Reversible Cerebral Vasoconstriction Syndrome 3 Months after Blood Transfusion

Case Report

Reversible Cerebral Vasoconstriction Syndrome 3 Months after Blood Transfusion Charles N. Braun, MD,* Richard L. Hughes, MD,*† and Patrick J. Bosque, MD*†

Reversible cerebral vasoconstriction syndrome is characterized by the prolonged but reversible constriction of cerebral arteries accompanied by a sudden onset of severe headache, and is sometimes complicated by subarachnoid hemorrhage or cerebral infarction. It is associated with various clinical conditions and treatments, although the precise pathophysiology is not understood. In particular, several cases of this syndrome have been described to occur in middle-aged women within 1 week of a blood transfusion. We encountered a patient with a reversible cerebral vasoconstriction syndrome who became symptomatic 3 months after a blood transfusion. No other cause for the syndrome was found. This case suggests that the risk for the reversible cerebral vasoconstriction may persist for months after blood transfusion. Key Words: Blood transfusion—cerebral infarction—chronic anemia—posterior reversible encephalopathy syndrome—reversible cerebral vasoconstriction—reversible posterior leukoencephalopathy syndrome—stroke— subarachnoid hemorrhage—thunderclap headache. Ó 2012 by National Stroke Association

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by the prolonged but reversible narrowing of cerebral arteries.1 The syndrome characteristically presents first with thunderclap headache, and .30% of cases may be complicated by nonaneurysmal cortical subarachnoid hemorrhage (cSAH).2 RCVS may be closely related to reversible posterior leukoencephalopathy syndrome (RPLS).1,3 This is a clinicoradiologic entity in which reversible vasogenic cerebral edema occurs, often accompanied by headache, delirium, seizures, and hypertension. Cases of RPLS with clinical features and

From the *Department of Neurology, University of Colorado Denver School of Medicine; and †Department of Medicine, Denver Health Medical Center, Denver, Colorado. Received August 4, 2011; revision received October 21, 2011; accepted January 20, 2012. Address correspondence to Patrick J. Bosque, MD, Department of Medicine, Denver Health Medical Center, 777 Bannock St, Denver, CO 80204-4507. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2012.01.013

vasoconstriction similar to that seen in RCVS have been reported.3,5-7 Likewise, cranial magnetic resonance imaging (MRI) scans of patients with RCVS sometimes reveals RPLS-like vasogenic edema of the white matter.2,4,8-10 In case series, approximately 10% of patients with RCVS develop RPLS.2,3 RPLS is particularly common in cases of RCVS complicated by cSAH.2 These reports indicate an overlap between the syndromes of RCVS and RPLS. The basic pathophysiology of RPLS is unknown. It is associated with a variety of conditions, including pregnancy and the puerperium, immunosuppressive and vasoactive medication, and migraines and other headache conditions. Middle-aged women seem particularly prone to the syndrome.2,3 A number of reports describe RCVS or RPLS occurring within 2 weeks of blood transfusion. We encountered a typical case of RCVS that occurred in a woman .3 months after blood transfusion.

Case Report A 46-year-old woman experienced an abrupt onset of a severe bifrontal headache and nausea (day 0). The

Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 8 (November), 2012: pp 915.e1-915.e5

915.e1

915.e2

Figure 1. Cranial computed tomographic scan obtained 3 days after symptom onset. Arrowheads indicate areas of subarachnoid hemorrhage.

headache would subside for a few hours then return in a thunderclap fashion. The patient came to the emergency department on day 3 after the headache had suddenly worsened. She had a 5-year history of menorrhagia until 3 months before the present admission, when she developed dyspnea and chest pain. An evaluation found hemoglobin of 4.1 g/dL (normal 12.0-16.0 g/dL). Leukoreduced packed red blood cells (750 mL) were transfused over 2 days. Her hemoglobin increased to 8.2 g/dL. A levonorgestrelreleasing intrauterine device was placed. She began taking ferrous sulfate and folate oral supplements. Hemoglobin was 14.4 g/dL and iron studies were normal 2 months after this event. She had no other medical problems and no

