- Email: [email protected]
Subarachnoid Hemorrhage After Ischemic Stroke Associated with Systemic Lupus Erythematosus and Antiphospholipid Syndrome
Journal Pre-proof Subarachnoid hemorrhage after ischemic stroke associated with systemic lupus erythematosus and antiphospholipid syndrome - Case report Eisuke Tsukamoto, M.D., Takafumi Tanei, Ph.D., M.D., Joe Senda, Ph.D., M.D., Takenori Kato, Ph.D., M.D., Takehiro Naito, Ph.D., M.D., Kazuki Ishii, M.D., Ko Okada, M.D., Toshinori Hasegawa, Ph.D., M.D. PII:
S1878-8750(20)30037-1
DOI:
https://doi.org/10.1016/j.wneu.2020.01.030
Reference:
WNEU 14059
To appear in:
World Neurosurgery
Received Date: 21 November 2019 Accepted Date: 6 January 2020
Please cite this article as: Tsukamoto E, Tanei T, Senda J, Kato T, Naito T, Ishii K, Okada K, Hasegawa T, Subarachnoid hemorrhage after ischemic stroke associated with systemic lupus erythematosus and antiphospholipid syndrome - Case report -, World Neurosurgery (2020), doi: https://doi.org/10.1016/ j.wneu.2020.01.030. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Elsevier Inc. All rights reserved.
TSUKAMOTO E ET AL.
Subarachnoid
hemorrhage
after
ischemic
stroke
associated
with
systemic
lupus
erythematosus and antiphospholipid syndrome - Case report -
Eisuke Tsukamoto, M.D.1, Takafumi Tanei, Ph.D., M.D.1, Joe Senda, Ph.D., M.D.2, Takenori Kato, Ph.D., M.D.1, Takehiro Naito, Ph.D., M.D.1, Kazuki Ishii, M.D.1, Ko Okada, M.D.1, Toshinori Hasegawa, Ph.D., M.D.1
1. Department of Neurosurgery, Komaki City Hospital, Komaki, Japan 2. Department of Neurology, Komaki City Hospital, Komaki, Japan
Corresponding author: Eisuke Tsukamoto, M.D. Address: Department of Neurosurgery, Komaki City Hospital 1-20 Jobushin, Komaki, 485-8520, Japan E-mail: [email protected] Tel: +81-568-76-4131; Fax: +81-568-76-4145
Key words: systemic lupus erythematosus, antiphospholipid syndrome, subarachnoid hemorrhage, fusiform aneurysm, ischemic stroke
Running head: SAH after infarction with SLE and APS
TSUKAMOTO E et al. 1
INTRODUCTION Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex mediated lesions in the blood vessels of multiple organs. Immune complexes cause vasculitis in small vessels, which can induce systemic inflammation in different organ systems.1 The central nervous system is affected in 25–50% of SLE patients, with presentations such as seizure, psychosis, and cerebrovascular events.2 SLE is associated with an increased risk of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH).3 Further, stroke in patients with SLE is often more severe compared to the general population, and accounts for 10–15% of deaths from SLE.4 Antiphospholipid syndrome (APS) is another autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis, frequently overlapping with other diseases, typically SLE.5 Here, we report the case of a patient presenting with SAH after ischemic stroke associated with SLE and APS.
