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Two young stroke patients associated with regular intravenous immunoglobulin (IVIg) therapy
Journal of the Neurological Sciences 361 (2016) 9–12
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Two young stroke patients associated with regular intravenous immunoglobulin (IVIg) therapy Yumiko Nakano a, Takeshi Hayashi a, Kentaro Deguchi a, Kota Sato a, Nozomi Hishikawa a, Toru Yamashita a, Yasuyuki Ohta a, Yoshiki Takao b, Tomohiro Morio c, Koji Abe a,⁎ a b c
Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Neurology, Kurashiki Heisei Hospital, Okayama, Japan Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 8 October 2015 Received in revised form 14 November 2015 Accepted 1 December 2015 Available online 2 December 2015 Keywords: Intravenous immunoglobulin Stroke Thrombotic complication Agammaglobulinemia
a b s t r a c t We recently experienced 2 young adult patients who developed ischemic stroke after regular intravenous immunoglobulin (IVIg) therapy for agammaglobulinemia with diagnosis of common variable immunodeficiency (CVID) in their childhood. Patient 1 was 26-year-old woman, who developed Wallenberg's syndrome 6 days after the last IVIg therapy, but had no further stroke recurrence with cilostazol later. Patient 2 was 37-year-old man, who developed recurrent cerebral infarction in the territory of bilateral lenticulostriate branches like branch atheromatous disease (BAD) several days after the IVIg therapy. However, he had no further stroke recurrence after bone marrow transplantation (BMT) therapy for his lymphoproliferative disorder. It was suggested that IVIg therapy was associated to these different types of ischemic stroke in our 2 young adult patients with minimal vascular risk factors. Although IVIg therapy is widely used as a relatively safe medication for immunodeficiency disorders or autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Case presentation
Intravenous immunoglobulin (IVIg) therapy has recently been used for immune deficiency such as common variable immunodeficiency (CVID) with agammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, and so on [6,15,16]. IVIg therapy is basically a safe medication, and the adverse events are usually mild and tolerated such as hypertension, fever and chills, nausea, myalgia or headache [7,17,18]. However, severe side effects have occasionally been reported for systemic thrombotic events including stroke after wider use of IVIg for various diseases [2,4]. Because there were only a few reports of stroke associated to IVIg therapy, the detailed temporal profiles and the mechanisms were not fully mentioned. Therefore, we here report 2 young adult patients with congenital agammaglobulinemia but minimal vascular risk factors, both of whom developed ischemic stroke several days after regular IVIg substitution therapy.
2.1. Patient 1
⁎ Corresponding author at: Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail address: [email protected] (K. Abe).
http://dx.doi.org/10.1016/j.jns.2015.12.001 0022-510X/© 2015 Elsevier B.V. All rights reserved.
A 13-year-old girl was diagnosed with congenital agammaglobulinemia, and has been regularly treated with intravenous gammaglobulin (IVIg, 0.37 g/kg, single dose) once a month. She was also diagnosed with CVID because there was no responsible gene identified by genetic testing for primary immunodeficiency disorders. When she became 25 years old, she suffered from hypoalbuminemia and diarrhea due to protein-losing gastroenteropathy. At age 26, she suddenly felt dizziness 6 days after the regular IVIg therapy, and was transferred to a hospital with a slight conscious disturbance. Her father has also received IVIg treatment with the same diagnosis as her, and he died of a brain hemorrhage at 42-year-old. On arrival to our hospital, she recovered to be conscious, but showed right Horner syndrome, dysarthria, dysphasia, right curtain sign, loss of right pharyngeal/soft palate reflex, ataxic gait, hypoalgesia/ thermohypoesthesia in her left face and body. Head magnetic resonance imaging-diffusion weighted image (MRI-DWI) revealed marked hyperintensity in the right lateral side of medulla and the right cerebellar hemisphere and vermis (Fig. 1a). Fluid-attenuated inversion recovery (FLAIR) image also showed hyperintensity in the same regions of medulla and cerebellum (Fig. 1b). Head and carotid magnetic resonance angiography (MRA) showed the occlusion of the right vertebral artery but no hallmark of dissection (Fig. 1c–e). She was admitted with a
10
Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
Fig. 1. Brain magnetic resonance imaging (MRI) of patient 1 on admission (4 days after the onset). Axial diffusion weighted image (a) and fluid-attenuated inversion recovery (FLAIR) image (b) showed acute infarction in right lateral medulla, right cerebellar vermis and hemisphere. Magnetic resonance angiography (c, d, arrowheads) revealed the occlusion of right vertebral artery without feature of dissection. Basi-parallel anatomical scanning (BPAS) showed no irregularity of vascular diameter of right occluded vertebral artery (e).
diagnosis of Wallenberg's syndrome showing the second type feature according to the Hayakawa's classification. She was a non-smoker, and had no other vascular risk factors (VRFs) such as obesity, hypertension, diabetes, and dyslipidemia. Laboratory test revealed significant decrease of immunoglobulin such as IgG of 428 mg/dl (normal: 870–1818), IgA of 6 mg/dl (110–424), and IgM of 3.4 mg/dl (31–252). Coagulation test suggested no apparent abnormal coagulation ability such as prothrombin time (PT) of 11.8 s, partial thromboplastin time (PTT) of 30.9 s, fibrinogen of 592 mg/dl, D-dimer of 1.3 μg/ml, fibrinogen and fibrin degradation products (FDP) of 3.8 μg/ml, and activity of antithrombin-Ш (AT-Ш) of 127%. However, platelet aggregation analysis showed a slight hyperaggregation by adenosine diphosphate (ADP) and collagen-induced aggregation. In addition, carotid duplex showed the occlusion of right vertebral artery and no significant stenosis of carotid arteries. The activities of protein C and protein S were within normal range. Lupus anticoagulant, anticardiolipin antibody and other antibodies associated with collagen diseases were negative. There was no arrhythmia on analysis of Holter electrocardiogram. Right-to-left shunt was not presented in the microbubble test using transesophageal echocardiography. We started initial treatment with intravenous heparin and edaravone in acute phase, followed by administration of cilostazol which shows a protective effect on vascular endothelium under consideration for the risk of hemorrhagic event due to recanalization. Her neurological symptom gradually improved with slight dysarthria and dysphasia, and she discharged one month after the onset. She has
been stable without further recurrence of ischemic stroke for 3 years to date with the medication of cilostazol. 2.2. Patient 2 From 7 years old, a boy has regularly received IVIg treatment (0.2 g/kg, single dose) for congenital agammaglobulinemia every 3 weeks for 30 years. He was diagnosed with CVID in the same way as patient 1. At 37 years old, he was admitted to a hospital presenting dysarthria, dysphasia, left hemiplegia, and hypesthesia in his left body with diagnosis of young onset acute cerebral infarction. At 2 months after his initial presentation, he showed a recurrent acute stroke in the other side, even though aspirin treatment (100 mg/day). When he was transferred to our hospital, he showed right facial paralysis, dysarthria, dysphasia, right hemiplegia, and poor coordination. Deep tendon reflexes were increased in all limbs with left Trömner reflex. MRI-DWI and FLAIR revealed hyperintensity region in the territory of left lenticulostriate branches (Fig. 2a, b). MRA showed neither significant stenosis nor occlusion of main cerebral and cervical arteries (Fig. 2c, d), and these MRI findings are similar to the feature of branch atheromatous disease (BAD). He was a heavy smoker, but had no other VRFs. His blood examination did not show any apparent coagulation disorder and collagen disease but significant decrease of immunoglobulin such as IgG of 439 mg/dl, IgA of 0.7 mg/dl, and IgM of 1.1 mg/dl. There was no arrhythmia on analysis of Holter electrocardiogram. Right-to-left shunt was not
Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
11
Fig. 2. Brain MRI/MRA of patient 2 on admission. DWI (a) and FLAIR (b) revealed hyperintensity region in the territory of left lenticulostriate branch like branch atheromatous disease (BAD). MRA (c, d) revealed neither significant stenosis nor occlusion of main cerebral and cervical arteries.
suggested in both of transesophageal echocardiogram and chest contrast-enhanced computed tomography (CT). Although the etiology of recurrent stroke was unclear, the medication for secondary prophylaxis was switched from aspirin to warfarin by considering the probability of cerebral embolism. He also continued to receive IVIg substitution therapy with the same dose and frequency. At 6 months after the discharge of our hospital, he suffered from the 3rd ischemic stroke in the territory of right lenticulostriate branches again (Fig. 3a, b), when CT scan subsequently revealed multiple neoplastic lesions in his liver and lungs. The histopathology of liver biopsy demonstrated EBV-associated lymphoproliferative disorder, then chemotherapy started. After 6 months of chemotherapy, he received allogenic bone marrow transplantation (BMT) donated by his sister. After this BMT, he has been stable without further stroke recurrence for 10 years to date with the same frequency and the half dose of IVIg therapy.
3. Discussion We present 2 cases of Japanese patients with ischemic stroke after the regular IVIg treatment for congenital agammaglobulinemia. Both patients were diagnosed with CVID, which is a primary immunodeficiency disorder characterized by impaired B cell differentiation with hypogammaglobulinemia. Although some responsible genes of this disorder were identified, its pathophysiology remains incompletely understood. In addition to recurrent infections, CVID is also associated with autoimmune disorders, chronic lung disease, gastrointestinal disease, and malignancy such as lymphoma, but not with thrombotic events [12]. On the other hand, stroke is a rare, but well-known complication of IVIg treatment [3,8,11]. Caress et al. reported 16 cases of stroke associated with IVIg administration [2], and among these 16 cases, 3 patients (Nos. 3–5 in Table 1) were regularly received IVIg substitution therapy
Fig. 3. Brain MRI on 3rd ischemic stroke of patient 2. DWI (a) and FLAIR (b) revealed hyperintensity region in the territory of right lenticulostriate branch, as well as previous cerebral infarction (Fig. 2).
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Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
Table 1 Clinical data from 2 stroke patients with CVID and comparison with previous report. Present cases
Onset age (years)/gender Indication for IVIg Infarct territory Vascular risk factors Number of previous IVIg treatment Time of stroke onset in relation to IVIg infusion Dose of the last IVIg
Previous report
No. 1
No. 2
No. 3
No. 4
No. 5
26/F CVID Right VA None Numerous 6 days after last infusion 0.37 g/kg
37/M CVID Bilateral corona radiate Smoking Numerous 9 days after last infusion 0.2 g/kg
40/M CVID Left MCA HT Numerous During infusion 50 g/time
62/M CVID Right MCA IHD, DM, HT, left ICA stenosis Numerous During infusion 0.4 g/kg
70/F Immunodeficiency Left thalamus HT Several During infusion ?
CVID, common variable immunodeficiency; DM, diabetes mellitus; HT, hypertension; ICA, internal carotid artery; IHD, ischemic heart disease; IVIg, intravenous immunoglobulin; MCA, middle cerebral artery; VA, vertebral artery.
for CVID or other immunodeficiency disorder similar to our present cases (Nos. 1–2 in Table 1). Although the previous 3 cases developed ischemic stroke just during the IVIg treatment, our present patients developed 6–9 days after the last IVIg treatment (Table 1), probably due to long serum half-life of IVIg up to 18–32 days after infusion [20]. Some of these cases with autoimmune disease such as CIDP and ITP showed ischemic stroke several days after the last IVIg therapy [2,11]. IVIg-related thrombotic complication may be due to the following factors such as platelet increase, platelet activation, increased serum viscosity, activated coagulation factor XI or antiphospholipid antibodies, arterial vasospasm, and the introduction of vasoactive cytokines or clotting factors [5,9,10,13,14,19]. Previous authors mentioned the increase of vasoactive cytokines and clotting factors only during IVIg infusion or immediately after completion of the infusion, and there is no knowing how long the increase of these factors will continue [1]. If the increase of these factors correlated to IVIg will maintain over several days after infusion, there were possibilities that both present cases were in the condition easily induced to hypercoagulability state. Although there is no definite conclusion in preventing thrombotic complications with IVIg, it could partly be attributable to cilostazol which inhibits ADP-induced platelet aggregation that patient 1 who showed slight hyperaggregation had no more stroke recurrence. Patient 2 also showed no more stroke recurrence for 10 years after BMT for his lymphoproliferative disorder of lung and liver. This may be due to that his serum gammaglobulin level increased and was maintained with the half of conventional IVIg dose after BMT. On the other hand, in the case of patient 2, IVIg probably would have promoted an underlying hypercoagulability state lead by his lymphoproliferative disorder, and develop recurrent stroke. Our present cases are unusual in that both patients were young (under the age of 40), and had little vascular risk factors, which suggested that IVIg might be related to their ischemic stroke. Although IVIg therapy has been widely used as a relatively safe medication in various diseases such as immunodeficiency disorders and autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy. Conflict of interest No conflict of interests to report. Acknowledgments This work was partly supported by Grant-in-Aid for Scientific Research (B) 25293202, (C) 15K09316 and Challenging Research 15K15527 and Young Research 15K21181, and by Grants-in-Aid from the Research Committees (Mizusawa H, Nakashima K, Nishizawa M,
Sasaki H, and Aoki M) from the Ministry of Health, Labour and Welfare, Japan.
References [1] A. Bagdasarian, S. Tonetta, W. Harel, R. Mamidi, Y. Uemura, IVIG adverse reactions: potential role of cytokines and vasoactive substances, Vox Sang. 74 (1998) 74–82. [2] J.B. Caress, M.S. Cartwright, P.D. Donofrio, J.E. Peacock Jr., The clinical features of 16 cases of stroke associated with administration of IVIg, Neurology 60 (2003) 1822–1824. [3] J.B. Caress, L. Hobson-Webb, L.V. Passmore, A.P. Finkbiner, M.S. Cartwright, Case– control study of thromboembolic events associated with IV immunoglobulin, J. Neurol. 256 (2009) 339–342. [4] W.J. Choi, M.J. Kim, C. Kim, J.H. Sohn, H.C. Choi, Acute cerebellar infarction associated with intravenous gammaglobulin treatment in idiopathic thrombocytopenic purpura, J. Stroke Cerebrovasc. Dis. 21 (917) (2012) e9–e11. [5] M.C. Dalakas, High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events, Neurology 44 (1994) 223–226. [6] M.C. Dalakas, W.M. Clark, Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record, Neurology 60 (2003) 1736–1737. [7] M.M. Eibl, Intravenous immunoglobulins in neurological disorders: safety issues, Neurol. Sci. 24 (Suppl. 4) (2003) S222–S226. [8] R.S. Go, T.G. Call, Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications, Mayo Clin. Proc. 75 (2000) 83–85. [9] J.A. Grillo, K.C. Gorson, A.H. Ropper, J. Lewis, R. Weinstein, Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders, Neurology 57 (2001) 1699–1701. [10] I. Krause, M. Blank, Y. Shoenfeld, Anti-DNA and antiphospholipid antibodies in IVIG preparations: in vivo study in naive mice, J. Clin. Immunol. 18 (1998) 52–60. [11] I. Marie, G. Maurey, F. Herve, M.F. Hellot, H. Levesque, Intravenous immunoglobulinassociated arterial and venous thrombosis; report of a series and review of the literature, Br. J. Dermatol. 155 (2006) 714–721. [12] T. Morio, Primary immunodeficiency diseases: common diseases that exhibit various clinical manifestations, [Rinsho ketsueki] The Japanese Journal of Clinical Hematology 54 (2013) 726–735. [13] D. Paran, Y. Herishanu, O. Elkayam, L. Shopin, R. Ben-Ami, Venous and arterial thrombosis following administration of intravenous immunoglobulins, Blood Coagul. Fibrinolysis 16 (2005) 313–318. [14] Y. Sherer, Y. Levy, P. Langevitz, L. Rauova, F. Fabrizzi, Y. Shoenfeld, Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases, Pharmacology 62 (2001) 133–137. [15] Y. Shoenfeld, 5th International Symposium on IVIG: IVIG in the third millenium, 25– 27 September 2003, Interlaken, Switzerland, Autoimmun. Rev. 3 (2004) 234–241. [16] Y. Shoenfeld, U. Katz, IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients, Autoimmunity 38 (2005) 123–137. [17] M. Wittstock, U.K. Zettl, Adverse effects of treatment with intravenous immunoglobulins for neurological diseases, J. Neurol. 253 (Suppl. 5) (2006) V75–V79. [18] M. Wittstock, R. Benecke, U.K. Zettl, Therapy with intravenous immunoglobulins: complications and side-effects, Eur. Neurol. 50 (2003) 172–175. [19] R.K. Woodruff, A.P. Grigg, F.C. Firkin, I.L. Smith, Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients, Lancet 2 (1986) 217–218. [20] R. Zaidan, M. Al Moallem, B.A. Wani, A.R. Shameena, A.R. Al Tahan, A.K. Daif, S. Al Rajeh, Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature, Eur. J. Neurol. 10 (2003) 367–372.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Two young stroke patients associated with regular intravenous immunoglobulin (IVIg) therapy Yumiko Nakano a, Takeshi Hayashi a, Kentaro Deguchi a, Kota Sato a, Nozomi Hishikawa a, Toru Yamashita a, Yasuyuki Ohta a, Yoshiki Takao b, Tomohiro Morio c, Koji Abe a,⁎ a b c
Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Department of Neurology, Kurashiki Heisei Hospital, Okayama, Japan Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 8 October 2015 Received in revised form 14 November 2015 Accepted 1 December 2015 Available online 2 December 2015 Keywords: Intravenous immunoglobulin Stroke Thrombotic complication Agammaglobulinemia
a b s t r a c t We recently experienced 2 young adult patients who developed ischemic stroke after regular intravenous immunoglobulin (IVIg) therapy for agammaglobulinemia with diagnosis of common variable immunodeficiency (CVID) in their childhood. Patient 1 was 26-year-old woman, who developed Wallenberg's syndrome 6 days after the last IVIg therapy, but had no further stroke recurrence with cilostazol later. Patient 2 was 37-year-old man, who developed recurrent cerebral infarction in the territory of bilateral lenticulostriate branches like branch atheromatous disease (BAD) several days after the IVIg therapy. However, he had no further stroke recurrence after bone marrow transplantation (BMT) therapy for his lymphoproliferative disorder. It was suggested that IVIg therapy was associated to these different types of ischemic stroke in our 2 young adult patients with minimal vascular risk factors. Although IVIg therapy is widely used as a relatively safe medication for immunodeficiency disorders or autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy. © 2015 Elsevier B.V. All rights reserved.
1. Introduction
2. Case presentation
Intravenous immunoglobulin (IVIg) therapy has recently been used for immune deficiency such as common variable immunodeficiency (CVID) with agammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, and so on [6,15,16]. IVIg therapy is basically a safe medication, and the adverse events are usually mild and tolerated such as hypertension, fever and chills, nausea, myalgia or headache [7,17,18]. However, severe side effects have occasionally been reported for systemic thrombotic events including stroke after wider use of IVIg for various diseases [2,4]. Because there were only a few reports of stroke associated to IVIg therapy, the detailed temporal profiles and the mechanisms were not fully mentioned. Therefore, we here report 2 young adult patients with congenital agammaglobulinemia but minimal vascular risk factors, both of whom developed ischemic stroke several days after regular IVIg substitution therapy.
2.1. Patient 1
⁎ Corresponding author at: Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail address: [email protected] (K. Abe).
http://dx.doi.org/10.1016/j.jns.2015.12.001 0022-510X/© 2015 Elsevier B.V. All rights reserved.
A 13-year-old girl was diagnosed with congenital agammaglobulinemia, and has been regularly treated with intravenous gammaglobulin (IVIg, 0.37 g/kg, single dose) once a month. She was also diagnosed with CVID because there was no responsible gene identified by genetic testing for primary immunodeficiency disorders. When she became 25 years old, she suffered from hypoalbuminemia and diarrhea due to protein-losing gastroenteropathy. At age 26, she suddenly felt dizziness 6 days after the regular IVIg therapy, and was transferred to a hospital with a slight conscious disturbance. Her father has also received IVIg treatment with the same diagnosis as her, and he died of a brain hemorrhage at 42-year-old. On arrival to our hospital, she recovered to be conscious, but showed right Horner syndrome, dysarthria, dysphasia, right curtain sign, loss of right pharyngeal/soft palate reflex, ataxic gait, hypoalgesia/ thermohypoesthesia in her left face and body. Head magnetic resonance imaging-diffusion weighted image (MRI-DWI) revealed marked hyperintensity in the right lateral side of medulla and the right cerebellar hemisphere and vermis (Fig. 1a). Fluid-attenuated inversion recovery (FLAIR) image also showed hyperintensity in the same regions of medulla and cerebellum (Fig. 1b). Head and carotid magnetic resonance angiography (MRA) showed the occlusion of the right vertebral artery but no hallmark of dissection (Fig. 1c–e). She was admitted with a
10
Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
Fig. 1. Brain magnetic resonance imaging (MRI) of patient 1 on admission (4 days after the onset). Axial diffusion weighted image (a) and fluid-attenuated inversion recovery (FLAIR) image (b) showed acute infarction in right lateral medulla, right cerebellar vermis and hemisphere. Magnetic resonance angiography (c, d, arrowheads) revealed the occlusion of right vertebral artery without feature of dissection. Basi-parallel anatomical scanning (BPAS) showed no irregularity of vascular diameter of right occluded vertebral artery (e).
diagnosis of Wallenberg's syndrome showing the second type feature according to the Hayakawa's classification. She was a non-smoker, and had no other vascular risk factors (VRFs) such as obesity, hypertension, diabetes, and dyslipidemia. Laboratory test revealed significant decrease of immunoglobulin such as IgG of 428 mg/dl (normal: 870–1818), IgA of 6 mg/dl (110–424), and IgM of 3.4 mg/dl (31–252). Coagulation test suggested no apparent abnormal coagulation ability such as prothrombin time (PT) of 11.8 s, partial thromboplastin time (PTT) of 30.9 s, fibrinogen of 592 mg/dl, D-dimer of 1.3 μg/ml, fibrinogen and fibrin degradation products (FDP) of 3.8 μg/ml, and activity of antithrombin-Ш (AT-Ш) of 127%. However, platelet aggregation analysis showed a slight hyperaggregation by adenosine diphosphate (ADP) and collagen-induced aggregation. In addition, carotid duplex showed the occlusion of right vertebral artery and no significant stenosis of carotid arteries. The activities of protein C and protein S were within normal range. Lupus anticoagulant, anticardiolipin antibody and other antibodies associated with collagen diseases were negative. There was no arrhythmia on analysis of Holter electrocardiogram. Right-to-left shunt was not presented in the microbubble test using transesophageal echocardiography. We started initial treatment with intravenous heparin and edaravone in acute phase, followed by administration of cilostazol which shows a protective effect on vascular endothelium under consideration for the risk of hemorrhagic event due to recanalization. Her neurological symptom gradually improved with slight dysarthria and dysphasia, and she discharged one month after the onset. She has
been stable without further recurrence of ischemic stroke for 3 years to date with the medication of cilostazol. 2.2. Patient 2 From 7 years old, a boy has regularly received IVIg treatment (0.2 g/kg, single dose) for congenital agammaglobulinemia every 3 weeks for 30 years. He was diagnosed with CVID in the same way as patient 1. At 37 years old, he was admitted to a hospital presenting dysarthria, dysphasia, left hemiplegia, and hypesthesia in his left body with diagnosis of young onset acute cerebral infarction. At 2 months after his initial presentation, he showed a recurrent acute stroke in the other side, even though aspirin treatment (100 mg/day). When he was transferred to our hospital, he showed right facial paralysis, dysarthria, dysphasia, right hemiplegia, and poor coordination. Deep tendon reflexes were increased in all limbs with left Trömner reflex. MRI-DWI and FLAIR revealed hyperintensity region in the territory of left lenticulostriate branches (Fig. 2a, b). MRA showed neither significant stenosis nor occlusion of main cerebral and cervical arteries (Fig. 2c, d), and these MRI findings are similar to the feature of branch atheromatous disease (BAD). He was a heavy smoker, but had no other VRFs. His blood examination did not show any apparent coagulation disorder and collagen disease but significant decrease of immunoglobulin such as IgG of 439 mg/dl, IgA of 0.7 mg/dl, and IgM of 1.1 mg/dl. There was no arrhythmia on analysis of Holter electrocardiogram. Right-to-left shunt was not
Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
11
Fig. 2. Brain MRI/MRA of patient 2 on admission. DWI (a) and FLAIR (b) revealed hyperintensity region in the territory of left lenticulostriate branch like branch atheromatous disease (BAD). MRA (c, d) revealed neither significant stenosis nor occlusion of main cerebral and cervical arteries.
suggested in both of transesophageal echocardiogram and chest contrast-enhanced computed tomography (CT). Although the etiology of recurrent stroke was unclear, the medication for secondary prophylaxis was switched from aspirin to warfarin by considering the probability of cerebral embolism. He also continued to receive IVIg substitution therapy with the same dose and frequency. At 6 months after the discharge of our hospital, he suffered from the 3rd ischemic stroke in the territory of right lenticulostriate branches again (Fig. 3a, b), when CT scan subsequently revealed multiple neoplastic lesions in his liver and lungs. The histopathology of liver biopsy demonstrated EBV-associated lymphoproliferative disorder, then chemotherapy started. After 6 months of chemotherapy, he received allogenic bone marrow transplantation (BMT) donated by his sister. After this BMT, he has been stable without further stroke recurrence for 10 years to date with the same frequency and the half dose of IVIg therapy.