C.N. BRAUN ET AL.

history of severe headache. Both the family and social histories were unremarkable. The blood pressure was 146/72 mm Hg. The neurologic examination was normal. The initial computed tomographic (CT) scan (Fig 1) revealed small bilateral cSAHs involving the frontal lobes. A CT angiogram of the cerebral arteries revealed diffuse large vessel focal narrowing of all intracranial vessels with normal appearing extracranial vessels of the neck (Fig 2). Some areas of narrowing were remote from the areas of SAH. A catheter angiogram on day 5 confirmed these findings with no evidence of aneurysm, venous abnormality, or thrombosis. A MRI scan on day 5 (Fig 3) found patchy right cerebellar infarcts in the posterior inferior cerebellar artery distribution as well as bilateral occipital infarcts in both posterior cerebellar artery distributions. Hemoglobin was 11.5 g/dL. The following tests were normal or negative: antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, complement levels, C-reactive protein, erythrocyte sedimentation rate, hepatitis B surface antigen, prothrombin time, partial thromboplastin time, von Willebrand factor, and antiphospholipid antibody syndrome screen. A cerebrospinal fluid analysis found 27 white blood cells per microliter (0.27 3 109 cells/L), 2172 red blood cells per microliter, a protein measurement of 26 mg/dL, and a glucose level of 49 mg/dL, no clonal bands, a normal immunoglobulin G index, and a negative polymerase chain reaction assay for varicella zoster virus DNA. The patient was intolerant of nimodipine because of low blood pressure, but she tolerated verapamil 80 mg (3 times/day). On day 8, the patient’s headache had completely resolved and she had no neurologic deficits on examination. A cerebral CT angiogram was repeated, revealing an improvement in the degree of vessel narrowing. Four months after discharge, she continued to be without complaints.

Figure 2. Three-dimensional reconstructions of computed tomographic angiography scans obtained 3 days after symptom onset. Moderate arterial stenosis (arrowheads) in (A) branches of the left middle cerebral and proximal left anterior cerebral arteries and (B) the proximal right posterior cerebral artery.

RCVS AFTER BLOOD TRANSFUSION

915.e3 11-14

Figure 3. Fluid-attenuated inversion recovery (FLAIR) image from a cranial magnetic resonance imaging scan obtained 5 days after symptom onset. Note the high-signal lesion involving the left occipital lobe. Diffusionweighted imaging revealed restriction, consistent with acute infarction. Similar lesions occurred in the contralateral occipital lobe and the right cerebellar hemisphere.

Discussion A variety of conditions appear to trigger RCVS and RPLS,1 but the only condition present in our patient was a history of blood transfusion. Four published reports describe RPLS triggered by blood transfusion in

adults. All involved middle-aged women with chronic anemia. Angiography revealed cerebral artery vasospasm that resolved in all these cases, and 3 of the 4 case reports describe severe headache at onset, so they can be classified as RCVS (Table 1). The present case differs from the others in that there was an interval of 106 days from blood transfusion to the onset of RCVS symptoms; in previous cases, the onset varied between 5 and 7 days after the transfusion. Cranial MRI scans of 3 of the 4 cases from the literature found RPLS-like posterior T2 signal abnormalities (Table 1). These abnormalities were absent in our case and 1 case from the literature. A syndrome of hypertension and thunderclap headache—sometimes accompanied by seizures and brain edema—has been reported to occur 2 to 14 days after blood transfusion for children with thalassemia or sickle cell anemia.15-17 There is 1 report of a RPLS-like syndrome in a 20-year-old man with sickle cell anemia 7 days after transfusion.18 The mechanism connecting RCVS or RPLS to blood transfusion is uncertain. All reported cases of transfusionassociated RCVS or RPLS have occurred in patients with chronic anemia.14 Speculated mechanisms by which transfusion might lead to RCVS have included the following: (1) an increase in blood volume leading to hypertension12; (2) an increase in blood viscosity leading to endothelial damage causing disrupted cerebral vascular autoregulation10; and (3) a disruption of unspecified adaptations of cerebral vasculature to chronic anemic hypoxia, analogous to postendarterectomy hyperperfusion syndrome.14 In our patient, the long latency period between transfusion and the onset of RCVS would seem to exclude simple rheologic mechanisms, such as altered blood viscosity or volume, as causes of the syndrome. We considered

