Accepted Manuscript “Sentinel seizure” as a warning sign preceding fatal rupture of a giant middle cerebral artery aneurysm Lukas Andereggen, MD, Robert H. Andres, MD PII: S1878-8750(17)30177-8 DOI: 10.1016/j.wneu.2017.02.017 Reference: WNEU 5248 To appear in: World Neurosurgery Received Date: 31 October 2016 Revised Date: 1 February 2017 Accepted Date: 2 February 2017 Please cite this article as: Andereggen L, Andres RH, “Sentinel seizure” as a warning sign preceding fatal rupture of a giant middle cerebral artery aneurysm, World Neurosurgery (2017), doi: 10.1016/ j.wneu.2017.02.017. 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 1 “Sentinel seizure” as a warning sign preceding fatal rupture of a giant 2 middle cerebral artery aneurysm 3 4 Lukas Andereggen, MD1,2 and Robert H. Andres, MD1 5 1 Department of Neurosurgery, University of Bern, Inselspital, Bern, Switzerland 7 2 Department of Neurosurgery and F.M. Kirby Neurobiology Center, Boston 8 RI PT 6 Children’s Hospital, Harvard Medical School, Boston, MA, USA 11 Robert H. Andres, MD 12 Department of Neurosurgery 13 University of Bern 14 Inselspital, Freiburgstrasse 10 15 3010 Bern 16 Switzerland 17 E- Mail robert.andres@hin.ch 18 Phone +41 31 991 79 79 19 Fax +41 31 991 31 69 22 23 24 Keywords: aneurysm, sentinel headache, seizure, and subarachnoid hemorrhage EP 21 Short title: “Sentinel seizure” preceding aneurysmal rupture AC C 20 M AN U Correspondence: TE D 10 SC 9 25 Abbreviations: CT = computed tomography; MCA = middle cerebral artery; SAH = 26 subarachnoid hemorrhage; SH = sentinel headache. 27 28 Ethical standards and patient consent: This study was approved by the Ethical Committee 29 of Bern (Kantonale Ethikkommision, KEK, Bern, Switzerland), the Swiss Ethic Committee 30 on research involving humans. The study has been performed in accordance with the ethical 31 standards laid down in the 1964 Declaration of Helsinki and its later amendments. 32 1 ACCEPTED MANUSCRIPT 33 Competing interests: This work or part of this work has not been previously published. The 34 authors report no conflict of interest concerning the materials or methods used in this study or 35 the findings specified in this paper. 36 Funding: 38 This research did not receive any specific grant from funding agencies in the public, 39 commercial, or not-for-profit sectors. RI PT 37 40 41 SC 42 43 44 ABSTRACT: 46 Background: Sentinel headache is a well-known warning sign preceding subarachnoid 47 hemorrhage (SAH) due to rupture of an intracranial aneurysm. New-onset seizure or “sentinel 48 seizure” preceding aneurysmal SAH, however, is uncommon. 49 Case Description: We report on a 51-year-old man who presented with a new-onset seizure. 50 Diagnostic work-up revealed a giant middle cerebral artery aneurysm without evidence of 51 subarachnoid or intracerebral hemorrhage. Anti-epileptic therapy was initiated, elective 52 diagnostic angiography and subsequent treatment was scheduled and the patient discharged 53 home. Four days later, he suddenly lost consciousness and subsequently died due to a 54 massive aneurysmal SAH. 55 Conclusions: As with sentinel headache, new-onset seizures in patients with unruptured 56 intracranial aneurysms might prompt immediate treatment to prevent imminent SAH with its 57 subsequent high morbidity and mortality. 59 60 TE D EP AC C 58 M AN U 45 61 62 63 64 65 66 2 ACCEPTED MANUSCRIPT BACKGROUND 68 Sentinel headache (SH) is a well-known warning sign for aneurysmal subarachnoid 69 hemorrhage (SAH).1 SH may precede aneurysmal rupture by hours to weeks. Its incidence 70 ranges from 10% to 60% of all patients eventually admitted with aneurysmal SAH.2 Mortality 71 is high, given that SH is strongly related to a higher risk of aneurysmal rupture.3, 4 Hence, 72 distinguishing SH from innocuous headache is essential for preventing a fatal outcome. New- 73 onset seizure or “sentinel seizure” has not previously been described as a warning sign of 74 aneurysmal rupture and SAH, although the