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. 2021 Feb 11;11:563037. doi: 10.3389/fneur.2020.563037

Cyclosporine-A-Induced Intracranial Thrombotic Complications: Systematic Review and Cases Report

Si-ying Song 1,2,3, Zhong-ao Wang 1,2,3, Yu-chuan Ding 3,4, Xun-ming Ji 1,2,3, Ran Meng 1,2,3,*
PMCID: PMC7906016  PMID: 33643175

Abstract

This study reported two cases of intracranial thrombotic events of aplastic anemia (AA) under therapy with cyclosporine-A (CsA) and reviewed both drug-induced cerebral venous thrombosis (CVT) and CsA-related thrombotic events systematically. We searched PubMed Central (PMC) and EMBASE up to Sep 2019 for publications on drug-induced CVT and Cs-A-induced thrombotic events. Medical subject headings and Emtree headings were used with the following keywords: “cyclosporine-A” and “cerebral venous thrombosis OR cerebral vein thrombosis” and “stroke OR Brain Ischemia OR Brain Infarction OR cerebral infarction OR intracerebral hemorrhage OR intracranial hemorrhage.” We found that CsA might be a significant risk factor in inducing not only CVT but also cerebral arterial thrombosis in patients with AA.

Keywords: cyclosporine-A, cerebral venous sinus thrombosis, cerebral arterial infarction, case report, systematic review

Background

Cyclosporine-A (CsA) is widely used as an immunosuppressive agent in organ transplantation (1–3), ulcerative colitis (UC) (4–6), and aplastic anemia (AA) (7). Most commonly, the high incidences of thromboembolic complications in the renal vascular system were found in patients with CsA use after kidney transplantation (8, 9), which might be due to acute and chronic nephrotoxicity of CsA. However, thrombotic complications in other organs secondary to CsA use are not fully analyzed in the clinical settings (10). In particular, cases of CsA-induced intracranial thrombotic complications in patients with AA were rather rare (7). Herein, we presented two cases of AA with CsA-related intracranial thrombotic events, involved in cerebral venous sinuses and cerebral arteries, respectively. Besides, we conducted a systematic literature review of CsA-related thrombotic events to give more clinical references to physicians in this field.

Moreover, it is well-known that oral contraceptive (OCP) use is regarded as the iatrogenic risk factor inducing cerebral venous thrombosis (CVT). However, there is by far no review on if any other medications that could also cause CVT. Therefore, inspired by our case of CsA-induced CVT, we further comprehensively reviewed drug-induced CVT.

Case Presentation

Case 1

A 15-year-old female with a 4-year history of AA with treatment of CsA (50 mg, bid) complained of an intermittently severe headache on her left frontoparietal areas for 8 months. Her headache could initially attenuate after intravenous injection of mannitol (125 ml, q8h) for 7 days. However, her headache was recurrent and even became aggressively severe with nausea and projectile vomiting 20 days ago, which could no longer be relieved by the former treatment of mannitol. Physical examination revealed a body temperature of 36.4°C, blood pressure of 105/85 mmHg, heart rate of 78/min, and respiratory rate of 20/min. No abnormal finding was found in the neurological examination. Fundoscopy showed stage V papilledema measured by the Frisén scale (Supplementary Figure 1).

Her complete blood cell (CBC) test indicated moderate normocytic normochromic anemia and a decreased platelet level due to her primary disease. The serum iron test was normal, which further excluded the differential diagnosis of iron deficiency anemia. Baseline levels of inflammatory biomarkers, including C-reactive protein (CRP) (37.2 mg/L, normal 1.0–8.0 mg/L), high-sensitivity CRP (hs-CRP) (25.75 mg/L, normal 0.0–3.0 mg/L), and interleukin 6 (IL-6) (19.6 pg/ml, normal 0.0010–7.0 pg/ml) were all above the upper normal limits (Supplementary Table 1), which suggested acute inflammatory reaction secondary to the primary disease. An increased level of D-dimer (2.47 μg/ml, normal range 0.01–0.5 μg/ml) and fibrinogen (4.21 g/L, normal range 2.0–4.0 g/L) remained over the upper limit of the normal range for several days after admission, suggesting the formation of thrombosis at acute stage (Supplementary Table 1). Serum neuron-specific enolase (NSE) level at admission was 51.52 ng/ml (normal range 0.0–17.0 ng/ml). The elevated NSE was related to damage to both neurons and the blood–brain barrier (BBB). Investigation for vasculitis [antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and antiphospholipid antibody (APLA)] was negative. The cerebrospinal fluid (CSF) profile revealed a slightly increased white blood cell (WBC) count (2 × 106/L), and lumbar puncture opening pressure (LPOP) was over 330 mm H2O. Contrast-enhanced magnetic resonance venography (CE-MRV) (Figure 1) and high-resolution MRI with black-blood thrombus image (MRBTI) of the brain (Figure 2) demonstrated subacute thrombosis in the superior sagittal sinus (SSS), straight sinus, right transverse sinus (TS), right sigmoid sinus (SS), and proximal part of right internal jugular vein (IJV). Moreover, no parenchymal lesion was found in MRBTI. The confirmed diagnosis of subacute CVT in multiple sites was made based on imaging findings, with involvement in cerebral venous sinuses and IJV. The CVT-induced cerebrospinal venous insufficiency could cause disturbance of CSF circulation, further leading to intracranial hypertension and related symptoms, such as severe headaches and projectile vomiting. However, the etiology of CVT development was hard to be explained in this case due to lacking common risk factors like other female CVT patients, such as obesity, pregnancy, or long-term OCP use. Moreover, no positive result was found in the workup of thrombophilia, including protein S (PS), protein C (PC), antithrombin-III (AT-III), Factor VII/VIII deficiency, or Factor V Leiden mutation. Then, we closely monitored her blood cell counts on an everyday basis. Her hypercoagulable state induced by moderate anemia secondary to AA and probable adverse effect of CsA on damaging venous vessel walls raised our attention. The procoagulant effect of the two factors might potentiate the formation of CVT.

