European Journal of Cardiovascular Medicine

Stroke is a significant cause of morbidity and mortality worldwide, with its growing incidence, particularly in younger population.¹ Acute stroke is characterised by abrupt onset of focal neurological deficits within a vascular territory due to underlying cerebrovascular pathologies. Ischemic stroke constitutes 68% of all strokes globally, of which 25% are cardioembolic whereas hemorrhagic strokes contribute to 32% of all strokes.^2,3 Up to one-third of strokes have no identifiable etiology and are considered cryptogenic. Embolic stroke of undetermined source (ESUS) is a subset of cryptogenic stroke, defined as a nonlacunar infarct without proximal arterial stenosis or source of cardioembolism. The various mechanisms of ESUS include cardioembolism due to occult paroxysmal atrial fibrillation, aortic atheromatous disease, paradoxical embolism through a patent foramen ovale (PFO), atrial septal defect, ventricular septal defect, or pulmonary arteriovenous malformation, undefined thrombophilia, substenotic cerebrovascular disease and other vasculopathies.  Malignancy has also been recognised as an important cause of ESUS. 5-10% of ESUS have been found to have active cancer.⁴

Malignancy is an established risk factor for ischemic stroke and other arterial thromboembolic events, especially in the first 6 months after diagnosis and in patients with distant metastases.^5,6 The stroke risk varies by cancer type and is highest in lung and pancreatic cancer. Approximately one-half of the ischemic strokes in patients with cancer are identified as ESUS. Stroke, particularly ESUS, can also be the initial presentation of cancer. The proposed mechanisms of malignancy-associated strokes include hypercoagulability, nonbacterial thrombotic endocarditis (NBTE), direct tumor embolism, paraneoplastic syndromes, chemotherapy and anti-cancer therapies.⁴ Reports also suggest that approximately 10% of patients with unprovoked venous thromboembolism had occult cancer, stressing on malignancy-induced hypercoagulability.

Young stroke is defined as stroke occurring in individuals under 45 years of age.⁷ Indian studies have shown that about 10% to 15% of strokes occur in the young.⁸ Apart from the traditional vascular risk factors, the most prevalent “rare” risk factors for stroke in young adults include valvular heart diseases, patent foramen ovale, migraine, illicit drug use, use of oral contraceptives, and pregnancy or puerperium.⁹ Adenomyosis is a commonly encountered gynecological condition characterised by benign invasion of the endometrium into the myometrium producing a diffusely enlarged uterus resulting in menorrhagia, pelvic pain, and dysmenorrhea. We report two cases of adenomyosis who expressed prothrombotic tendency including ischemic stroke and thereby discuss the need to consider adenomyosis as a rare risk factor for young stroke in females. This case series highlights two uncommon etiologies of ischemic stroke: one secondary to underlying malignancy and the other associated with uterine adenomyosis.

Case 1

A 63-year-old male with a history of type 2 diabetes mellitus, who was diagnosed with metastatic papillary renal cell carcinoma- status post right radical nephrectomy was admitted with altered sensorium, involuntary micturition and recurrent hypoglycemia. On presentation, he was disoriented but had no focal neurological deficits. Initial investigations revealed neutrophilic leukocytosis, severe hyponatremia and recurrent hypoglycemia. A CT brain showed no acute pathology. Supportive treatment including iv dextrose and 3% saline were initiated. However, his neurological status remained altered, prompting further evaluation. An MRI brain revealed multiple bilateral embolic infarcts (Figure 1). A transthoracic echocardiogram (ECHO) was done to search for cardiac sources of embolism but showed no evidence of infective endocarditis or intracardiac thrombi or septal defects or PFO. Holter monitoring showed no arrhythmias. Blood cultures were sterile. His D-dimer was elevated (3800 ng/ml). Workup for autoimmune etiology and other thrombophilia was negative.