CASE DESCRIPTION A 22-year-old man suddenly developed left hemiplegia and dysarthria, although symptoms improved within a few minutes. Magnetic resonance (MR) images showed cerebral infarction in the right corona radiata (Fig. 1A). He had no contributory past or family histories. At the same time, aneurysm of the right anterior cerebral artery (ACA) was incidentally suggested on MR angiography (Fig. 1B). Cerebral angiography confirmed a 4-mm fusiform aneurysm at the right ACA (Fig. 1C, D). The incidental aneurysm was not treated during this hospitalization. Several screening examinations were performed to detect causes inducing juvenile cerebral infarction. No abnormalities or abnormal lesions were apparent from cardiac or carotid echography or whole-body computed tomography (CT). Blood examinations detected some abnormal positive findings, such as antinuclear antibody (640; reference range, <39), lupus anticoagulant (1.49; reference range, <1.29) and anti-β2-glycoprotein-І (aβ2-GPI) antibody (9.5 U/mL; reference range, <3.49 U/mL). These findings suggested SLE, but did not fulfill the diagnostic criteria at that time. Ten days later, he was discharged from our hospital without any neurological deficits. He was treated with oral
TSUKAMOTO E et al. 2
antiplatelets on outpatient visits. We introduced him to a specialist in autoimmune diseases at another hospital, where he underwent detailed laboratory examinations (Table 1). Overall results of examinations and clinical symptoms confirmed the diagnosis of APS. Seventy days after the first ischemic stroke, he presented with sudden headache. CT showed subarachnoid hemorrhage (Fig. 2A). Cerebral angiography depicted the same fusiform aneurysm of the ACA without any change in shape, and no new aneurysms were evident. We therefore diagnosed SAH from rupture of the fusiform aneurysm of the ACA. Balloon occlusion testing of the right ACA for 20 min was performed without causing any neurological symptoms. The right ACA was therefore trapped using coils (Fig. 2B, C). After coil embolization, cerebral angiography showed disappearance of the fusiform aneurysm, and bilateral ACAs were supplied by the left internal carotid artery (Fig. 2D, E). About 2 weeks after embolization, MR images showed no recurrence of the aneurysm and no new cerebral infarctions (Fig. 2F). Six months after discharge, he presented with new optic hyperesthesia and facial butterfly-shaped erythema. As the criteria for SLE were now fulfilled, a definitive diagnosis of SLE was made by the specialist in autoimmune diseases. As of 2 years after initial presentation, he has experienced no neurological deficits or recurrence of either aneurysm or ischemic stroke.
DISCUSSION Immune-mediated diseases such as ankylosing spondylitis, autoimmune hemolytic anemia, Crohn’s disease, hyperthyroid conditions, idiopathic thrombocytopenia purpura, pernicious anemia, psoriasis, rheumatoid arthritis and SLE are known to be associated with increased risks of ischemic and hemorrhagic stroke.6 Some immune-mediated diseases, particularly SLE, are strongly associated with a high risk of SAH.7 A previous study reported that 10 of 1077 SLE patients presented with SAH (0.93%), and mean age at onset was 37.4 ± 15.25 years.4 In SAH with SLE, 60% of patients showed severe clinical grade and a saccular aneurysm was identified in only 50%.8 The risk ratio of overall stroke in SLE patients compared to the general population was 2.53, and those of stroke subtypes were: ischemic stroke, 2.10; intracerebral hemorrhage, 2.72; and SAH,
TSUKAMOTO E et al. 3
3.85. The highest relative risk of SAH was observed at ages younger than 50 years old.3 Increasing risk factors for stroke in patients with SLE were within 1 year of diagnosis of SLE and prescription of a steroid, which may indicate high disease activity.9 Some diseases occurring concomitant with SLE, such as APS, immune deposits, and Libman-Sacks endocarditis may contribute to an increased risk of thrombosis. APS is recognized by clinical manifestations including deep vein thrombosis, stroke, and heart attack. Single-vessel or multiple vascular occlusions may give rise to a wide variety of presentations in APS. APS can be found in laboratory examinations as the presence of pathogenic autoantibodies known as antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies, or aβ2-GPI antibodies.5 Around 40% of patients with SLE show antiphospholipid antibodies, which can induce a pro-thrombotic status decreasing the thrombophilic threshold by inducing a prothrombotic, pro-inflammatory phenotype in endothelial cells.10 A trigger acting