Figure 1.

Figure 1

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Magnetic resonance venography images of head in Case 1. The red arrow indicates the focal stenosis of cerebral venous sinus and venous collateral circulation.

Figure 2.

Figure 2

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Non-contrast enhanced (A,C,E) and contrast-enhanced (B,D,F) black-blood thrombus images of the head in Case 1. The red arrow indicates the focal stenosis of the internal jugular vein and cerebral vein sinus.

Intravenous injection of mannitol (125 mL, q8h) was continued after the admission. Subcutaneous injection enoxaparin sodium (0.6 ml, qd) was started when the diagnosis of CVT was confirmed and usage of CsA was suspended after consultation with the department of hematology. The usage of enoxaparin sodium was then bridged to rivaroxaban (20 mg, qd) when she was discharged. Outpatient follow-up after 6 months of standard anticoagulation was evaluated by the Patients' Global Impression of Change (PGIC) scale. The patient reported a definite improvement of her symptoms (PGIC score = 6) and was transferred to the department of hematology to further treat AA.

Case 2

A 34-year-old male with a 1-year treatment of CsA (50 mg, bid) for AA presented with right homonymous hemianopia for 20 days, accompanied by dizziness and right-hand numbness. There was no history of nausea and vomiting, motor or sensory symptoms in the limbs, facial bulbar symptoms, sphincter incontinence, and loss of consciousness or seizures. He denied a family history of blood clotting disorders. Physical examination showed his body temperature was 36.9°C, blood pressure was 130/84 mmHg, heart rate was 72 beats/min, and respiratory rate was 18 beats/min. Neurological examination revealed no positive findings.

Peripheral blood test demonstrated mild normocytic normochromic anemia (hemoglobin, 110 g/L, normal range 120–160 g/L; hematocrit 34.8%, normal range 38.0–50.8%). The evaluation of thrombophilia showed increased levels of fibrinogen (4.11 g/L, normal range 2.0–4.0 g/L), D-dimer (1.4 μg/ml, normal range 2.0–4.0 g/L), AT-III (134%, normal range 80.0–120.0%), and protein C (181%, normal range 65.0–140.0%). All the results of serological tests, including aPL, ANA, ANCA, and complements C3 and C4, were negative. Workups of proinflammatory biomarkers, such as CRP, hs-CRP, and IL-6, were all negative. LPOP was 200 mmH2O, and a slightly elevated level of protein (57 mg/dl, normal range 15.0–45.0 mg/dl) and WBC count in CSF was found (5 × 106/L). Serum NSE was more than two times higher than the normal upper limit (36.59 ng/ml, normal range 0.0–17.0 ng/ml). MRI indicated cerebral infarction in the left occipital lobe (Figure 3A) and both sides of the cerebellum (Figure 3B). Magnetic resonance angiography (MRA) showed focal stenosis in the distal branches of the left posterior cerebral artery (PCA) and a partial filling defect in both sides of the superior cerebellar arteries (Figure 4). CE-MRV excluded the possibility of CVT (Figure 5). As this patient has not been identified to have any vascular risk factors, such as diabetes mellitus (DM), hypertension, hyperlipidemia, obesity or smoking history, family history of small vessel disease, or state of hypercoagulability, and the evidence of systemic autoimmune diseases was also negative, we assumed that the cerebral atrial infarction was caused by emboli from cardiac source or thrombosis in situ secondary to certain unknown injuries. Then, to further evaluate the potential cause of stroke, transesophageal echocardiography (TEE) was conducted, with negative findings of atrial septal abnormalities [patent foramen ovale (PFO), atrial septal defect (ASD), or atrial septal aneurysm (ASA)]. Based on the patient's medical history of using CsA, the direct or indirect adverse effect of CsA may contribute to the damage in arterial vessel walls, which further initiated the formation of thrombosis in situ. The usage of CsA was withdrawn after consultation with the department of hematology due to his relatively well-controlled condition of AA. Aspirin (100 mg, qd) was prescribed at discharge.

Figure 3.

Figure 3

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(A) Magnetic resonance images of the head in Case 2. The red arrow indicates the focal ischemic infarction in left occipital lobe [(a) T1 sequence; (b–d) T1 sequence with contrast-enhancing; (e) T2 sequence; (f) T2 FLAIR sequence; (g) DWI sequence; (h) ADC sequence]. (B) Magnetic resonance images of the head in Case 2. The red arrow indicates the focal ischemic infarction in cerebellum [(a) T1 sequence; (b) T2 sequence; (c) T2 FLAIR sequence; (d) DWI sequence].

Figure 4.

Figure 4

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(A–D) Magnetic resonance arthrography images of the head in Case 2. The red arrow indicates partial filling defects.

Figure 5.

Figure 5

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Magnetic resonance venography images of the head (A–C) and neck (D–F) in Case 2.