Given the clinical picture, a possible diagnosis of malignancy-associated embolic stroke was considered, probably secondary to NBTE from malignancy-related hypercoagulability, and a transesophageal ECHO (TEE) was planned. Anticoagulation, prophylactic antiepileptics and neuroprotective agents were added. The patient showed an initial transient improvement but later developed further deterioration in sensorium. TEE was deferred due to his worsening clinical condition. Despite intensive supportive measures, the patient’s clinical status continued to deteriorate and he succumbed to his illness.

Figure 1. Diffusion-weighted imaging and T2 FLAIR hyperintense small signal intensities seen in bilateral fronto-parietal and occipital lobes with ADC isointense signal- consistent with subacute embolic infarcts.

CASE 2

A 70-year-old-male presented with weight loss of around 7 kg over the last 3 months, pain and swelling of right leg for 2 weeks, and weakness of right hand for 2 days. On examination, patient had right upper limb monoparesis and right cervical lymphadenopathy. Initial investigations revealed neutrophilic leukocytosis, elevated D-dimer (2548ng/ml), and acute deep vein thrombosis in right posterior tibial and soleal veins on venous doppler. MRI brain showed numerous acute embolic infarcts involving bilateral fronto-parietal watershed territories, bilateral PCA, bilateral PICA and right ACA territories (Figure 2a). Transthoracic ECHO was normal. However, a transesophageal ECHO revealed a 11 x 7mm echogenic structure with independent mobility attached to the posterior mitral leaflet of mitral valve, with mild mitral regurgitation (Figure 2b). Blood cultures were sterile. CT pulmonary angiogram showed acute thromboembolism in segmental branches of bilateral lower lobes, along with mediastinal, right hilar and right level IV lymphadenopathy with heterogeneous enhancement. CT abdomen revealed an infarct in lower pole of right kidney. With this clinical picture, in the absence of fever and blood culture negativity, the vegetations found were more likely to be NBTE. Hence, the possibility of a primary malignancy with associated marantic endocarditis and systemic as well as pulmonary embolization was considered. Workup for autoimmune etiology and other thrombophilia was negative. However, PET -CT showed metabolically active lesions in enlarged right supraclavicular and hilar lymph nodes and multiple enlarged mediastinal lymph nodes. A right supraclavicular lymph node biopsy was done which was suggestive of metastatic carcinoma. Immunohistochemistry marker CK was positive, but CD20, p40, TTF1, and napsin A were negative which suggested a probable primary in upper aerodigestive tract or pancreaticobiliary tree. CA 19-9 and LDH were elevated (256.9 U/mL and 369 U/L respectively). However, upper gastrointestinal endoscopy, and endoscopic ultrasound of hepatobiliary system showed no evidence of primary malignancy. A diagnostic nasal endoscopy was done to rule out occult primary like nasopharyngeal carcinoma but was normal. Patient is currently on palliative chemotherapy.

Figure 2a. Bilateral fronto-parietal and occipital lobes showing scattered small T2 FLAIR hyperintensities with restricted diffusion, favouring acute embolic infarcts.

Figure 2b: Transesophageal ECHO showing a 11 x 7mm echogenic structure with independent mobility attached to the posterior mitral leaflet, mainly on the left atrial aspect of mitral valve.

CASE 3

A 40-year-old woman, with a 3-year history of adenomyosis and bilateral ovarian endometriosis, who was managed medically, presented with severe anemia secondary to menorrhagia. The patient had heavy menstrual bleeding for the last four years resulting in severe iron deficiency anemia which was partially corrected with blood transfusions and iron supplementation. She also had significantly elevated serum CA 125 (628 U/ml; normal range <35 U/ml) and CA 19-9 (108 U/ml; normal range <37 U/ml) levels. Imaging of abdomen and pelvis including ultrasound and MRI showed an enlarged uterus 11.7x 7.4x 9 cm, with features of adenomyosis especially in the posterior myometrium, and few follicles in bilateral ovaries with hemorrhagic contents. There was no evidence of any gynecological malignancy.