as a second hit will then induce thrombotic events.11 About 53% of APS patients show neither clinical nor laboratory evidence of any other definable condition (primary APS), and 36% patients display an association with SLE.12 Some SLE patients do not initially exhibit symptoms of SLE; instead APS could exist as a primary syndrome.13 APS patients with previous vascular embolic events are treated using anti-platelet agents and/or anticoagulants.5 The endothelial dysfunction and vasculitis seen in SLE may lead to intracranial hemorrhage and the development of cerebral aneurysm, increasing the risk of SAH.14,15 The ratio of saccular aneurysms in SLE patients appears low compared to the general population, whereas uncommon aneurysms such as fusiform or pseudo-aneurysms are more often detected.8,16,17 Several cases of SLE patients with SAH did not reveal any aneurysms on angiography.16,18 In the general population, such cases of SAH with angio-negative aneurysm tend to be older and usually follow a benign clinical course.19 On the other hand, SLE patients showing SAH with angio-negative aneurysm are often relatively young and show a high mortality rate.8,16,17 Reasons for the increased incidence of SAH in SLE patients remain unclear. Classical risk factors for SAH such as atherosclerosis and hypertension are relevant complications among SLE patients. The treatment of
TSUKAMOTO E et al. 4
SLE in the acute phase is medical therapy with steroids and/or cytotoxic immunosuppressants. These drugs can also cause hypertension as a side effect.20 Daily use of high-dose steroid (>10 mg/day) represents an independent risk factor for increasing incidence of SAH.9 Saccular aneurysms would be induced by atherosclerosis and hypertension. Inflammation of the arteries narrows the arterial lumen, compromises cerebral blood flow, and causes a variety of atherosclerotic-like symptoms leading to hemodynamic stress. Furthermore, focal vasculitis could be a cause of the uncommon aneurysms in unusual locations.17 Focal vasculitis could be related to the incidence of fusiform aneurysms, which have proven anatomopathlogical findings supporting focal transmural angiitis.21 Pseudo-aneurysms with wall defect but without lymphocytic infiltration have also been reported.16 The arterial walls of these uncommon aneurysms were so fragile that the risk of rupture was high. Another feature of SLE patients is the higher frequency of multiple aneurysms. The incidences of single and multiple aneurysms among SLE patients were 69.5% and 31.6%, respectively.17,22 Therapeutic management of SAH in SLE patients has still not been established. The frequent hematologic and renal complications are important comorbidities for invasive procedures. Whichever surgical or endovascular procedures are chosen for aneurysm occlusion, these procedures are challenging because intracranial arterial walls are fragile and susceptible to prompt rupture.23 Treatment of fusiform aneurysms rarely involves direct clipping or coil embolization, and instead requires occlusion techniques like trapping with or without revascularization. The rupture of aneurysms might be related to SLE activity due to complications of arterial hypertension. Therefore, management for non-ruptured aneurysms among SLE patients to prevent rupture include treatment of active SLE and strict control of cardiovascular risk factors. In our case, no common risk factors for ischemic stroke were seen, such as hypertension, smoking history, carotid artery stenosis or cardiac dysrhythmia. The first ischemic stroke was thus considered to be induced by APS and underlying SLE. SLE was consequently diagnosed on presentation of additional clinical symptoms, such as optic hyperesthesia and facial butterfly-shaped erythema, despite symptoms at the first visit not fulfilling the SLE criteria. This means that the
TSUKAMOTO E et al. 5
incipient SLE gradually became activated. The patient had no history of hypertension or pharmacotherapy with steroid. Fusiform aneurysm of the ACA may occur due to focal vasculitis, with activation of SLE leading to aneurysm rupture.
CONCLUSIONS In cases involving young individuals presenting with stroke without any apparent risk factors, autoimmune diseases are one of the pathogeneses. When aneurysms are incidentally detected before definitive diagnosis of an autoimmune disease such as SLE, strict control of cardiovascular risk factors is warranted, with consideration of early therapeutic intervention for aneurysms because of the high risk of rupture.
INFORMED CONSENT Informed consent for the publication was obtained from the patient.