MRI follow-up at 6 months post-stroke showed no new-onset parenchymal lesions, and his symptoms were partially relieved and evaluated by PGIC scale (PGIC score = 6).

Literature Review

We searched PubMed Central (PMC) and EMBASE up to Sep 2019 for publications on CsA-induced thrombotic events and drug-induced CVT. We used Medical subject headings and Emtree headings combining with the following keywords: “cyclosporine-A” and “cerebral venous thrombosis OR cerebral vein thrombosis” and “stroke OR Brain Ischemia OR Brain Infarction OR cerebral infarction OR intracerebral hemorrhage OR intracranial hemorrhage.” We also screened reference lists of included articles for additional relevant studies. Intracranial thrombotic events had to be diagnosed by MRI, conventional angiography, computed tomography (CT) angiography, or at surgery or autopsy. Articles written in languages other than English were only selected if they had an English abstract with sufficient data.

We identified 322 publications related to drug-induced cerebral venous sinus thrombosis (CVST), of which 109 were selected for full-length review (Figure 6). Among these, 79 articles with a total of 706 patients were included based on our inclusion criteria. However, nine articles within the inclusion criteria were not collected due to no access to full texts despite that we searched for several times and tried to contact corresponding authors by e-mail. Herein, we listed these nine references in Supplementary Materials. Most of the eligible studies were case reports or case series (n = 68) and retrospective studies (n = 9), and only one meta-analysis and one prospective study were found (Table 1) (11–89). Western countries reported 95% of the cases, followed by eastern countries (4%), while only one case was from African countries. The mean age of patients was 33.8 ± 17.9 years, and 68.5% of patients were female. There were 94 pediatric cases (94/706, 13.3%). The most common symptoms were seizures (48.6%), headaches (38.1%), nausea/vomiting (19.5%), altered mental status (drowsiness, confusion, syncope, or coma) (17.6%), motor/sensory disorder (12.9%), visual disturbance (9.0%), and aphasia/dysphasia (7.6%). The least common symptoms were personality/behavior change (aggressiveness, n = 1; irritability, n = 4; poor personal care, n = 1) (2.9%) and ataxia (2.4%). Only few cases reported symptoms like general malaise/fatigability (n = 2), fever (n = 2), diarrhea (n = 2), and urinary incontinence (n = 1). CVT was confirmed by CE-MRV (n = 55) and MRI (n = 18). Although digital subtraction angiography (DSA) was considered the gold standard, only 13 cases conducted DSA to make the defined diagnosis. Besides, CT (n = 5), CT venography (CTV) (n = 5) and autopsy (n = 5) were also mentioned as method to detect CVT. Among all sinuses, SSS (n = 123) was most likely involved in drug-induced CVT, followed by the TS (n = 119), SS (n = 97), and straight sinus (n = 80). Thrombosis was usually formed bilaterally in the TS (n = 26), while it was less common in the left TS (LTS) (n = 23) and the right TS (RTS) (n = 14). However, the left SS (LSS) more potentially formed thrombosis (n = 18) than the right SS (RSS) (n = 9); 60.3% of cases had multiple sinus thromboses (105/174). CVST combined with cortical vein thrombosis (CoVT) and isolated CoVT were reported in 102 cases and 6 cases, respectively. Drug-induced deep cerebral vein thrombosis was only found in a vein of Galen, combined with CVST (n = 2). Furthermore, CVST was also found to coexist with jugular system thrombosis (n = 70), while isolated jugular system thrombosis was very rare (n = 2). Nineteen articles indicated contraceptive drug-induced CVT, and 14 studies reported heparin-induced thrombocytopenia (HIT) that resulted in CVT. l-Asparaginase was widely used in patients with acute lymphoblastic leukemia (ALL), while 10 publications demonstrated the close relationship between CVT and l-asparaginase. Furthermore, CsA use was also a risk factor for CVT (n = 7).

Figure 6.

Figure 6

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Flow diagram of the study selection process on drug-induced cerebral venous sinus thrombosis (CVST).

Table 1.

Drug induced cerebral venous thrombosis.