mechanisms might be similar to those reported in 75 SH. RI PT 67 SC 76 CASE DESCRIPTION 78 A previously healthy 51-year-old man with a history of migraine was referred to the 79 emergency department due to a new-onset secondary generalized tonic–clonic seizure lasting 80 for 10 minutes. No history of hypertension was recorded. Initial blood pressure at presentation 81 was 148/80 mmHg, which had dropped to 125/70 mmHg at first discharge. No injuries were 82 detected upon clinical examination apart from tongue bites. A non-enhanced cerebral 83 computed tomography (CT) scan showed a hyperdensity measuring 27 × 25 × 26 mm, at the 84 left M1 trunk of the middle cerebral artery (MCA). There was no distinct radiological 85 evidence of SAH, either in the non-enhanced cerebral computed tomography scan (CT scan, 86 Fig. 1A), or in the magnetic resonance imaging using fluid attenuated inversion recovery 87 (FLAIR) of the magnetic resonance images (Fig. 1B) at the time of seizure, which yields a 88 higher detection rate for subarachnoid hemorrhage (SAH) than CT alone.2, 5 However, the 89 perfused portion of the aneurysm showed an irregular shape in the CT-angiographic 90 reconstruction (Fig. 1A, insert) – a known risk factor for aneurysmal rupture. 6 The 91 subsequent magnetic resonance angiography (MRA) revealed a giant, partially thrombosed 92 aneurysm arising at the junction of the M1 and M2 segments of the left MCA (Fig. 1C). 93 Moreover, there was no evidence of perianeurysmal edema at the time of the seizure (Fig. 94 1B), a predictive sign of aneurysmal rupture including risk for immediate rupture. 7 95 The subsequent magnetic resonance angiography (MRA) revealed a giant, partially 96 thrombosed aneurysm arising at the junction of the M1 and M2 segments of the left MCA 97 (Fig. 1C). No xanthochromia of the cerebrospinal fluid (CSF) was detected 12 hours 98 following the epileptic seizure. Past medical history and family history of intracranial 99 aneurysms or SAH were negative. Neurological examination was normal. Anti-epileptic 100 therapy with levetiracetam was initiated. The patient was scheduled for elective diagnostic AC C EP TE D M AN U 77 3 ACCEPTED MANUSCRIPT angiography with subsequent treatment and was discharged home. Four days later, his wife 102 found him comatose. Upon arrival at the emergency department, he presented with bilaterally 103 fixed, dilated pupils. CT revealed acute aneurysmal rupture with massive SAH and left 104 temporal and intraventricular hemorrhage, as well as midline shift, uncal herniation and 105 hypodensity of the brain stem (Fig. 1D and E). CT angiography showed circulatory arrest 106 (Fig. 1F), and the diagnosis of brain death was established by clinical criteria. RI PT 101 107 DISCUSSION 109 To the best of our knowledge, new-onset seizures or “sentinel seizures” have not been 110 described as a warning sign of aneurysmal rupture or SAH. A few cases of unruptured 111 aneurysms associated with epilepsy have been reported; these were most likely related to 112 subclinical hemorrhages,8 presence of thrombus9, 10 or aneurysm location related to the 113 temporomesial region,11-13 but none of these aneurysms were related to the index SAH, or 114 associated with SAH several days following diagnosis. As for SH, warning symptoms may 115 occur a few hours up to a few months prior to SAH and suggest minor leaks (sentinel bleeds) 116 or structural changes within the aneurysm wall, mostly characterized by severe headache with 117 the characteristics of SAH.2 SH may also precede aneurysmal rupture without any bleeding.14 118 Jea et al. reported on a 48-year-old man suffering from a giant internal carotid artery– 119 ophthalmic artery aneurysm, who experienced a potential warning bleed with subsequent 120 visual deterioration but evidence of SAH was absent on imaging scans and upon operative 121 exploration.15 It might be plausible that minor leaks, as described in SH, result in cortical 122 irritation and subsequent