control patients [10]. In fact, Probert et al. have discussed the possibility that testosterone affects the male dominance of pediatric RCVS cases [8]. However, it is SC unclear whether this association is indeed present. M AN U PRES is a clinical syndrome with acute neurological findings resulting from the disruption of the blood-brain barrier and accompanies evidence of vasogenic edema on brain imaging [11]. Endothelial dysfunction is a key factor in PRES, but vascular stenosis is not a major finding [3]. The radiological features of PRES include TE D subcortical vasogenic edema that predominantly involves the bilateral parieto-occipital regions and resolves within days or weeks. The presence of restricted diffusion is EP compatible with a diagnosis of PRES. Moreover, Fugate et al. have reported that brain AC C edema is not uncommon in cases of PRES affecting regions other than the classic parieto-occipital areas [3]. For example, edema can affect the cerebellum in up to half of the patient population, as observed in the present case. A diagnosis of PRES should be considered in several different settings, although cases such as ours have similar radiological findings. Hypertension is common in pediatric PRES, although blood pressure at the 9 ACCEPTED MANUSCRIPT onset of PRES is lower because the cerebral blood flow autoregulation threshold is lower in children than in adults [3]. In fact, Siebert et al. have reported that the mean RI PT blood pressure at the time of presentation in pediatric patients with PRES in three medical centers in Germany was 140/85 mmHg, as in our case [12]. It is unclear SC whether our patient can be diagnosed with PRES without typical clinical symptoms, M AN U such as seizure, encephalopathy, and visual disturbance, although PRES has been reported in 17-38% of patients with RCVS [3]. Pediatric cases of PRES occur occasionally [11], although pediatric patients with both RCVS with PRES are extremely rare, probably due to the fact that RCVS mainly occurs in middle-aged adults. Akazawa TE D et al. reported the first pediatric case of RCVS with PRES [1]. However, the patient may have also had endothelial dysfunction associated with an underlying condition, which EP was diagnosed genetically as Loeys-Dietz syndrome. Therefore, this is the first healthy AC C pediatric case diagnosed with RCVS, with similar radiographical findings to PRES. In our case, cerebral arterial narrowing was completely resolved within 1 day of the initial evaluation, although the vascular changes may have begun when the patient had the mild headaches before admission. Since the affected arteries may improve within a few days, a large number of patients with RCVS may be undiagnosed. Furthermore, many more pediatric patients with RCVS with or without PRES may exist, 10 ACCEPTED MANUSCRIPT as the diagnosis of pediatric cases is particularly difficult given the need for MRI and MRA [5, 13]. This is especially true for healthy children without neurological deficits. RI PT In conclusion, we report the first healthy pediatric case of RCVS with similar radiographical findings to PRES. Pediatric cases of RCVS are rare, but a larger number SC of cases may be detected as more and more MRIs and MRAs are performed in pediatric M AN U patients with severe headaches. We emphasize that RCVS with or without PRES should AC C EP TE D be considered in pediatric patients with thunderclap headaches. 11 ACCEPTED MANUSCRIPT Funding: none. RI PT Informed consent The parent of the patient has consented to the submission of this case report to the AC C EP TE D Conflicts of interest: none. M AN U SC journal. 12 ACCEPTED MANUSCRIPT Figure legends RI PT FIGURE 1. (a) Brain magnetic resonance angiography (MRA) on the 1st day of admission showing multiple, bilateral segmental narrowings of the middle cerebral SC artery and the right posterior cerebral artery (arrow). (b) Follow-up MRA on the 2nd M AN U day showing complete resolution of the cerebral artery constrictions. FIGURE 2. Brain magnetic resonance imaging (MRI) on the 1st day of admission showing relatively large hyperintense lesions of the left cerebellum on fluid-attenuated TE D inversion recovery (FLAIR), (b) but not on diffusion-weighted imaging (DWI) (a). The bilateral occipital lobes contain hyperintense lesions on both DWI (c) and FLAIR (d). EP Follow-up MRI DWI (e, g) and FLAIR (f, h) after 1 month showing marked AC C improvements in the bilateral occipital lobe and the left cerebellum lesions. Table 1. Clinical and radiological features of pediatric cases with reversible cerebral vasoconstriction syndrome in published literature 13 ACCEPTED MANUSCRIPT References Akazawa Y, Inaba Y, Hachiya A, et al. Reversible cerebral vasoconstriction 2. syndrome and posterior reversible encephalopathy syndrome in a boy with Loeys-Dietz syndrome. Am J Med Genet A 2015;167:2435-2439. Mehdi A, Hajj-Ali RA. Reversible cerebral vasoconstriction syndrome: a comprehensive update. Curr Pain Headache Rep 2014;18:443. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. The Lancet Neurology 2015;14:914-925. SC 3. RI PT 1. Ghosh PS, Rothner AD, Zahka KG, Friedman NR. Reversible Cerebral Vasoconstriction Syndrome: A Rare Entity in Children Presenting With Thunderclap Headache. J Child Neurol. 2011;26:1580-1584. 5. Kazato Y, Fujii K, Oba H, et al. Reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. Brain Dev 2012;34:696-699. Kirton A, Diggle J, Hu W, Wirrell E. A Pediatric Case of Reversible Segmental Cerebral Vasoconstriction. Can J Neurol Sci 2006;33:250-253. 9. 10. 11. 12. TE D 8. Liu HY, Fuh JL, Lirng JF, Chen SP, Wang SJ. Three paediatric patients with reversible cerebral vasoconstriction syndromes. Cephalalgia 2010;30:354-359. Probert R, Saunders DE, Ganesan V. Reversible cerebral vasoconstriction syndrome: rare or underrecognized in children? Dev Med Child Neurol 2013;55:385-389. Yoshioka S, Takano T, Ryujin F, Takeuchi Y. A pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage. Brain Dev 2012;34:796-798. Normann S, de Veber G, Fobker M, et al. Role of endogenous testosterone EP 7. AC C 6. M AN U 4. concentration in pediatric stroke. Ann Neurol 2009;66:754-758. Chen TH, Lin WC, Tseng YH, Tseng CM, Chang TT, Lin TJ. Posterior Reversible Encephalopathy Syndrome in Children: Case Series and Systematic Review. J Child Neurol 2013;28:1378-1386. Siebert E, Spors B, Bohner G, Endres M, Liman TG. Posterior reversible encephalopathy syndrome in children: radiological and clinical findings - a retrospective analysis of a German tertiary care center. Eur J Paediatr Neurol 2013;17:169-175. 14 ACCEPTED MANUSCRIPT Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral EP TE D M AN U SC RI PT arteriopathies. Cephalalgia 2011;31:1067-1070. AC C 13. 15 Table 1 : Clinical and radiological features of pediatric cases with reversible cerebral vasoconstriction syndrome in published literature ACCEPTED MANUSCRIPT Age (y) Sex Angiographical improvement Outcome 1 13 M CT : normal (day 1, 5), MRI : normal (day 5) Smooth narrowing of bilateral proximal vessels (day 6) day16 Headache free > 18 months 2 10 M MRI : small hyperintense lesion of the left occipital lobe and hyperintensities in the sulci of the bilateral posterior temporal and the occipital lobes on FLAIR (day 12) Multiple segmental narrowing in MCA and PCA bilaterally (day 4) day 44 Headache free > 3 months 3 16 M Not described Multiple segmental narrowing over bilateral PCAs and irregularity of left MCA 2 months Headache free > 2 years 4 10 M Not described Multiple segmental narrowing over bilateral MCAs and PCAs day 31 Headache free > 2 years 5 15 M CT : normal (day 2), MRI : normal (day 2) Multifocal vascular irregularities of posterior and anterior circulation (day 4, 6) 6 weeks Headache free > 3 months 6 12 M CT : normal (day 1), MRI : cortical SAH of the right occipital, the left frontal, and the bilateral parietal lobes (day 5) Multifocal narrowing of cerebral arteries (day 5) 3 months Headache free > 3 months 7 7 F CT : parenchymal hemorrhage of the left occipital and parietal lobes (day 2), MRI : post hemorrhagic (day 28) Diffuse cerebral vasoconstriction (day 28) day 60 Not described (Aplastic anemia) 8 13 M CT : normal (day 5), MRI : multiple acute infarcts in the territory of the posterior circulation (day 12) Beading and stenosis of both VAs, ICAs, and MCAs (day 18) 5 weeks Headache free > 3 years 9 9 M MRI : cortical SAH of the right parietal lobe (day 1), hyper lesions of the left posterior lobe, the right temporal lobe, and the bilateral cerebellum on FLAIR (day 6) Mild narrowing of bilateral ICAs (day 1) Significant narrowing of bilateral ICAs (day 5) 2 months Not described (Loeys-Dietz syndrome) Present case 10 M MRI : large hyper lesions of the bilateral posterior lobes and the left cerebellum on DWI and FLAIR (day 1) Multiple, segmental, mild to moderate narrowing of bilateral MCAs and right PCA (day 1) day 2 Headache free > 6 months Cerebrovascular imaging RI PT Brain imaging M AN U SC Case AC C EP TE D M, male; F, female; CT, computed tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; MCA, middle cerebral artery; PCA, posterior cerebral artery; SAH, subarachnoid hemorrhage; VA, vertebral artery; ICA, internal carotid artery; DWI, diffusion weighted imaging. AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT