ARTICLE IN PRESS Case Studies Young Ischemic Stroke in Association with Ovarian Hyperstimulation Syndrome Pawani Sachar, MBBS, MD, and Kumar Rajamani, MBBS, MD, DM Background: Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially fatal complication of medical ovarian stimulation. Uncommonly, it is associated with thromboembolic complications with venous thrombosis being more common than arterial thromboembolic events. We present a case of cerebral infarction in the setting of severe OHSS secondary to in vitro fertilization treatment with no residual neurological deficits. Materials and Methods: We also performed a review of previously published ischemic cerebral infarction and cerebral venous sinus thrombosis (CVST) cases associated with OHSS to evaluate common patterns in presentations, commonly affected central nervous system sites, trends for therapeutic options in these cases, and outcomes. Conclusion: We have included 27 cases of ischemic cerebral infarction and 7 cases of CVST previously published in English literature. We have included cases of central retinal artery occlusion in the ischemic cerebral infarction group, and central retinal vein occlusion in the CVST group. Mean ages of presentation were 31 ± 4.84 and 34 ± 4.90 years for ischemic cerebral infarction and CVST, respectively. Ischemic strokes commonly affect large cortical areas with unilateral weakness, aphasia, unilateral sensory changes, and visual field deficits being the common presentations. Middle cerebral artery (n = 7) is the common site of vascular occlusion where vascular imaging has been reported, followed by internal carotid artery occlusion (n = 5). OHSS cannot be considered a direct risk for pathogenesis, but OHSS is frequently associated with hyperviscosity, which may add to the risk factors. Key Words: Ovarian hyperstimulation syndrome—ischemic stroke—in vitro fertilization—cerebral venous sinus thrombosis. © 2016 Published by Elsevier Inc. on behalf of National Stroke Association. Case Report A previously healthy 36-year-old right-handed Caucasian woman presented with an episode of right upper From the Department of Neurology, Detroit Medical Center/ Wayne State University, Detroit, MI. Received December 7, 2015; revision received April 9, 2016; accepted April 27, 2016. Address correspondence to Pawani Sachar, MBBS, MD, Department of Neurology, Detroit Medical Center/Wayne State University, Detroit, MI 48201. E-mail: pawani_sachar@yahoo.com. 1052-3057/$ - see front matter © 2016 Published by Elsevier Inc. on behalf of National Stroke Association. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.023 extremity weakness and expressive aphasia lasting for about 15-20 minutes. The patient was undergoing treatment for infertility and had egg retrieval for in vitro fertilization (IVF) 7 days prior to the onset of these symptoms. The patient developed abdominal pain, nausea, malaise, and dyspnea 2 days after egg retrieval. Abdominal ultrasound confirmed the presence of ascites and ovarian enlargement, and the patient was diagnosed with ovarian hyperstimulation syndrome (OHSS). Embryos were not implanted and were frozen. The result of the neurological exam was normal on initial evaluation (National Institutes of Health Stroke Scale score of 0). The white blood cell count was 17 (76% neutrophils, 19% lymphocytes, 6% monocytes); platelet count, 535; hemoglobin level, Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■ 1 ARTICLE IN PRESS P. SACHAR AND K. RAJAMANI 2 all of which had been normal. The patient was discharged home with aspirin and simvastatin. Repeat MRA of the head 2 months later showed improvement of the left MCA attenuation (Fig 2B). The patient had mild occipital headaches after discharge, which was associated with mild photophobia. The patient did not develop any other neurological symptoms. The headaches improved spontaneously. Repeat MRA head 3 months later showed complete resolution of the MRA signal attenuation seen on the first study. The patient has been symptom free for about 6 months after the initial episode and has been taking aspirin 81 mg daily. Discussion Figure 1. Diffusion-weighted magnetic resonance imaging of the brain showing acute infarction. 17.7; and hematocrit level, 52.5. Serum electrolytes were also deranged: Na, 130; K, 4.1; CO2, 22; Cl, 100; blood urea nitrogen, 14, and creatinine, 1.4. Total estrogens level and total estradiol levels were 2730 and 1520 pg/mL, respectively. Repeat abdominal ultrasound showed an enlarged liver with moderate to severe ascites. The portal vein was patent. The patient was found to have a left posterior insular infarction on magnetic resonance imaging of the brain (Fig 1), and there was attenuation of the left middle cerebral artery vasculature on magnetic resonance angiography (MRA) of the head (Fig 2). Magnetic resonance venography of the head did not show any signs of venous sinus or cortical vein thrombosis. Fasting lipid profile showed a low-density lipoprotein level of 58. The hemoglobin A1c level was 5.3. The rest of the stroke workup including carotid duplex, 2-D echo, and telemonitoring were normal. The patient was treated with aggressive intravenous hydration and albumin infusions and had subsequent improvement in clinical status and electrolyte abnormalities. Aspirin, simvastatin, and subcutaneous heparin were started. The patient also had hypercoagulable workup including antithrombin III, protein C, protein S, factor V Leiden, antiphospholipid antibodies, beta-2 glycoprotein antibodies, Anti-nuclear Antibodies (ANA), and Extractable Nuclear Antigen Antibodies (ENA), OHSS is a serious and potentially fatal complication of ovarian stimulation for assisted reproduction technologies. Mild forms are common and reported frequencies for OHSS are approximately 20%-33% for mild cases, 3%6% for moderate cases, and .1%-2.0% for severe cases. It is a broad spectrum of signs and symptoms that include abdominal distention and discomfort, enlarged ovaries, ascites, and other complications of enhanced vascular permeability. The pathophysiology is hypothesized to be increased capillary permeability with the loss of fluid into the third space, likely from overexpression of vascular endothelial growth factor in the ovary and release of vasoactive–angiogenic substances resulting in functional impairment of blood vessels systemically, often causing impairment of cardiac, renal, pulmonary, and liver functions. Clinically, OHSS has been classified as mild, moderate, severe, and critical. Thromboembolic complications are typically seen in the latter 2 forms with venous thrombosis (64.3%) being more common than arterial thromboembolic events (37.5%).1 Major risk factors for OHSS are previous episode of OHSS, polycystic ovary syndrome, and younger age, which has been reported as a possible risk factor along with low body weight. Potential biomarkers of risk are a basal serum anti-Müllerian hormone concentration greater than 3.3 ng/mL and an antral follicle count greater than 8. Secondary risk factors related to ovarian response are the number of follicles (the risk rises with increasing number Figure 2. (A and B) Magnetic resonance angiography of the brain showing narrowing of the left middle cerebral artery with attenuated branches and followup scan 3 months later showing significant improvement. Previous thromboembolism Polycystic ovaries Max estradiol level (pg/mL) No. of mature follicles Severity of OHSS Days to development of stroke symptoms Year Mozes et al Rizk et al Kermode et al 1965 1990 1993 37 30 34 None None None None None Yes NR NR NR NR NR NR Severe Severe Severe 5 days post HCG injection 12 days post ET 9 days post ET Inbar et al Aurousseau et al Cluroe et al 1994 1995 1995 22 34 40 None None None Yes None None NR NR NR Multiple NR NR None None Severe 7 days post HCG injection 3 days post ET transfer 6 days post ET Aboulghar et al Aboulghar et al Hwang et al 1998 1998 1998 33 25 22 None None None None None None 2100 2800 NR 12 16 NR Moderate Moderate Severe 11days post ET 9 days post ET 12 days post ET El Sadek et al Yoshii et al Davies et al Worrell et al Turkistani et al Koo et al 1998 1998 1999 2001 2001 2002 24 26 33 34 34 33 None None None None None None None None None None None None 3000 NR NR 2663 NR NR 34 NR NR NR NR NR Severe Severe Moderate Mild Moderate Severe 6 days post ET NR NR 7 days post ET NR 14 days post ET Elford et al 2002 28 None None 3132 NR Severe 7 days post ET Di Micco et al 2003 32 None None 3800 NR Moderate NR Togay-Isikay et al 2004 27 None None NR NR Severe 12 days post IUI Demirol et al Giner et al Marti et al Bartkova et al 2007 2007 2008 2008 21 35 34 31 None None None None None None None None 2118 NR NR 1440 16 NR NR NR None Severe Moderate Severe 2 days post HCG injection NR 3 days post ET 9 days post ET Qazi et al Song et al 2008 2008 30 31 None None None Yes NR 4300 NR NR Severe Severe NR NR Jing et al Gervasi et al Current case 2011 2012 2013 30 34 36 None None None None Yes None 4267 NR 1520 13 NR Severe Severe Severe 7 hours post ET 7 days post HCG injection 8 days post HCG injection Stroke symptoms Left hemiplegia, coma Left hemiplegia, left hemisensory loss, left hemianopsia Right hemiplegia, right hemisensory loss, right hemianopsia, aphasia, left-sided Horner seizure Headache, nausea, amnesia, dysarthria Left hemiplegia Left hemiplegia, left hemisensory loss, right gaze deviation, left tongue deviation, lethargy Left hemiparesis Left hemiparesis, seizure Left hemiparesis, left facial weakness, left hemisensory loss, dysarthria Right hemiparesis Left hemiparesis, dysarthria, Left hemiparesis, headache Right hemiparesis, aphasia Left unilateral visual loss Left hemiparesis, Left visual field deficit, right gaze preference, left hemineglect, dysarthria Left hemiplegia, left facial weakness, dysarthria, drowsiness Right hemiplegia, right facial weakness, right visual field deficit Sensory loss left face, right hemisory loss, ataxia, Horner syndrome, nystagmus Right hemisensory loss, aphasia, disorientation Right hemiparesis, aphasia Left visual loss Left hemiparesis, left facial weakness, right head deviation, left sided gaze palsy, drowsiness Left hemiparesis, dysarthria Left hemiparesis, left facial weakness, left visual field deficit, nystagmus Right hemisensory loss, aphasia, disorientation, dizziness Right hemiparesis, aphasia Right upper extremity weakness, aphasia (continued on next page) ARTICLE IN PRESS Author Age (years) ISCHEMIC STROKE ASSOCIATED WITH OHSS Table 1. Ischemic cerebral infarction cases 3 Area of cerebral infarction on imaging Author Mozes et al NR Rizk et al Kermode et al Right MCA territory Left frontal and parietal Inbar et al Right temporoparietal Aurousseau et al NR Left extracranial ICA occlusion with intracranial extension No abnormalities NR Other sites of thrombosis None None Right internal iliac vein No abnormalities None Right ICA dissection and None thrombosis NR None NR None NR None Right MCA occlusion Myxomatous mitral valve Left choroidal artery None occlusion Right ICA occlusion None Turkistani et al Koo et al Central retinal artery occlusion NR Right MCA territory Right MCA occlusion None None Elford et al Left MCA territory Left MCA occlusion None Di Micco et al Togay-Isikay et al Demirol et al Giner et al NR Bilateral PICA territory Left ICA occlusion Left vertebral occlusion None None Left MCA territory Left parietal, left lenticular nucleus, right caudate Left thalamus Left MCA occlusion NR None See below Central retinal artery occlusion Left MCA occlusion Carotid atherosclerosis No abnormalities None Yoshii et al Marti et al Bartkova et al Qazi et al Song et al Jing et al Gervasi et al Left basal ganglia Right MCA territory Right MCA territory, left cerebellum Left MCA territory Left fronto-temporal-occipital Current case Left insula NR None Left distal ICA occlusion Intracardiac thrombus Left MCA occlusion NR Left MCA occlusion None None None Maternal outcome Fetal outcome Treatment NR Death No pregnancy Mechanical thrombectomy NR NR Term delivery No pregnancy Aspirin NR None None Recovery Residual motor and speech deficits Recovery Recovery No pregnancy Aspirin Therapeutic abortion Heparin NR None None None None Death Recovery Recovery Residual motor deficits Recovery No pregnancy No pregnancy No pregnancy Therapeutic abortion No pregnancy Temporary elevation of TAT and D-dimer, temporary reduction of protein S Recovery Therapeutic abortion NR None Mildly decreased protein S Recovery Residual motor and speech deficits NR Residual motor deficits NR Spontaneous miscarriage Preterm labor Therapeutic abortion None Low protein S and high IgM anticardiolipin antibodies None Residual motor, visual, and Normal vaginal sensory deficits delivery None Improvement, not specified No pregnancy Activated protein C resistance, Residual motor deficits NR factor V Leiden mutation None Recovery No pregnancy Antiphospholipid antibody Recovery No pregnancy syndrome None Residual visual deficits No pregnancy None None Temporarily low protein S and antithrombin III None homozygosity Left ventricular thrombus, MTHF reductase variant tetralogy of Fallot None None Recovery Recovery Residual motor and speech deficits Residual unknown deficits NR Recovery NR Heparin Heparin NR Heparin- > aspirin