seizures. In the present case, the new-onset seizure might have been 123 provoked by microbleeding in the brain, changes in the aneurysmal wall, or intraaneurysmal 124 thrombus formation with subsequent cortical irritation- suggested mechanisms described in 125 patients with unruptured giant aneurysms presenting with seizures.10, 13 As for cerebral 126 microbleeding, the absence of subarachnoid blood in the MRI might be due to the 127 concentration of hemoglobin being below the detection threshold of fluid attenuated inversion 128 recovery (FLAIR) sequences (Fig. 1B). In fact, FLAIR MRI sequences were only positive in 129 16.7% of cases where CT findings were negative for SAH that was confirmed by lumbar 130 puncture.16 Despite the high sensitivity and specificity of a CT scan plus lumbar puncture in 131 detecting SAH,17 negative findings in patients with SH have been described, similar to the 132 results of our diagnostic work-up in the patient with “sentinel seizures”.18 The fact that the 133 patient had suffered from migraine for the past 10 years probably did not contribute to the 134 higher risk of SAH. A recent meta-analysis concluded that migraine potentially increases the AC C EP TE D M AN U SC 108 4 ACCEPTED MANUSCRIPT risk of hemorrhagic stroke;19 however, evidence as to whether there is an increased risk for 136 SAH in migraineurs remains ambiguous.20 Similar controversy exists as to whether there is a 137 higher prevalence of seizures in patients with migraine,21 and no increased prevalence of SH 138 in patients with migraine has been described.22 139 To sum up, the presence of “sentinel seizures” may act as a warning sign for aneurysmal 140 SAH, as is known to be the case for SH. Proper identification, decision-making and initiation 141 of therapy is essential in an attempt to prevent aneurysmal rupture with its subsequent high 142 morbidity and mortality. The impact of “sentinel seizures” requires further clarification to 143 confirm its importance as a warning sign preceding aneurysmal SAH and we are aware that 144 no firm conclusion can be drawn based on one single case report with a seizure episode in the 145 absence of significant perianeurysmal edema. Nevertheless, we feel that immediate treatment 146 may be warranted until the significance of this potentially harmful feature becomes clearer. SC RI PT 135 M AN U 147 148 Acknowledgment: The assistance of Ms. Susan Kaplan in editing this manuscript is 149 acknowledged. 150 151 REFERENCES 153 154 1. 155 Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. The New England journal of medicine. Jan 6 2000;342(1):29-36. 2. Oda S, Shimoda M, Hirayama A, et al. Neuroradiologic Diagnosis of Minor Leak EP 156 TE D 152 157 prior to Major SAH: Diagnosis by T1-FLAIR Mismatch. AJNR. American journal of 158 neuroradiology. Sep 2015;36(9):1616-1622. 3. 160 aneurysmal subarachnoid hemorrhage. Stroke; a journal of cerebral circulation. Nov 161 162 Beck J, Raabe A, Szelenyi A, et al. Sentinel headache and the risk of rebleeding after AC C 159 2006;37(11):2733-2737. 4. Biesbroek JM, Rinkel GJ, Algra A, van der Sprenkel JW. Risk factors for acute 163 subdural hematoma from intracranial aneurysm rupture. Neurosurgery. Aug 164 2012;71(2):264-268; discussion 268-269. 165 5. Verma RK, Kottke R, Andereggen L, et al. Detecting subarachnoid hemorrhage: 166 comparison of combined FLAIR/SWI versus CT. European journal of radiology. Sep 167 2013;82(9):1539-1545. 5 ACCEPTED MANUSCRIPT 168 6. Lindgren AE, Koivisto T, Bjorkman J, et al. Irregular Shape of Intracranial Aneurysm 169 Indicates Rupture Risk Irrespective of Size in a Population-Based Cohort. Stroke; a 170 journal of cerebral circulation. May 2016;47(5):1219-1226. 171 7. Pahl FH, de Oliveira MF, Ferreira NP, de Macedo LL, Brock RS, de Souza VC. Perianeurysmal edema as a predictive sign of aneurysmal rupture. Journal of 173 neurosurgery. Nov 2014;121(5):1112-1114. 174 8. RI PT 172 Lin F, Wan H, Kang D, Lin Y. Small Unruptured Intracranial Aneurysm (