She gave a history of young stroke at the age of 39 years, during her menstrual phase when she presented with acute onset of dysarthria, vomiting, weakness of the left side of the body, and numbness of the right side of the body. MRI brain taken then showed acute lacunar infarct in the left thalamus, midbrain, a tiny infarct in the right occipital lobe, and multiple small acute infarcts in the cerebellum. CT angiography showed a large thrombus occluding the basilar tip and the origin of both posterior cerebral arteries. Carotid CT angiography did not show atherosclerotic changes. She was managed with intravenous tissue plasminogen activator followed by mechanical thrombectomy. She took antiplatelets for one month but later discontinued them because of severe menorrhagia. Thrombophilia and autoimmune workups done then were inconclusive. Transthoracic and transesophageal ECHO showed a small, thin, mobile echodensity of 0.4 cm size on the atrial side of posterior mitral valve leaflet at P2 scallop with mild mitral regurgitation. An implantable cardiac event recorder was placed with no arrhythmia detected. Blood workup showed iron deficiency anemia with mild thrombocytopenia. She had complete neurological recovery at the time of discharge. Follow-up investigations showed partially corrected iron deficiency anemia and highly elevated serum CA-125 (548 U/ml) and CA 19-9 (98 U/ml) levels.

During present admission, the patient developed fever and dyspnea during a blood transfusion. Clinical examination revealed pallor, a pansystolic murmur over mitral area, an early diastolic murmur over aortic area, and an enlarged uterus of 16 weeks size. The blood picture showed severe iron deficiency anemia with mild thrombocytopenia. An ultrasound abdomen showed an enlarged uterus measuring 16x 12x 9cm with markedly thickened posterior myometrium with a heterogeneously hyperechoic mass measuring 10x 6 cm showing ill-defined cystic spaces suggestive of a large adenomyoma, and bilateral endometriotic cysts. She had highly elevated CA 125 (588 U/ml), CA 19-9 (109 U/ml) and D-dimer (3500 ng/ml). A transthoracic ECHO showed a myxomatous mitral valve with moderate mitral regurgitation, moderate aortic regurgitation with echogenic structure attached to aortic valve suggestive of vegetations. Empirical antibiotics were started for possible infective endocarditis after taking blood samples for culture. In retrospection, the history of young stroke in 2019 and the finding of a mobile echodensity in the mitral valve then (in the absence of fever), were suggestive of a non-infective vegetation dislodging to produce a cardioembolic stroke. With this clinical picture, the possibility of recurrence of non-bacterial thrombotic endocarditis was considered more likely than infective endocarditis. In view of thrombosis with thrombocytopenia, a possibility of antiphospholipid syndrome (APS) was considered. However, a repeat APS and autoimmune workup was negative. Hence thrombocytopenia was considered to be secondary to severe iron deficiency. Serial blood cultures were sterile.

The patient also developed right external jugular vein cannulation site thrombosis and deep vein thrombosis in the left leg, confirmed by venous doppler, suggestive of a high prothrombotic tendency. Transesophageal echocardiography confirmed the vegetations in both mitral and aortic valves with moderate mitral regurgitation and severe aortic regurgitation and vegetations prolapsing into the left ventricular outflow tract, suggestive of NBTE (Figures 3a, 3b). In view of the high risk of systemic embolization of NBTE, the need for anticoagulation was considered but deferred due to severe menorrhagia. Since the patient was a poor surgical candidate considering her cardiac status, hysterectomy could not be done. Hence, uterine artery embolization which is a minimally invasive intervention was done for the patient. Post uterine artery embolization, her menorrhagia subsided and she was discharged on warfarin and hematinics. On follow-up at six months, ECHO showed complete resolution of the vegetations with trivial aortic regurgitation and mitral regurgitation. Her anemia and thrombocytopenia have been corrected. Repeat CA 125, CA-19-9, and D-Dimer were still elevated. The patient is doing well, awaiting hysterectomy.

Figure 3a: Transesophageal ECHO showing a mobile echogenic structure, attached to the tip of the anterior mitral leaflet.