NR tPA, heparin> warfarin Heparin NR intra-arterial tPA, dalteparin Heparin- > aspirin Heparin, aspirin Aspirin, warfarin Anticoagulation, not specified Heparin- > warfarin> aspirin Term delivery Heparin- > aspirin No pregnancy Heparin, aspirin Therapeutic abortion Heparin- > aspirin NR NR Ozagrel, aspirin NR No pregnancy Aspirin, heparin Abbreviations: ET, embryo transfer; HCG, human chorionic gonadotrophin; ICA, internal carotid artery; IUI, Intra-uterine Insemination; MCA, middle cerebral artery; MTHF, methylenetetrahydrofolate; NR, not reported; OHSS, ovarian hyperstimulation syndrome; PICA, posterior inferior cerebellar artery; tPA, tissue plasminogen activator. P. SACHAR AND K. RAJAMANI Davies et al Worrell et al Right MCA territory Cortical area, not specified Left parieto-occipital Right MCA territory Left basal ganglia and corona radiata Right internal capsular, bilateral corona radiata, bilateral parietal, right occipital Right MCA territory Left MCA territory infarction Coagulation abnormalities ARTICLE IN PRESS Cluroe et al Aboulghar et al Aboulghar et al Hwang et al El Sadek et al Vascular imaging findings (continued) 4 Table 1. OHSS Days to development of stroke symptoms Waterstone et al Tang et al Ou et al Edris et al 1992 2000 2003 2007 29 34 29 38 None None None None None None None None NR 5668 3707 3346 2 NR 7 16 Severe Severe Moderate Severe 12 days post HCG injection 14 days post ET 9 days post ET 4 days post ET Lee et al Santoro et al 2008 2009 36 31 None None None None NR NR NR NR None Moderate NR NR Man et al 2011 42 None None 2616 NR Severe 1 day post HCG injection Vascular imaging findings Waterstone et al NR Right transverse sinus, internal cerebral vein, vein of Galen Cortical vein Tang et al Left frontal hemorrhagic infarction Ou et al Right frontal, left frontoparietal Superior sagittal sinus Edris et al Periventricular white matter Lee et al None Santoro et al NR Man et al Right frontal Superior sagittal sinus, transverse sinus, cortical veins Central retinal vein occlusion Rectal sinus, transverse venous sinus Superior sagittal sinus, right cortical veins Other sites of thrombosis Coagulation abnormalities Stroke symptoms Left hemiplegia, seizure, coma Right hand weakness, seizure Left hemiplegia, seizures Headache, lethargy, confusion, neck pain Right visual loss Hemiparesis unknown side, headache, visual complains Left hemiparesis, headache Maternal outcome Fetal outcome Treatment None NR Residual motor deficits Spontaneous miscarriage Heparin- > warfarin Inferior vena cava, right common iliac, left femoral and left external iliac None No abnormalities Recovery Therapeutic abortion Heparin- > warfarin Temporarily low protein S Residual motor deficits, seizures Term delivery None No abnormalities Recovery No pregnancy Mechanical thrombectomy, urokinase- > heparin Heparin- > warfarin None No abnormalities NR NR NR None G20210A prothrombin mutation Recovery NR Heparin- > warfarin None No abnormalities NR NR Heparin Abbreviations: ET, embryo transfer; HCG, human chorionic gonadotrophin; NR, not reported; OHSS, ovarian hyperstimulation syndrome. ARTICLE IN PRESS Year Author Polycystic ovaries No. of mature follicles Author Area of cerebral infarction on imaging Previous thromboembolism Max estradiol level (pg/mL) Age (years) ISCHEMIC STROKE ASSOCIATED WITH OHSS Table 2. Venous cerebral infarction cases 5 ARTICLE IN PRESS P. SACHAR AND K. RAJAMANI 6 of follicles >20 over 10 mm in diameter) and high (or rapidly rising) serum estradiol concentration. In 1 study, the incidence of OHSS in women with preovulatory serum estradiol concentrations greater than 3500 pg/mL or greater than 6000 pg/mL was 1.5% and 38%, respectively. The commonly affected sites are the deep extremity veins, the internal jugular vein, and the subclavian vein. Mozes et al reported a fatal case of ischemic stroke associated with severe OHSS in 1965,2 and there have been several other reports of ischemic cerebral infarction and cerebral venous sinus thrombosis (CVST) since then. We present another case of cerebral infarction in the setting of OHSS with no residual neurological deficits. We also performed a review of previously published ischemic cerebral infarction and CVST cases to evaluate common patterns in presentations, commonly affected central nervous system sides, trends for therapeutic options in these cases, and outcomes. We have included 27 cases of ischemic cerebral