TSUKAMOTO E et al. 6
REFERENCES 1. Ramos-Casals M, Nardi N, Lagrutta M, et al. Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients. Medicine (Baltimore). 2006;85:95-104. 2. Muscal E, Brey RL. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin. 2010;28:61-73. 3. Holmqvist M, Simard JF, Asplund K, Arkema EV. Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies. RMD Open. 2015;1:e000168. 4. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82:299-308. 5. Pons-Estel GJ, Andreoli L, Scanzi F, Cervera R, Tincani A. The antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun. 2017;76:10-20. 6. Zöller B, Li X, Sundquist J, Sundquist K. Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. BMC Neurol. 2012;12:41. 7. Ramagopalan SV, Pakpoor J, Seminog O, Goldacre R, Graham L, Goldacre MJ. Risk of subarachnoid haemorrhage in people admitted to hospital with selected immune-mediated diseases: record-linkage studies. BMC Neurol. 2013;13:176. 8. Baizabal Carvallo JF, Cantú Brito C, Estañol B, García Ramos GS. Subarachnoid hemorrhage as a complication of systemic lupus erythematosus. Cerebrovasc Dis. 2007;24:301-304. 9. Chang YS, Liu CJ, Chen WS, et al. Increased risk of subarachnoid hemorrhage in patients with systemic lupus erythematosus: a nationwide population-based study. Arthritis Care Res (Hoboken). 2013;65:601-606. 10. Meroni PL, Borghi MO, Raschi E, et al. Inflammatory response and the endothelium. Thromb Res. 2004;114:329-334. 11. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive
TSUKAMOTO E et al. 7
patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20:206-218. 12. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019-1027. 13. Mackworth-Young CG, Loizou S, Walport MJ. Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis. 1989;48:362-367. 14. Fayyaz A, Igoe A, Kurien BT, et al. Haematological manifestations of lupus. Lupus Sci Med. 2015;2:e000078. 15. Feigin VL, Rinkel GJ, Lawes CM, et al. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke. 2005;36:2773-2780. 16. Torné R, Rodríguez-Hernández A, Bernard T, Arikan Abelló F, Vilalta Castan J, Sahuquillo J. Subarachnoid hemorrhage in systemic lupus erythematosus: systematic review and report of three cases. Clin Neurol Neurosurg. 2015;128:17-24. 17. Mimori A, Suzuki T, Hashimoto M, et al. Subarachnoid hemorrhage and systemic lupus erythematosus. Lupus. 2000;9:521-526. 18. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955-1977. Semin Arthritis Rheum. 1979;8:212-221. 19. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306-318. 20. Murphy G, Lisnevskaia L, Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013;382:809-818. 21. Asai A, Matsutani M, Kohno T, Fujimaki T, Takakura K. Multiple saccular cerebral aneurysms associated with systemic lupus erythematosus--case report. Neurol Med Chir (Tokyo). 1989;29:245-247. 22. Owada T, Takahashi K, Kita Y. Subarachnoid hemorrhage in systemic lupus erythematosus in
TSUKAMOTO E et al. 8
Japan: two case reports and a review of the literature. Mod Rheumatol. 2009;19:573-580. 23. Rodríguez-Hernández A, Zador Z, Rodríguez-Mena R, Lawton MT. Distal aneurysms of intracranial arteries: application of numerical nomenclature, predilection for cerebellar arteries, and results of surgical management. World Neurosurg. 2013;80:103-112.
FIGURE LEGENDS Fig. 1 A) Diffusion-weighted images show high-intensity areas at the right corona radiata. B) Magnetic resonance angiography suggests aneurysm of the right anterior cerebral artery. C, D) Cerebral angiography confirms a 4-mm fusiform aneurysm at the right anterior cerebral artery.
Fig. 2 A) Computed tomography shows subarachnoid hemorrhage. B, C) Right internal carotid angiography (oblique view) shows trapping of the right anterior cerebral artery using coils and disappearance of the fusiform aneurysm. D, E) Bilateral cerebral angiography (anterior-posterior views) shows disappearance of the fusiform aneurysm and bilateral anterior cerebral arteries supplied by the left internal carotid artery. F) About 2 weeks after embolization, magnetic resonance angiography shows no recurrence of the aneurysm.
Table 1 Details of laboratory data Reference range WBC (x102/µl)
68
50-80
22.9
30.3-40.5
RBC (x10 /µl)
510
450-510
Hemogrobin (g/dL)
15.7
13.9-16.0
Hematocrit (%)
44.9
41.4-49.2
25.8
18.0-35.0
C3 (mg/dL)
79
65-135
C4 (mg/dL)
15.8
13.0-35.0
CH50 (U/mL)
46.9
30.0-40.0
ANA
1280
<40
anti-ds-DNA antibody (IU/L)
102
<12
anti-β2-GPI antibody (U/mL)
8.3
<3.5
Lupus anticoagulant
1.71
<1.30
Lymphocyte (%) 4
4
Platelet (x 10 /µl)
anti-RNP antibody
negative
anti-Sm antibody
negative
urine protein
negative
urine RBC (HPF)
<1
<4
WBC: white blood cell, RBC: red blood cell, C: complement, CH50: 50% hemolytic unit of complement, ANA: antinuclear antibody, dsDNA: double-stranded deoxyribonucleic acid, β2-GPI: β2glycoprotein-І, RNP: ribonucleoprotein, Sm: smooth muscle, HPF: Hi power field
TSUKAMOTO E ET AL.
Abbreviation List ACA: anterior cerebral artery aβ2-GPI: anti-β2-glycoprotein-І APS: antiphospholipid syndrome CT: computed tomography MR: magnetic resonance SAH: subarachnoid hemorrhage SLE: systemic lupus erythematosus
S1878-8750(20)30037-1
DOI:
https://doi.org/10.1016/j.wneu.2020.01.030
Reference:
WNEU 14059
To appear in:
World Neurosurgery
Received Date: 21 November 2019 Accepted Date: 6 January 2020
Please cite this article as: Tsukamoto E, Tanei T, Senda J, Kato T, Naito T, Ishii K, Okada K, Hasegawa T, Subarachnoid hemorrhage after ischemic stroke associated with systemic lupus erythematosus and antiphospholipid syndrome - Case report -, World Neurosurgery (2020), doi: https://doi.org/10.1016/ j.wneu.2020.01.030. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Elsevier Inc. All rights reserved.
TSUKAMOTO E ET AL.
Subarachnoid
hemorrhage
after
ischemic
stroke
associated
with
systemic
lupus
erythematosus and antiphospholipid syndrome - Case report -
Eisuke Tsukamoto, M.D.1, Takafumi Tanei, Ph.D., M.D.1, Joe Senda, Ph.D., M.D.2, Takenori Kato, Ph.D., M.D.1, Takehiro Naito, Ph.D., M.D.1, Kazuki Ishii, M.D.1, Ko Okada, M.D.1, Toshinori Hasegawa, Ph.D., M.D.1
1. Department of Neurosurgery, Komaki City Hospital, Komaki, Japan 2. Department of Neurology, Komaki City Hospital, Komaki, Japan
Corresponding author: Eisuke Tsukamoto, M.D. Address: Department of Neurosurgery, Komaki City Hospital 1-20 Jobushin, Komaki, 485-8520, Japan E-mail: [email protected] Tel: +81-568-76-4131; Fax: +81-568-76-4145
Key words: systemic lupus erythematosus, antiphospholipid syndrome, subarachnoid hemorrhage, fusiform aneurysm, ischemic stroke
Running head: SAH after infarction with SLE and APS
TSUKAMOTO E et al. 1
INTRODUCTION Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex mediated lesions in the blood vessels of multiple organs. Immune complexes cause vasculitis in small vessels, which can induce systemic inflammation in different organ systems.1 The central nervous system is affected in 25–50% of SLE patients, with presentations such as seizure, psychosis, and cerebrovascular events.2 SLE is associated with an increased risk of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH).3 Further, stroke in patients with SLE is often more severe compared to the general population, and accounts for 10–15% of deaths from SLE.4 Antiphospholipid syndrome (APS) is another autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis, frequently overlapping with other diseases, typically SLE.5 Here, we report the case of a patient presenting with SAH after ischemic stroke associated with SLE and APS.
CASE DESCRIPTION A 22-year-old man suddenly developed left hemiplegia and dysarthria, although symptoms improved within a few minutes. Magnetic resonance (MR) images showed cerebral infarction in the right corona radiata (Fig. 1A). He had no contributory past or family histories. At the same time, aneurysm of the right anterior cerebral artery (ACA) was incidentally suggested on MR angiography (Fig. 1B). Cerebral angiography confirmed a 4-mm fusiform aneurysm at the right ACA (Fig. 1C, D). The incidental aneurysm was not treated during this hospitalization. Several screening examinations were performed to detect causes inducing juvenile cerebral infarction. No abnormalities or abnormal lesions were apparent from cardiac or carotid echography or whole-body computed tomography (CT). Blood examinations detected some abnormal positive findings, such as antinuclear antibody (640; reference range, <39), lupus anticoagulant (1.49; reference range, <1.29) and anti-β2-glycoprotein-І (aβ2-GPI) antibody (9.5 U/mL; reference range, <3.49 U/mL). These findings suggested SLE, but did not fulfill the diagnostic criteria at that time. Ten days later, he was discharged from our hospital without any neurological deficits. He was treated with oral
TSUKAMOTO E et al. 2
antiplatelets on outpatient visits. We introduced him to a specialist in autoimmune diseases at another hospital, where he underwent detailed laboratory examinations (Table 1). Overall results of examinations and clinical symptoms confirmed the diagnosis of APS. Seventy days after the first ischemic stroke, he presented with sudden headache. CT showed subarachnoid hemorrhage (Fig. 2A). Cerebral angiography depicted the same fusiform aneurysm of the ACA without any change in shape, and no new aneurysms were evident. We therefore diagnosed SAH from rupture of the fusiform aneurysm of the ACA. Balloon occlusion testing of the right ACA for 20 min was performed without causing any neurological symptoms. The right ACA was therefore trapped using coils (Fig. 2B, C). After coil embolization, cerebral angiography showed disappearance of the fusiform aneurysm, and bilateral ACAs were supplied by the left internal carotid artery (Fig. 2D, E). About 2 weeks after embolization, MR images showed no recurrence of the aneurysm and no new cerebral infarctions (Fig. 2F). Six months after discharge, he presented with new optic hyperesthesia and facial butterfly-shaped erythema. As the criteria for SLE were now fulfilled, a definitive diagnosis of SLE was made by the specialist in autoimmune diseases. As of 2 years after initial presentation, he has experienced no neurological deficits or recurrence of either aneurysm or ischemic stroke.
DISCUSSION Immune-mediated diseases such as ankylosing spondylitis, autoimmune hemolytic anemia, Crohn’s disease, hyperthyroid conditions, idiopathic thrombocytopenia purpura, pernicious anemia, psoriasis, rheumatoid arthritis and SLE are known to be associated with increased risks of ischemic and hemorrhagic stroke.6 Some immune-mediated diseases, particularly SLE, are strongly associated with a high risk of SAH.7 A previous study reported that 10 of 1077 SLE patients presented with SAH (0.93%), and mean age at onset was 37.4 ± 15.25 years.4 In SAH with SLE, 60% of patients showed severe clinical grade and a saccular aneurysm was identified in only 50%.8 The risk ratio of overall stroke in SLE patients compared to the general population was 2.53, and those of stroke subtypes were: ischemic stroke, 2.10; intracerebral hemorrhage, 2.72; and SAH,
TSUKAMOTO E et al. 3
3.85. The highest relative risk of SAH was observed at ages younger than 50 years old.3 Increasing risk factors for stroke in patients with SLE were within 1 year of diagnosis of SLE and prescription of a steroid, which may indicate high disease activity.9 Some diseases occurring concomitant with SLE, such as APS, immune deposits, and Libman-Sacks endocarditis may contribute to an increased risk of thrombosis. APS is recognized by clinical manifestations including deep vein thrombosis, stroke, and heart attack. Single-vessel or multiple vascular occlusions may give rise to a wide variety of presentations in APS. APS can be found in laboratory examinations as the presence of pathogenic autoantibodies known as antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies, or aβ2-GPI antibodies.5 Around 40% of patients with SLE show antiphospholipid antibodies, which can induce a pro-thrombotic status decreasing the thrombophilic threshold by inducing a prothrombotic, pro-inflammatory phenotype