3. Discussion We present 2 cases of Japanese patients with ischemic stroke after the regular IVIg treatment for congenital agammaglobulinemia. Both patients were diagnosed with CVID, which is a primary immunodeficiency disorder characterized by impaired B cell differentiation with hypogammaglobulinemia. Although some responsible genes of this disorder were identified, its pathophysiology remains incompletely understood. In addition to recurrent infections, CVID is also associated with autoimmune disorders, chronic lung disease, gastrointestinal disease, and malignancy such as lymphoma, but not with thrombotic events [12]. On the other hand, stroke is a rare, but well-known complication of IVIg treatment [3,8,11]. Caress et al. reported 16 cases of stroke associated with IVIg administration [2], and among these 16 cases, 3 patients (Nos. 3–5 in Table 1) were regularly received IVIg substitution therapy
Fig. 3. Brain MRI on 3rd ischemic stroke of patient 2. DWI (a) and FLAIR (b) revealed hyperintensity region in the territory of right lenticulostriate branch, as well as previous cerebral infarction (Fig. 2).
12
Y. Nakano et al. / Journal of the Neurological Sciences 361 (2016) 9–12
Table 1 Clinical data from 2 stroke patients with CVID and comparison with previous report. Present cases
Onset age (years)/gender Indication for IVIg Infarct territory Vascular risk factors Number of previous IVIg treatment Time of stroke onset in relation to IVIg infusion Dose of the last IVIg
Previous report
No. 1
No. 2
No. 3
No. 4
No. 5
26/F CVID Right VA None Numerous 6 days after last infusion 0.37 g/kg
37/M CVID Bilateral corona radiate Smoking Numerous 9 days after last infusion 0.2 g/kg
40/M CVID Left MCA HT Numerous During infusion 50 g/time
62/M CVID Right MCA IHD, DM, HT, left ICA stenosis Numerous During infusion 0.4 g/kg
70/F Immunodeficiency Left thalamus HT Several During infusion ?
CVID, common variable immunodeficiency; DM, diabetes mellitus; HT, hypertension; ICA, internal carotid artery; IHD, ischemic heart disease; IVIg, intravenous immunoglobulin; MCA, middle cerebral artery; VA, vertebral artery.
for CVID or other immunodeficiency disorder similar to our present cases (Nos. 1–2 in Table 1). Although the previous 3 cases developed ischemic stroke just during the IVIg treatment, our present patients developed 6–9 days after the last IVIg treatment (Table 1), probably due to long serum half-life of IVIg up to 18–32 days after infusion [20]. Some of these cases with autoimmune disease such as CIDP and ITP showed ischemic stroke several days after the last IVIg therapy [2,11]. IVIg-related thrombotic complication may be due to the following factors such as platelet increase, platelet activation, increased serum viscosity, activated coagulation factor XI or antiphospholipid antibodies, arterial vasospasm, and the introduction of vasoactive cytokines or clotting factors [5,9,10,13,14,19]. Previous authors mentioned the increase of vasoactive cytokines and clotting factors only during IVIg infusion or immediately after completion of the infusion, and there is no knowing how long the increase of these factors will continue [1]. If the increase of these factors correlated to IVIg will maintain over several days after infusion, there were possibilities that both present cases were in the condition easily induced to hypercoagulability state. Although there is no definite conclusion in preventing thrombotic complications with IVIg, it could partly be attributable to cilostazol which inhibits ADP-induced platelet aggregation that patient 1 who showed slight hyperaggregation had no more stroke recurrence. Patient 2 also showed no more stroke recurrence for 10 years after BMT for his lymphoproliferative disorder of lung and liver. This may be due to that his serum gammaglobulin level increased and was maintained with the half of conventional IVIg dose after BMT. On the other hand, in the case of patient 2, IVIg probably would have promoted an underlying hypercoagulability state lead by his lymphoproliferative disorder, and develop recurrent stroke. Our present cases are unusual in that both patients were young (under the age of 40), and had little vascular risk factors, which suggested that IVIg might be related to their ischemic stroke. Although IVIg therapy has been widely used as a relatively safe medication in various diseases such as immunodeficiency disorders and autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy. Conflict of interest No conflict of interests to report. Acknowledgments This work was partly supported by Grant-in-Aid for Scientific Research (B) 25293202, (C) 15K09316 and Challenging Research 15K15527 and Young Research 15K21181, and by Grants-in-Aid from the Research Committees (Mizusawa H, Nakashima K, Nishizawa M,
Sasaki H, and Aoki M) from the Ministry of Health, Labour and Welfare, Japan.