infarction1-25 and 7 cases of CVST26-32 previously published in English literature (Tables 1, 2). We have included cases of central retinal artery occlusion in the ischemic cerebral infarction group and central retinal vein occlusion in the CVST group. The mean ages of presentation were 31 ± 4.84 and 34 ± 4.90 years for ischemic cerebral infarction and CVST, respectively. Ischemic strokes commonly affect large cortical areas with unilateral weakness, aphasia, unilateral sensory changes, and visual field deficits being the common presentations. The middle cerebral artery (n = 7) is the common site of vascular occlusion where vascular imaging has been reported, followed by internal carotid artery occlusion (n = 5). Posterior circulation is rarely affected with only 1 reported case of vertebral occlusion.19 Ischemic strokes usually occur in association with moderate–severe OHSS (~85%), but there has been 1 case reported with mild OHSS and 3 cases without OHSS. These cases without OHSS happened also after IVF or ovulation induction without any determined etiology. By contrast, venous sinus thrombosis has always been associated with moderate–severe OHSS. The maximum serum estradiol level reported is 2831 ± 1000 pg/ mL in ischemic strokes and 3834 ± 1304 pg/mL in CVST. The exposure to higher levels of estrogens in the women with other potential risk factors is the likely pathogenesis in these cases. In fact, other concomitant hypercoagulable risk factors have been found in 7 cases of ischemic strokes and in 2 cases of CVST. The true prevalence of hypercoagulable risk factors in these patients is difficult to estimate due to small numbers and as some of the case reports have not reported any testing for them. It is difficult to definitely draw conclusions as very few of the reported cases of OHSS with ischemic stroke and CVST in our review were found to have concomitant coagulation abnormalities, primarily because of lack of hypercoagulability testing in the majority of the cases. Out of 22 cases of ischemic stroke, 2 patients had mild protein S deficiency; 1 patient had protein S deficiency along with high anticardiolipin antibodies; 1 patient had protein C resistance along with factor V Leiden mutation; and 1 patient had antiphospholipid antibody syndrome. In patients with CVST and OHSS, 1 patient had temporarily low protein S deficiency and another patient had a G20210A prothrombin gene mutation. Because thromboembolic complications are relatively rare, routine screening for thrombophilia in women planning to undergo ovarian stimulation is not recommended. It is debatable whether women with an underlying known thrombophilia should receive prophylaxis or not prior to ovulation induction to prevent thromboembolic complications. OHSS is frequently associated with hyperviscosity, which may add to the risk factors. As there have been such few reports of high prevalence of inherited thrombophilias in patients with OHSS,33,34 whether it is cost effective to screen all women undergoing ovarian stimulation for these conditions is debatable.35 We will suggest, though, a detailed discussion with the patients planning for IVF or ovulation induction who may have known risk factors. Therapeutic options have been varied in the past with no particular trends. Two patients were treated with intravenous tissue plasminogen activator without any significant complications. All ischemic strokes in the acute setting should be treated with thrombolytics and/or mechanical intervention as per American Heart Association guidelines.36 Secondary stroke prophylaxis in these cases is debatable. Previously antiplatelets, warfarin, and heparin products have been used in various regimens. Our patient has done well with only aspirin, and we will recommend an individualized approach on a case-to-case basis. About 48% of the ischemic stroke patients experienced complete recovery and 7% (n = 2) of the patients died. This outcome can be considered relatively good considering that most of these patients had large hemispheric strokes. References 1. Jing Z, Yanping L. Middle cerebral artery thrombosis after IVF and ovarian hyperstimulation: a case report. Fertil Steril 2011;95:e13-e15. 2. Mozes M, Bogokowsky H, Antebi E, et al. Thromboembolic phenomena after ovarian stimulation with human gonadotrophins. Lancet 1965;2:1213-1215. 3. Bartkova A, Sanak D, Dostal J, et al. 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