in endothelial cells.10 A trigger acting as a second hit will then induce thrombotic events.11 About 53% of APS patients show neither clinical nor laboratory evidence of any other definable condition (primary APS), and 36% patients display an association with SLE.12 Some SLE patients do not initially exhibit symptoms of SLE; instead APS could exist as a primary syndrome.13 APS patients with previous vascular embolic events are treated using anti-platelet agents and/or anticoagulants.5 The endothelial dysfunction and vasculitis seen in SLE may lead to intracranial hemorrhage and the development of cerebral aneurysm, increasing the risk of SAH.14,15 The ratio of saccular aneurysms in SLE patients appears low compared to the general population, whereas uncommon aneurysms such as fusiform or pseudo-aneurysms are more often detected.8,16,17 Several cases of SLE patients with SAH did not reveal any aneurysms on angiography.16,18 In the general population, such cases of SAH with angio-negative aneurysm tend to be older and usually follow a benign clinical course.19 On the other hand, SLE patients showing SAH with angio-negative aneurysm are often relatively young and show a high mortality rate.8,16,17 Reasons for the increased incidence of SAH in SLE patients remain unclear. Classical risk factors for SAH such as atherosclerosis and hypertension are relevant complications among SLE patients. The treatment of
TSUKAMOTO E et al. 4
SLE in the acute phase is medical therapy with steroids and/or cytotoxic immunosuppressants. These drugs can also cause hypertension as a side effect.20 Daily use of high-dose steroid (>10 mg/day) represents an independent risk factor for increasing incidence of SAH.9 Saccular aneurysms would be induced by atherosclerosis and hypertension. Inflammation of the arteries narrows the arterial lumen, compromises cerebral blood flow, and causes a variety of atherosclerotic-like symptoms leading to hemodynamic stress. Furthermore, focal vasculitis could be a cause of the uncommon aneurysms in unusual locations.17 Focal vasculitis could be related to the incidence of fusiform aneurysms, which have proven anatomopathlogical findings supporting focal transmural angiitis.21 Pseudo-aneurysms with wall defect but without lymphocytic infiltration have also been reported.16 The arterial walls of these uncommon aneurysms were so fragile that the risk of rupture was high. Another feature of SLE patients is the higher frequency of multiple aneurysms. The incidences of single and multiple aneurysms among SLE patients were 69.5% and 31.6%, respectively.17,22 Therapeutic management of SAH in SLE patients has still not been established. The frequent hematologic and renal complications are important comorbidities for invasive procedures. Whichever surgical or endovascular procedures are chosen for aneurysm occlusion, these procedures are challenging because intracranial arterial walls are fragile and susceptible to prompt rupture.23 Treatment of fusiform aneurysms rarely involves direct clipping or coil embolization, and instead requires occlusion techniques like trapping with or without revascularization. The rupture of aneurysms might be related to SLE activity due to complications of arterial hypertension. Therefore, management for non-ruptured aneurysms among SLE patients to prevent rupture include treatment of active SLE and strict control of cardiovascular risk factors. In our case, no common risk factors for ischemic stroke were seen, such as hypertension, smoking history, carotid artery stenosis or cardiac dysrhythmia. The first ischemic stroke was thus considered to be induced by APS and underlying SLE. SLE was consequently diagnosed on presentation of additional clinical symptoms, such as optic hyperesthesia and facial butterfly-shaped erythema, despite symptoms at the first visit not fulfilling the SLE criteria. This means that the
TSUKAMOTO E et al. 5
incipient SLE gradually became activated. The patient had no history of hypertension or pharmacotherapy with steroid. Fusiform aneurysm of the ACA may occur due to focal vasculitis, with activation of SLE leading to aneurysm rupture.
CONCLUSIONS In cases involving young individuals presenting with stroke without any apparent risk factors, autoimmune diseases are one of the pathogeneses. When aneurysms are incidentally detected before definitive diagnosis of an autoimmune disease such as SLE, strict control of cardiovascular risk factors is warranted, with consideration of early therapeutic intervention for aneurysms because of the high risk of rupture.