Drug Age/gender Primary disease Symptoms CVST References Country Article type Study size
Modality Location
Contrast
Iopamidol 36/F Myelography NR DSA SSS (11) France Case report 1
24/M Recurrent left sciatica (Myelography) Headache (severe), nausea and vomiting DSA SSS, RLS (12) France Case report 1
Recreational drug
MDMA type synthetic drugs
   Ecstasy 22/F None Headache, nausea, visual disturbance (photophobia, visual fortification spectra), expressive dysphasia, and right hemisensory loss. DSA TS (13) UK Case report 1
   Speed 19/F None Uncontrollable aggressiveness MRV LTS (14) Spain Case report 1
   Cocaine 30/M None Headache (Occipital) and vomiting MRV SSS, TS (15) UK Case report 1
Phosphodiesterase-5 (PDE5) inhibitors
Tadalafil 45/M None Headache (severe, posterior, sudden-onset, 3-day), and seizure (generalized tonic-clonic) MRI RCoVT (16) Japan Case report 1
Sildenafil 57/M Two episodes of venous thrombosis (DVT; hemorrhoid plexus thrombosis) Headache (occipital, 2-week) and visual disturbance (blurry vision) MRV SSS, RSS, RTS (17) Italy Case report 1
IVIG 16/F ITP Headache (severe), neck rigidity, and vomiting MRI SSS (18) USA Case report 1
11/M ITP Headache (severe, transient frontotemporal) CTV SSS (19) Canada Case report 1
11/M Humoral immunodeficiency (Bruton's disease) Expressive aphasia, right upper extremity heaviness CTV SSS (20) Lebanon Case report 1
13/F ITP Headache MRI LIJV (21) USA Case report 1
Others
Dulaglutide 52/F DM-2 Headache (3-day) and visual disturbance (blurry vision) MRV RTS (22) India Case report 1
Romiplostim 45/F ITP Headache (severe, occipital) MRV SSS, TS (23) Taiwan Case report 1
Epoetin alfa 37/F End stage renal disease Headache (progressive, several-day) MRV SSS, SS (24) USA Case report 1
Dietary supplements 63/M well-controlled hypertension Seizure (generalized tonic-clonic) DSA SS, vein of Galen (25) USA Case report 1
Lithum 30/F Bipolar disorder Headache (progressive), confusion, visual disturbance (blurry vision), and left hemiparesis. DSA SSS, LSS, LTS, straight sinus (26) USA Case report 1
Finasteride 35/M (case 1)
41/M (case 2)		 Male-pattern hair loss Headache and seizures (case 1);
Headache (case 2)		 CTV SSS (27) Japan Case report 2
Combination tacrolimus/sirolimus 67/M Renal transplantation Seizure (generalized) and right hemiparesis MRI TS (28) Australia Case report 1
Clozapine 30/F Chronic paranoid schizophrenia Vomiting, irritability, fatigability, poor personal care (5-day) MRV SSS, ISS, RTS, RIJV (29) USA Case report 1
Levetiracetam 6.5/M None Headache and vomiting (2-day), then seizures (generalized) MRI LTS, LSS (30) UK Case report 1
Synthetic sex steroids
Oral contraception
Phytoestrogens 52/F None Headache (diffuse and continuous, 2-month) MRV LLS, LSS (31) Portugal Case report 1
Third-generation CHCs (containing desogestrel or gestoden) 16–49/F CVTh Seizure (n = 52) CTV/MRV CVT: dural sinuses, DCVT, CoVT, IJV (32) USA Retro 57
Ethinylestradiol/
levonorgestrel		 21/F None Headache (severe, 4-day) CTV SSS, CoVT, RTS, RSS (33) USA Case report 1
NR 18/F (case 1)
23/F (case 2)		 Protein C resistance (case 1);
Anti-thrombin III deficiency (case 2)		 Headache, nausea, vomiting and visual disturbance (photophobia) (case 1);
Headache, vomiting, altered sensorium (case 2)		 MRI SSS, TS, LSS (case 1)
SSS (case 2)		 (34) India Case report 2
NR 18/F (case 1)
18/F (case 2)		 None (case 1);
ADHD and bipolar disorder (case 2)		 Headache (intermittent right-sided) and visual disturbance (blurry vision) (3-day) (case 1);
Headache (intermittent right-sided) and visual disturbance (double vision) (6-week) (case 2)		 MRV LTS, LSS (case 1);
RTS, IJV (case 2)		 (35) USA Case report 2
NR 27/F (case 1)
23/F (case 2)		 None Headache (retroauricular), vomiting, drowsiness, fever (several days) (case 1);
Headache, vomiting, increasing drowsiness and extra-pyramidal movements (1 day) (case 2).		 DSA (case 1)
MRI (case 2)		 LTS, SS (case 1);
SSS, SS (case 2)		 (36) Italy Case report 2
Ethinylestradiol/
desogestrel		 24/F None Headache (severe, 1 week), vomiting. DSA SSS, RLS, RSS, vein of Galen (37) Czech Republic Case report 1
Noracyclina (case 1)
Ovulenb (case 2)		 50/F (case 1)
41/F (case 2)		 None (case 1);
Thrombosis of left common carotid (case 2)		 Fluctuated conscious status, aphasia, right arm weakness, and several epileptic seizures (case 1);
Right hand numbness and rapid-onset unconsciousness (case 2)		 Necropsy SSS, CoVT (case 1, 2); (38) Switzerland Case report 2
Lyndiol 2, 5 (case 1)
Metrulen-M (case 2)
Anovlar (case 3)
Gynovlar (case 4)
Nuvacon (case 5)		 24/F (case 1)
49/F (case 2)
30/F (case 3)