Table 1. Cases of reversible cerebral vasoconstriction syndrome after blood transfusion in adults* Patients age (y)

Study

Cause of anemia

48

Boughammoura Menometrorrhagia (uterine myoma) et al11

45

Ito et al12

47

Heo et al13

32

Huang et al14

46

Present study

Menometrorrhagia (uterine myoma) Aplastic anemia Menorrhagia (uterine myoma) Menorrhagia

Volume of PRBCs Days to transfused (mL) onsety 1000

6

800

6

Unknownx

7

1600

5

750

106

Brain imaging

Vasoconstrictionz

Multiple small cortical and subcortical FLAIR hyperintensities T2 hyperintensity bilateral occipital and parietal lobes T2 hyperintensity bilateral occipital and parietal lobes T2 hyperintensity bilateral occipital lobes Bilateral small SAH, small postcirculation infarctions

Diffuse proximal and distal Distal PCA Diffuse distal Left PCA Diffuse proximal

Abbreviations: FLAIR, fluid-attenuated inversion recovery; PCA, posterior cerebral artery; PRBC, packed red blood cell; SAH, subarachnoid hemorrhage. *All patients were women. yLatency between first transfusion and symptom onset. zDistribution of segmental vasoconstriction in cerebral arteries. xReceived filtered red blood cells, filtered platelets, and fresh frozen plasma. This patient was also treated with cyclosporine A.

915.e4

whether long-lasting adaptations of the cerebral vasculature to chronic anemia, immunologic effects, or a shared physiologic basis for menorrhagia and abnormalities of cerebral hemodynamics might result in delayed RCVS after blood transfusion.

Long-lasting Dysregulation of Cerebral Vasculature Data are lacking on the cerebrovascular response to anemia and subsequent transfusion associated with chronic blood loss, as seen in menorrhagia. The cerebrovascular response to blood transfusion in children with sickle cell disease and to erythropoietin therapy in adults with anemia related to renal failure has been investigated. Notably, RCVS or RPLS have been reported in both clinical situations.17-19 In both conditions, patients have increased cerebral blood flow and increased flow velocities in cerebral arteries in the anemic state, and correction of the anemia moves both parameters toward normal levels. In children with sickle cell disease who receive blood transfusions, both cerebral blood flow and cerebral arterial velocities fall rapidly after transfusion, with substantially more normal blood flow and arterial velocities within hours.20 However, the degree of response is variable between subjects. In a study of children with sickle cell disease and initially high internal carotid or middle cerebral artery velocities, as measured by transcranial Doppler, scheduled transfusions led to normal arterial velocities in about 80% of transfused patients, but in some cases these normal velocities were achieved only after .30 months.21 This indicates that in sickle cell disease, changes in the regulation of cerebral blood flow are improved by transfusion, but this improvement may take many months to develop. Because of the gradual effect of erythropoietin therapy, it is not possible to determine how rapidly cerebrovascular regulation responds to improved hematocrit. In both sickle cell disease and chronic renal failure, alterations in cerebrovascular regulation may have causes other than mere anemia. However, data from studies of these conditions indicate that it is possible that cerebrovascular regulation remains abnormal for months after blood transfusion for chronic anemia. Perhaps this dysregulation can promote the development of RCVS.

Immunologic Effects In some RCVS cases not associated with transfusion, immunosuppressant medications appear to have triggered the syndrome.1 This raises the possibility that immune system dysfunction might promote the vascular dysregulation seen in RCVS. Blood transfusion is known to lead to important long-term alterations in recipient immune function22; therefore, the delayed response in our patient might have been the result of delayed effects of immunomodulation induced by the transfusion.

C.N. BRAUN ET AL.