INFORMED CONSENT Informed consent for the publication was obtained from the patient.
TSUKAMOTO E et al. 6
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patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011;20:206-218. 12. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019-1027. 13. Mackworth-Young CG, Loizou S, Walport MJ. Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis. 1989;48:362-367. 14. Fayyaz A, Igoe A, Kurien BT, et al. Haematological manifestations of lupus. Lupus Sci Med. 2015;2:e000078. 15. Feigin VL, Rinkel GJ, Lawes CM, et al. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke. 2005;36:2773-2780. 16. Torné R, Rodríguez-Hernández A, Bernard T, Arikan Abelló F, Vilalta Castan J, Sahuquillo J. Subarachnoid hemorrhage in systemic lupus erythematosus: systematic review and report of three cases. Clin Neurol Neurosurg. 2015;128:17-24. 17. Mimori A, Suzuki T, Hashimoto M, et al. Subarachnoid hemorrhage and systemic lupus erythematosus. Lupus. 2000;9:521-526. 18. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955-1977. Semin Arthritis Rheum. 1979;8:212-221. 19. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306-318. 20. Murphy G, Lisnevskaia L, Isenberg D. Systemic lupus erythematosus and other autoimmune rheumatic diseases: challenges to treatment. Lancet. 2013;382:809-818. 21. Asai A, Matsutani M, Kohno T, Fujimaki T, Takakura K. Multiple saccular cerebral aneurysms associated with systemic lupus erythematosus--case report. Neurol Med Chir (Tokyo). 1989;29:245-247. 22. Owada T, Takahashi K, Kita Y. Subarachnoid hemorrhage in systemic lupus erythematosus in
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FIGURE LEGENDS Fig. 1 A) Diffusion-weighted images show high-intensity areas at the right corona radiata. B) Magnetic resonance angiography suggests aneurysm of the right anterior cerebral artery. C, D) Cerebral angiography confirms a 4-mm fusiform aneurysm at the right anterior cerebral artery.
Fig. 2 A) Computed tomography shows subarachnoid hemorrhage. B, C) Right internal carotid angiography (oblique view) shows trapping of the right anterior cerebral artery using coils and disappearance of the fusiform aneurysm. D, E) Bilateral cerebral angiography (anterior-posterior views) shows disappearance of the fusiform aneurysm and bilateral anterior cerebral arteries supplied by the left internal carotid artery. F) About 2 weeks after embolization, magnetic resonance angiography shows no recurrence of the aneurysm.
Table 1 Details of laboratory data Reference range WBC (x102/µl)
68
50-80
22.9
30.3-40.5
RBC (x10 /µl)
510
450-510
Hemogrobin (g/dL)
15.7
13.9-16.0
Hematocrit (%)
44.9
41.4-49.2
25.8
18.0-35.0
C3 (mg/dL)
79
65-135
C4 (mg/dL)
15.8
13.0-35.0
CH50 (U/mL)
46.9
30.0-40.0
ANA
1280
<40
anti-ds-DNA antibody (IU/L)
102
<12
anti-β2-GPI antibody (U/mL)
8.3
<3.5
Lupus anticoagulant
1.71
<1.30
Lymphocyte (%) 4
4
Platelet (x 10 /µl)
anti-RNP antibody
negative
anti-Sm antibody
negative
urine protein
negative
urine RBC (HPF)
<1
<4
WBC: white blood cell, RBC: red blood cell, C: complement, CH50: 50% hemolytic unit of complement, ANA: antinuclear antibody, dsDNA: double-stranded deoxyribonucleic acid, β2-GPI: β2glycoprotein-І, RNP: ribonucleoprotein, Sm: smooth muscle, HPF: Hi power field
TSUKAMOTO E ET AL.
Abbreviation List ACA: anterior cerebral artery aβ2-GPI: anti-β2-glycoprotein-І APS: antiphospholipid syndrome CT: computed tomography MR: magnetic resonance SAH: subarachnoid hemorrhage SLE: systemic lupus erythematosus