23/F (case 4)
29/F (case 5)		 RIJVS (case 1)
Diabetes (case 2)
Right pulmonary embolus (case 3)
Thrombosis of choroid plexus (case 4)
Marfan's syndrome; thrombosis of iliac vein (case 5)		 Headache, vomiting and drowsiness (5-day) (case 1);
Headache, vomiting, seizure (generalized, left-sided) (case 2);
Deeply comatose (case 3);
Diarrhea, headache (severe) and further unconsciousness (case 4);
Abdominal pain, headache (severe, 1-day), and vomiting (5-day) (case 5).		 Necropsy SSS, RTS, SS, CoVT, IJV (case 1);
SSS, RTS, LTS, CoVT (case 2, 3, 5);
All sinuses thrombosis, CoVT (case 4)		 (39) NR Case report 5
Norethynodrel and mestranol 35/F Eclampsia during pregnancy; obesity Headache (severe, persistent, temporal) (4-day), vomiting, diarrhea, seizure, urinary incontinence, upper limb weakness (left-sided), and visual disturbance (photophobia) Necropsy SSS, LTS, CoVT (40) NR Case report 1
Enovid (case 1)
Ortho novum (case 2)		 29/F (case 1, 2) Multiple arterial thrombi; thrombosis of left opththalmic vein;
Marfan's syndrome (case 2)		 NR Necropsy All sinuses thrombosis, CoVT (case 1);
SSS (case 2)		 (41) NR Case report 2
Combined oral contraceptives (COCs), progestin-only contraceptives or cyproterone acetate. 15–49/F Former thromboembolic event (including PE, CVT, ischemic stroke, or MI) NR NR CVT (42) France Retro 452
Yasmin 28c 18/F None Headache (Throbbing, frontal and occipital, 1-month) MRV RTS, RSS, IJV, CoVT (43) USA Case report 1
NR 22/F None Severe headache (1 week) CT/MRV/DSA LTS, LSS (44) China Case report 1
Cyproterone/gestodene 50/F Heterozygous factor II polymorphism NR NR CVST (45) Italy Retro 1/28
NR 23–45/F Prothrombin mutation G20210A (n = 2) Headache (n = 11), vomiting (n = 2), aphasia (n = 1) MRA (n = 10)
DSA (n = 7)		 Straight sinus (n = 15)
TS (n = 7)		 (46) Spain Retro 15
Other contraceptive drugs
Norethisterone enanthate injection 23/F None Headaches (progressive), vomiting (repeated) and syncope (2–3 min) MRV SSS, RTS, RSS (47) USA Case report 1
Vaginal contraceptive ringd 28/F None Headache CT LSS, TS (48) USA Case report 1
33/F None Seizures (multiple tonic-clonic), headaches CT LTS, LSS, LIJV (49) Canada Case report 1
Androgen analog
Oxymetholone 40/F AA NR MRI SSS, LTS (50) South Korea Case report 1
Nandrolone decaonoate 22/M None Headaches and vomiting (repeated) (3-day) MRV SSS, TS (51) Iran Case report 1
Fluoxymesterone 52/F (case 1)
39/F (case 2)		 Hypoplastic anemia Headaches (severe), seizures, aphasia and hemiplegia, coma (case 1)
Headaches (severe) and seizure (focal) (case 2)		 DSA SSS (case 1)
SSS, CoVT (case 2)		 (52) USA Case report 3
Methenolone-enanthate 26/F (case 3) Headaches, visual disturbance (blurred vision), and hemiparesis (right-sided) (case 3) SSS, CoVT (case 3)
Danazole 40/M AA Headache (acute onset) and altered sensorium CT CoVT (53) India Case report 1
19/M IHA Headache and visual disturbance (transient obscurations of vision) DSA SSS, CoVT, straight sinus (54) USA Case report 1
Steroid 32/F Relapsing-remitting multiple sclerosis Numbness and weakness (both legs) MRV LTS, LSS (55) Turkey Case report 1
31/M IHA Headaches, anorexia, general malaise DSA SSS, CoVT, straight sinus (52) Japan Case report 1
HIT-related CVST
LMWH 60/F Bilateral extensive varicose veins in legs Right focal seizures with secondary generalization followed by headache, slurred speech, and altered sensorium MRI/CTV LTS, LSS (56) India Case report 1
52/F Kyphoplasty and posterior spinal fusion Acute onset altered mental status with significant agitation and non-sensical speech. MRV LTS, LSS, LIJV (57) USA Case report 1
55/F Partial gastrectomy NR MRV SSS, SS, LIJV (58) Germany Case report 1
57/F Antiphospholipid syndrome and possible systemic lupus erythematosus Fever, altered mental status, and aphasia (expressive and sensory) MRV SSS, LSS, LIJV (59) Greece Case report 1
69/F Knee replacement for osteoarthritis Seizures (right arm focal type) MRV SSS, CoVT (60) USA Case report 1
72/M Left knee joint surgery Comatose Necropsy SSS, SS, CoVT (61) Germany Case report 1
38 ± 28 NR NR MRV CVT (62) Germany Retro 3/120
Unfractionated heparin 61/F Retinal transient ischemic attack; DVT of the leg Headache (progressive) and aphasia MRI LLS (63) France Case report 1
18/M Extensive UC Headache (severe), nausea and vomiting MRI RTS, confluence area (64) Sweden Case report 1
45/F Cystic pituitary adenoma. Aphasia and visual disturbances MRI LTS, LSS (65) USA Case report 1
67/F NR NR CTV SSS (66) Germany Case report 1
63/F Polycythemia vera Seizures (right-sided focal type) Contrast-enhanced CT SSS (67) USA Case report 1
36/F PNH Headache, nausea, then developed dysphasia and right hemiparesis MRV LTS, LSS (68) Japan Case report 1
67/F Antiphospholipid syndrome Headache (transient), vertigo, tinnitus and right hemifacial par-aesthesia with propagation down to the ipsilateral arm. MRV RTS, RSS, IJV (69) Switzerland Case report 1
Anti-cancer drugs
Tamoxifen 40/F Breast cancer Headache and hemiparesis (left-sided) (10-day) MRI SSS, RLS, RIJV (70) Turkey Case report 1
30/F Breast cancer Headache (acute-onset) and hemiparesis (left-sided) DSA/MRI SSS (71) South Korea Case report 1
46/F Breast cancer Headache (severe) and nausea (subacute onset, 2-week) MRI/CT SSS, straight sinus (72) South Korea Case report 1
47/F Breast cancer Headache (Severe), seizure (generalized tonic-clonic) MRV SSS, CoVT (73) USA Case report 1
L-asparaginase 15/M ALL Acute severe headache and recurrent vomiting MRV SSS, TS, straight sinus (74) Germany Case report 1
10/M (case 1)
13/F (case 2)		 ALL (case 1)
Acute mixed phenotypic leukemia (case 2)		 Headache, vomiting, seizures and loss of consciousness (case 1)
Headache and focal seizure (case 2)		 MRV SSS (case 1 & 2) (75) India Case report 2
5–16 ALL (n = 8)
Non-Hodgkin lymphoma (n = 1)		 Headaches (chronic, daily), and seizures (partial-complex)g MRV LTS, LSS, LIJV (case 1)
CVST (case 2)
SSS (case 3)
TS (case 4)		 (76) USA Retro 9/200
2.3/M (case 1)
3.5/F (case 2)		 ALL (case 1 & 2) Seizure (left focal seizure evolving into generalized tonic-colonic seizure and subsequently status epilepticus) (case 1);
Seizure (left focal seizure evolving into status epilepticus) (case 2)		 MRV (case 1 & 2) SSS (case 1 & 2) (77) India Case report 2
(1–17)/(38/10, M/F) ALL Headache (n = 14), a decreased level or loss of consciousness (n = 15), visual impairment (n = 3), focal or generalized seizures (n = 18), photophobia (n = 1), vomiting (n = 8), irritability (n = 3), hemiparesis (n = 5), ataxia (n = 2), speech impairment (n = 6), and cranial nerve palsy (n = 1). CT (n = 38), MRV (n = 27) CoVT (n = 3),
CVST (n = 26),
CVST combined with CoVT (n = 4)		 (78) Italy Retro 33/48
5.6 (1.0–17.0)/(38/33, M/F) ALL NR MRI CVT (79) Austria Pro 3/71
9/M ALL Headache (Acute-onset, severe) and then seizures (left-sided focal type) and right arm sensory disturbance. MRI SSS (80) Saudi Arabia Case report 1
32 (15–59)/(144/96, M/F) ALL or lymphoblastic lymphoma NR NR CVT (81) France Retro 5/214
NA ALL NR NR CVT (82) Italy Meta-analysis 26/1,752
16/M ALL Headache, vomiting, and multiple episodes of seizures Contrast enhanced CT CoVT (83) India Case report 1
L-asparaginase or Tamoxifenf 44.5 (10-71)/(16/4, M/F) Hematologic malignancies (n = 9); Solid tumor (n = 11) Headache (n = 8), seizure (n = 6), nausea/vomiting (n = 5), hemiparesis/aphasia (n = 4), altered metal status/coma (n = 3), dizziness (n = 3), visual disturbance (n = 2), gait disturbance (n = 1), incidental finding (n = 1), not available (n = 1) MRV SSS (n = 13), TS (n = 8), SS (n = 5), IJV (n = 4), straight sinus (n = 1) (84) USA Retro 20
Cisplatin and BEP 16/F Immature teratoma Hemiparesis (left-sided) MRI SSS (85) Tunisia Case report 1
Thalidomide 74/F Multiple myeloma Headache (right-sided, frontal), confusion and speech difficulty (acute-onset) MRI LTS, straight sinus, CoVT, LIJV (86) USA Case report 1
Methotrexate 12/M ALL Hemiparesis (right-sided), aphasia, altered mental status, persistent seizure activity, and progressive neurological deterioration MRI LTS, LSS (87) USA Case report 1
ATRA 22/F APML Visual disturbance (blurred vision on the right eye) MRV SSS, RSS, TS, IJV (88) Malaysia Case report 1
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R, right; L, left; SS, sigmoid sinus; SSS, superior sagittal sinus; TS, transverse sinus; LS, lateral sinus; CVT, cerebral venous thrombosis; CVST, cerebral venous sinus thrombosis; CoVT, cortical vein thrombosis; IJVS, internal jugular vein stenosis; DVT, deep vein thrombosis; ALL, acute lymphoblastic leukemia; APML, acute promyelocytic leaukaemia; HIT, Heparin-induced thrombocytopenia; AA, Aplastic anemia; DM, diabetes mellites; PNH, Paroxysmal nocturnal hemoglobinuria; UC, ulcerative colitis; MI, myocardial infarction; ADHD, attention deficit hyperactivity disorder; IHA, immune hemolytic anemia; ITP, immune thrombocytopenia; PE, pulmonary emboli; MRI, magnetic resonance imaging; CTV, CT venography; MRV, magnetic resonance venography; DSA, digital subtraction angiography; CHCs, combined hormonal contraceptives; ATRA, All-trans retinoic acid; BEP, bleomycin and etoposide; IVIG, Intravenous immunoglobulins; Retro, retrospective; Pro, prospective; NR, not reported.