Menorrhagia and Cerebral Hemodynamics Menorrhagia may be more common in women with migraine headaches,23 and migraine is associated with RCVS,1 although our patient did not have migraines. In addition, the association of RCVS with middle-aged women and case reports of RCVS or RPLS associated with hormonal therapies (discussed below) suggests that hormonal dysregulation might cause RCVS. These observations raise the question of whether the pathophysiology of menorrhagia might be linked—perhaps through abnormalities of hormonal regulation—to abnormalities of cerebral hemodynamics that might predispose some women to RCVS. We considered whether the levonorgestrel-releasing intrauterine device might have been responsible for RCVS in our patient. Hormone therapies have been rarely associated with this syndrome. Subcutaneous injections of follicle-stimulating hormone followed by human chorionic gonadotropin, used to stimulate ovulation, appear to have triggered RCVS in 1 patient.24 There is 1 report of RCVS occurring in a 42-year-old woman 1 month after beginning an estrogen/progestin combination oral contraceptive pill and another in a 28-year-old woman who had been taking a combination oral contraceptive for 5 years.25 RCVS is associated with the puerperium, which is a period of initially high and then falling progesterone levels. Nonetheless, neither RCVS nor RPLS has been reported in patients taking oral or implantable forms of levonorgestrel. Both of these methods deliver substantially higher blood levels of levonorgestrel than does the intrauterine device.26 We believe that it is unlikely that low systemic levels of a progestin would cause RCVS, although a causal or contributing role cannot be completely excluded. Our patient had a mild CSF pleocytosis, raising the possibility of a cerebral vasculitis. There were no laboratory signs of a systemic vasculitis. The angiographic features of primary angiitis of the central nervous system (CNS) can be similar to those of RCVS.1 However, primary angiitis of the CNS usually has an insidious onset, with a gradual evolution of a dull headache and an accumulation of focal neurologic deficits caused by small infarctions of the gray and white matter. When focal arterial stenoses are detected in this condition, they tend not to resolve spontaneously.27 Our patient presented with recurrent thunderclap headache, no focal neurologic deficits, and, most importantly, had a spontaneous resolution of her symptoms and angiographic abnormalities without immunosuppressive treatment. Therefore, her presentation is more consistent with RCVS than primary angiitis of the CNS.1,28 A mild CSF pleocytosis, as detected in our patient, is more common with primary angiitis of the CNS than with RCVS, but can occur in the latter condition.1 The occurrence of RCVS .3 months after our patient’s blood transfusion raises the question of whether this

RCVS AFTER BLOOD TRANSFUSION

adverse reaction might be more common than the literature would suggest. The widespread recognition of RCVS has developed only recently, probably as a result of the availability of less invasive means of cerebral vascular imaging.1 Some cases of RCVS manifest only as severe headache, a symptom that may not lead to an angiographic evaluation. Investigations of the epidemiology of severe headache or stroke after blood transfusion for chronic anemia may be revealing, as would studies of cerebral hemodynamics after blood transfusion for chronic anemia in situations other than sickle cell disease. It is important to correctly diagnose RCVS not only because the condition can have grave consequences and may be treatable, but because the presentation can be mistaken for primary angiitis of the CNS, a condition with a different prognosis and course of treatment.1 Our case indicates that RCVS should be considered in any patient who develops a severe headache or neurologic deficit for some months after transfusion.

References 1. Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: Reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007;146:34-44. 2. Ducros A, Fiedler U, Porcher R, et al. Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: Frequency, features, and risk factors. Stroke 2010;41:2505-2511. 3. Chen SP, Fuh JL, Lirng JF, et al. Is vasospasm requisite for posterior leukoencephalopathy in patients with primary thunderclap headaches? Cephalalgia 2006;26:530-536. 4. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007;130:3091-3101. 5. Dodick DW, Eross EJ, Drazkowski JF, et al. Thunderclap headache associated with reversible vasospasm and posterior leukoencephalopathy syndrome. Cephalagia 2003; 10:994-997. 6. Ay H, Buonanno FS, Schaefer PW, et al. Posterior leukoencephalopathy without severe hypertension: Utility of diffusion-weighted MRI. Neurology 1998;51:1369-1376. 7. Lin JT, Wang SJ, Fuh JL, et al. Prolonged reversible vasospasm in cyclosporin A–induced encephalopathy. AJNR Am J Neuroradiol 2003;24:102-104. 8. Chatterjee N, Domoto-Reilly K, Fecci PE, et al. Licoriceassociated reversible cerebral vasoconstriction with PRES. Neurology 2010;75:1939-1941. 9. Soo Y, Singhal AB, Leung T, et al. Reversible cerebral vasoconstriction syndrome with posterior leukoencephalopathy after oral contraceptive pills. Cephalagia 2010; 30:42-45.