References [1] A. Bagdasarian, S. Tonetta, W. Harel, R. Mamidi, Y. Uemura, IVIG adverse reactions: potential role of cytokines and vasoactive substances, Vox Sang. 74 (1998) 74–82. [2] J.B. Caress, M.S. Cartwright, P.D. Donofrio, J.E. Peacock Jr., The clinical features of 16 cases of stroke associated with administration of IVIg, Neurology 60 (2003) 1822–1824. [3] J.B. Caress, L. Hobson-Webb, L.V. Passmore, A.P. Finkbiner, M.S. Cartwright, Case– control study of thromboembolic events associated with IV immunoglobulin, J. Neurol. 256 (2009) 339–342. [4] W.J. Choi, M.J. Kim, C. Kim, J.H. Sohn, H.C. Choi, Acute cerebellar infarction associated with intravenous gammaglobulin treatment in idiopathic thrombocytopenic purpura, J. Stroke Cerebrovasc. Dis. 21 (917) (2012) e9–e11. [5] M.C. Dalakas, High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events, Neurology 44 (1994) 223–226. [6] M.C. Dalakas, W.M. Clark, Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record, Neurology 60 (2003) 1736–1737. [7] M.M. Eibl, Intravenous immunoglobulins in neurological disorders: safety issues, Neurol. Sci. 24 (Suppl. 4) (2003) S222–S226. [8] R.S. Go, T.G. Call, Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications, Mayo Clin. Proc. 75 (2000) 83–85. [9] J.A. Grillo, K.C. Gorson, A.H. Ropper, J. Lewis, R. Weinstein, Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders, Neurology 57 (2001) 1699–1701. [10] I. Krause, M. Blank, Y. Shoenfeld, Anti-DNA and antiphospholipid antibodies in IVIG preparations: in vivo study in naive mice, J. Clin. Immunol. 18 (1998) 52–60. [11] I. Marie, G. Maurey, F. Herve, M.F. Hellot, H. Levesque, Intravenous immunoglobulinassociated arterial and venous thrombosis; report of a series and review of the literature, Br. J. Dermatol. 155 (2006) 714–721. [12] T. Morio, Primary immunodeficiency diseases: common diseases that exhibit various clinical manifestations, [Rinsho ketsueki] The Japanese Journal of Clinical Hematology 54 (2013) 726–735. [13] D. Paran, Y. Herishanu, O. Elkayam, L. Shopin, R. Ben-Ami, Venous and arterial thrombosis following administration of intravenous immunoglobulins, Blood Coagul. Fibrinolysis 16 (2005) 313–318. [14] Y. Sherer, Y. Levy, P. Langevitz, L. Rauova, F. Fabrizzi, Y. Shoenfeld, Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases, Pharmacology 62 (2001) 133–137. [15] Y. Shoenfeld, 5th International Symposium on IVIG: IVIG in the third millenium, 25– 27 September 2003, Interlaken, Switzerland, Autoimmun. Rev. 3 (2004) 234–241. [16] Y. Shoenfeld, U. Katz, IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients, Autoimmunity 38 (2005) 123–137. [17] M. Wittstock, U.K. Zettl, Adverse effects of treatment with intravenous immunoglobulins for neurological diseases, J. Neurol. 253 (Suppl. 5) (2006) V75–V79. [18] M. Wittstock, R. Benecke, U.K. Zettl, Therapy with intravenous immunoglobulins: complications and side-effects, Eur. Neurol. 50 (2003) 172–175. [19] R.K. Woodruff, A.P. Grigg, F.C. Firkin, I.L. Smith, Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients, Lancet 2 (1986) 217–218. [20] R. Zaidan, M. Al Moallem, B.A. Wani, A.R. Shameena, A.R. Al Tahan, A.K. Daif, S. Al Rajeh, Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature, Eur. J. Neurol. 10 (2003) 367–372.