a

Noracyclin = Lynestrenol/mestranol.

b

Ovulen = Ethinodiol diacetate/mestranol.

c

Yasmin 28 = drospirenone.

d

Vaginal contraceptive ring (NuvaRing): etonogestrel and ethinyl-estradiol per day.

e

Danazol is an attenuated androgen derived from ethisterone (17 α-ethinyltestosterone).

f

This study enrolled patients with hematologic malignancies or solid tumors.

g

All patients survived, with 4 experiencing complications possibly related to CVST. In this article, report these four patients in detail.

h

Female patients with diagnosed cerebral venous thrombosis (CVT) of the dural sinuses, involvement of the deep venous system (DCVT), cortical venous thrombosis, or with thrombosis of the jugular system.

We further searched articles related to CsA-induced thrombotic events to explore if CsA would bring extensive damage to different kinds of blood vessels. One hundred forty articles were identified, and full texts of 67 articles were screened (Figure 7). Only studies with sufficient information and a clear description of the relationship between CsA and thrombosis were finally included (n = 29). CsA was more likely associated with venous thrombotic events (n = 16), followed by capillary thrombotic events (n = 9) and arterial thrombotic events (n = 8). CVT was the most common thrombosis in CsA-induced thrombotic events (Table 2) (1–9, 90–109). Thrombosis in the renal vessel system was more likely formed due to CsA use in renal transplantation (n = 13).

Figure 7.

Figure 7

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Flow diagram of the study selection process on cyclosporine-A (CsA)-induced thrombosis.

Table 2.

Cyclosporine-A induced thrombosis.

Age/gender Thrombosis location Primary disease References Country Study size Article type
NR DVT (n = 25),
PE (n = 4),
DVT with PE (n = 11)		 Renal transplantation (90) UK 40/480 Retro
41 ± 12 DVT Renal transplantation (91) Switzerland 9/97 Pro
52/M (case 1)
26/M (case 2)
32/M (case 3)
61/M (case 4)
11/M (case 5)
54/M (case 6)
45/F (case 7)		 Glomerular capillary;
Renal afferent artery		 Renal transplantation (cadaver-donor) (92) UK 7 Case report
NA Cyclosporine-associated arteriopathy (acute tubular necrosis; acute vasculitis; glomerular ischemia; interstitial intimate; Intima proliferation; venous thrombosis) Renal transplantation (cadaver-donor) (93) USA 16/200 Retro
36.7 ± 1.3/(49/41, M/F) PE (n = 10),
Renal vein (n = 1),
DVT (n = 3),
Hemorrhoidal artery (n = 3)		 Renal transplantation (cadaver-donor) (8) Belgium 13/90 Retro
35.9 ± 13.8 DVT Renal transplantation (cadaver-donor, living-donor) (94) Sweden 9/97 Pro
53/F (case 1) 33/M (case 2)
48/F (case 3)		 HUS,
Glomerular capillaries,
Renal artery		 Renal transplantation (95) Canada 3 Case report
33/F Glomerular capillaries Renal transplantation (cadaver-donor) (96) UK 1 Case report
NA Glomerular capillaries (Platelet microthrombi) Renal transplantation (97) UK 12/32 Retro
NA Renal artery Renal transplantation (cadaver-donor, living-donor) (98) China 1/14 Retro
6 (case 1)
6 (case 2)
17 (case 3)
48 (case 4)
53 (case 5)
51 (case 6)		 Renal vein Renal transplantation (cadaver-donor, living-donor) (99) UK 6/791 Retro
NA HUS, Glomerular capillaries Behcet's disease (100) France 2 Case report
NA CVST SSINS (101) UK 1/53 Retro
45.1 ± 12.3 Renal vein Renal transplantation (cadaver-donor) (102) UK 16 Pro
NA Eyeground artery Recurrent nephrotic syndrome (103) Japan 1 Case report
NA CVT Renal transplantation (104) Spain 1 Case report
25.0 ± 26.4 HUS Renal transplantation (105) USA 10/672 Retro
NA Hepatic vein Inflammatory bowel disease and latent thrombocythemia (106) France 1 Case report
19/M CVST Severe active UC (5) Japan 1 Case report
48/F CVST (LTS, LSS), LIJVS Chronic UC (4) USA 1 Case report
NA Thrombotic microangiopathy SPK transplantation (107) Belgium 1/102 Retro
(18–55) Pancreas graft thrombosis (n = 10),
Kidney graft thrombosis (n = 1)		 SPK transplantation (9) Belgium 11/102 Pro
31 ± 11 Graft thrombosis (combined arterial and venous thrombotic occlusion, n = 5; arterial occlusion, n = 3, venous occlusion, n = 1) SPK transplantation (3) Austria 9/67 Retro
30/F Central retinal vein Renal transplantation (cadaver-donor) (108) Croatia 1 Case report
56.7 ± 10.1 Coronary artery Heart transplantation (2) Canada 18/129 Retro
25/M CVST (SSS, TS) Renal transplantation (living-donor) (1) Sri Lanka 1 Case report
23/F CVT Neuro-Behcet's disease (109) Brazil 3/40 Retro
18–64/(28/33, F/M) Venous thrombosis Acute steroid-refractory or dependent UC (6) Finland 1/61 Pro
44/F CVST AA (7) China 1 Case report
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R, right; L, left; CVT, cerebral vein thrombosis; CVST, cerebral vein sinus thrombosis; CoVT, cortical vein thrombosis; SSS, superior sagittal sinus; TS, transverse sinus; DVT, deep vein thrombosis; PE, Pulmonary emboli; SPK transplantation, Simultaneous pancreas-kidney transplantation; HUS, Hemolytic Uremic Syndrome; AA, Aplastic anemia; SSINS, steroid sensitive idiopathic nephrotic syndrome; UC, ulcerative colitis; IBD, inflammatory bowel disease; Retro, retrospective; Pro, prospective; NR, not reported.