915.e5 10. Singhal AB. Postpartum angiopathy with reversible posterior leukoencephalopathy. Arch Neurol 2004;61: 411-416. 11. Boughammoura A, Touz
e E, Oppenheim C, et al. Reversible angiopathy and encephalopathy after blood transfusion. J Neurol 2003;250:116-118. 12. Ito Y, Niwa H, Iida H, et al. Post-transfusion reversible posterior leukoencephalopathy syndrome with cerebral vasoconstriction. Neurology 1997;49:1174-1175. 13. Heo K, Park SA, Lee JY, et al. Post-transfusion leukoencephalopathy with cytotoxic and vasogenic edema precipitated by vasospasm. Cerebrovasc Dis 2003;15:230-233. 14. Huang YC, Tsai PL, Yeh JH, et al. Reversible posterior leukoencephalopathy syndrome caused by a blood transfusion: A case report. Acta Neurol Taiwan 2008; 17:258-262. 15. G€ urgey A, Kalayci O, G€ umr€ uk F, et al. Convulsion after blood transfusion in four beta-thalassemia intermedia patients. Pediatr Hematol Oncol 1994;11:549-552. 16. Wasi P, Na-Nokorn S, Pootrakul P, et al. A syndrome of hypertension, convulsion, and cerebral hemorrhage in thalassemic patients after multiple blood-transfusions. Lancet 1978;2:602-604. 17. Frye RE. Reversible posterior leukoencephalopathy syndrome in sickle-cell anemia. Pediatr Neurol 2009;40: 298-301. 18. Warth JA. Hypertension and seizure following transfusion in an adult with sickle cell anemia. Arch Intern Med 1984;144:607-608. 19. Delanty N, Vaughan C, Frucht S, et al. Erythropoietinassociated hypertensive posterior leukoencephalopathy. Neurology 1997;49:686-689. 20. Venketasubramanian N, Prohovnik I, Hurlet A, et al. Middle cerebral artery velocity changes during transfusion in sickle cell anemia. Stroke 1994;25:2153-2158. 21. Kwiatkowski JL, Yim E, Miller S, et al. Effect of transfusion therapy on transcranial Doppler ultrasonography velocities in children with sickle cell disease. Pediatr Blood Cancer 2011;56:777-782. 22. Brand A. Immunological aspects of blood transfusion. Transpl Immunol 2002;10:183-190. 23. Tietjen GE, Conway A, Utley C, et al. Migraine is associated with menorrhagia and endometriosis. Headache 2006;46:422-428. 24. Freilinger T, Schmidt C, Duering M, et al. Reversible cerebral vasoconstriction syndrome associated with hormone therapy for intrauterine insemination. Cephalagia 2010; 30:1127-1132. 25. Oz O, Demirkaya S, Bek S, et al. Reversible cerebral vasoconstriction syndrome: Case report. J Headache Pain 2009;10:295-298. 26. Sivin I. Mechanism of action of intrauterine contraceptive devices. Am J Obstet Gynecol 1997;177:718-719. 27. Hajj-Ali RA, Singhal AB, Benseler S, et al. Primary angiitis of the CNS. Lancet Neurol 2011;10:561-572. 28. Sattar A, Manousakis G, Jensen MB. Systematic review of reversible cerebral vasoconstriction syndrome. Expert Rev Cardiovasc Ther 2010;8:1417-1421.