Statistical Analysis

Quantitative variables with a normal distribution were specified as mean ± standard deviation. Analyses were performed with Stata software (version 15.0 SE, Stata Corp, LP, Texas, USA).

Discussion

This was the first systematic review on drug-induced CVT and CsA-related thrombosis based on the clinical cases. CVT is a rare subtype of stroke, accounting for <1% of all strokes (110). Severe CVT can be fatal. Common etiologies of CVT are postpartum period, infection, and coagulopathies (111). However, drug-induced CVT should not be neglected, as this kind of CVT could be reversible and preventable if we avoid certain drugs when treating primary diseases, for instance, the two cases presented in this study. In line with CVT of other etiologies, the most common symptoms in drug-induced CVT were seizures (48.6%) and headaches (38.1%). Furthermore, women or young people were mainly involved. Both CE-MRV and black-blood thrombus image (BBTI) are useful imaging tools to make a definitive diagnosis.

It would be worth noticing that CsA can induce not only CVT but also cerebral arterial thrombosis, as in Case 2 of this report. Interestingly, drug-induced CVT is more likely involved in multiple sinuses, cortical veins, or IJV, such as Case 1 in this paper. It is well-known that OCP can promote CVT in women, whereas CsA-related CVT should also raise our concern.

Cyclosporine thrombogenicity manifested mostly with CVT. However, the underlying mechanism is still controversial. Several adverse effects of CsA had been reported in patients: Firstly, CsA enhanced secretion of von Willebrand factor (VWF), a classic platelet agonist, from endothelial cells (112). Then, platelet aggregation was increased due to a higher level of VWF in circulation (113). Thirdly, CsA-induced endothelial cell dysfunction by suppressing nitric oxide production and initiating intrinsic coagulation pathway (10, 114). Further, CsA was associated with increased D-dimer and fibrinogen levels, which were observed in our patients after the onset of the thrombotic event, which was consistent with other studies (4, 8, 115). However, some animal and clinical studies showed that CsA therapy was not related to thrombosis in renal transplant and even provided strong protection from both reperfusion injury (97) and congestive heart failure (116) or improved recovery after treatment of coronary thrombosis with angioplasty (117).

Moreover, apart from the thrombogenic effect of CsA, patients with AA frequently presented with decreased levels of WBC, RBC, or platelet. Anemia secondary to AA could also be associated with both CVT (118) and arterial ischemic stroke (AIS) (119). More importantly, anemia was correlated with stroke severity and poor clinical outcomes in AIS patients (120, 121). Thus, a well-controlled condition of AA is vital to prevent cerebral thrombotic events. Besides, a stronger association between anemia and CVT in men than in women (118), which reminded us that the potential confounders, such as age and gender, should also be taken into consideration when treating AA patients with thrombotic complications.

Although we cannot prove the clear relationship between the potential adverse effect of CsA, anemia secondary to AA, and intracranial thrombotic events in these two cases due to the rarity of similar cases, CsA-induced intracranial thrombosis in AA patients was firstly reported. This observation may at least warrant caution of monitoring thrombotic events during CsA treatment in patients with AA. Therefore, we suggested that future studies could shed more light on the mechanism of the prothrombotic effects of Cs-A in the treatment of AA patients. Additionally, the systematic literature review on CsA-related thrombotic events and drug-induced CVT would give more clinical references to physicians in this field, especially when treating patients with unknown reasons for stroke.

Summary Table

What Is Known About This Topic?

  • A possible association may exist between cyclosporine-A use and thrombotic events in patients with aplastic anemia.

  • Currently, there is a lack of information on comprehensive review on drug-induced cerebral venous thrombosis and cyclosporine-A-related thrombotic events.

What Does This Paper Add?

  • This real-world study provides two cases with aplastic anemia that developed intracerebral thrombotic events due to cyclosporine-A use.

  • Articles on cyclosporine-A-related thrombotic events were reviewed. CsA-induced thrombosis may involve the arteries, veins, and capillaries. Damage to the renal vascular system was most commonly reported due to the acute and chronic nephrotoxicity of CsA.

  • Studies on drug-induced cerebral venous thrombosis were selected, of which we summarized features of clinical characteristics and neuroimaging findings.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics Statement

The studies involving human participants were reviewed and approved by Xuanwu Hospital, Beijing, China. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author Contributions

RM drafted and revised the manuscript and provided the study concept and design. S-YS drafted and revised the manuscript, provided the study concept and design, and carried out collection, assembly, and interpretation of the data. RM, S-YS, Y-CD, Z-AW, and X-MJ wrote the manuscript and gave final approval of the manuscript. Y-CD intensively edited the revised version and contributed to the critical revision. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We would like to thank the two patients for allowing us to publish their medical experience for scientific use.

Footnotes

Funding. This study was sponsored by the National Key R&D Program of China (2017YFC1308400), the National Natural Science Foundation (81371289), and the Project of Beijing Municipal Top Talent for Healthy Work of China (2014-2-015).

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2020.563037/full#supplementary-material

Supplementary Figure 1

Funduscopic imaging of Case 1.

Click here for additional data file. (107KB, JPEG)
Supplementary Table 1

Follow up of abnormal examination in Case 1.

Click here for additional data file. (131.7KB, DOCX)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figure 1

Funduscopic imaging of Case 1.

Click here for additional data file. (107KB, JPEG)
Supplementary Table 1

Follow up of abnormal examination in Case 1.

Click here for additional data file. (131.7KB, DOCX)

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

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