Figure 3b: Transesophageal ECHO showing mobile echogenic structures attached to aortic valve and anterior mitral leaflet.

CASE 4

A 41-year-old woman with a 10-year history of adenomyosis with menorrhagia and severe iron deficiency anemia presented with holocranial headache, recurrent vomiting and blurring of vision for 3 days and one episode of generalised tonic clonic seizures. She had a recent acute coronary syndrome with evolved anterior wall myocardial infarction 3 months ago during her menstrual phase. Coronary angiogram showed two-vessel disease of left anterior descending artery and left circumflex artery and percutaneous coronary intervention to mid-left anterior descending artery was done and she was started on antiplatelets and statins.

During present admission, MRI brain was suggestive of posterior reversible encephalopathy syndrome (Figure 4a) with a chronic lacunar infarct in the left corona radiata extending into the lentiform nucleus (Figure 4b). She had severe iron deficiency anemia, significant neutrophilic leukocytosis and thrombocytosis. Carotid CT angiography, transesophageal ECHO, and ambulatory ECG were normal. In view of recent myocardial infarction and old ischemic stroke as evidenced on brain imaging, a prothrombotic state was suspected. Further laboratory investigations revealed elevated D-dimer (1759 ng/mL), CA 125 (397.2 U/mL) and CA 19-9 (395.5 U/mL) levels. Thrombophilia and autoimmune workups were negative. EEG was non-specific. MRI pelvis (plain and contrast) showed moderately enlarged globular appearing uterus with grossly thickened heterogeneous signal intensity posterior myometrium- consistent with marked focal adenomyosis, and normal ovaries. No evidence of gynecological malignancy was found.

She continued to have severe menorrhagia. But antiplatelets could not be stopped due to recent myocardial infarction. Since the patient was a poor candidate for hysterectomy, she underwent uterine artery embolization. Post-procedure, her menorrhagia subsided, and leukocyte count came back to normal. Anemia was corrected with oral hematinics. However, her D-dimer, CA 125 and CA 19-9 levels were persistently elevated. Four months later, she underwent hysterectomy, following which her D-dimer, CA 125 and CA 19-9 returned to normal and there was no recurrence of prothrombotic events.

Figure 4a. T2 FLAIR images showing multifocal patchy hyperintensities predominantly located in bilateral parieto-occipital lobes, cerebellar hemispheres and also in bilateral thalami - Consistent with PRES.

Figure 4b. Gliotic- encephalomalacic changes, with focal ex-vacuo dilatation of the left lateral ventricle and diffusion facilitation- consistent with a chronic lacunar infarct in the left corona radiata extending into the lentiform nucleus.

The first case reported here is of an elderly man with diagnosed metastatic papillary renal cell carcinoma who developed an acute embolic stroke during hospital stay, emphasising the hypercoagulable state in active malignancy. The embolic stroke could have been related to NBTE formation and subsequent embolization, but TEE could not be done to confirm the presence of NBTE due to the patient’s poor clinical condition. The second patient presented with an embolic stroke, deep vein thrombosis of leg veins, acute pulmonary thromboembolism and NBTE as the initial manifestations of an underlying malignancy.

Although relatively rare among ischemic strokes, malignancy-associated stroke is increasingly being recognised in patients with active or occult malignancies. Emerging evidence suggests that cancer-associated stroke may represent a distinct subtype of stroke.⁴ Previous studies suggested that the most frequent neurological complication in cancer patients was metastases followed by cerebral infarction and hemorrhage.¹⁰ The underlying mechanisms for the development of ischemic stroke in cancer patients differ from those without cancer. These are related to the cancer itself, or with the type of treatment. Stroke in cancer patients may be ischemic or hemorrhagic, with embolic stroke being the commonest.¹¹

The pathophysiology of malignancy-associated stroke includes variable interconnected mechanisms. Generally, hypercoagulability is the most common cause for malignancy-associated ischemic stroke.¹² Cancer induces a hypercoagulable state through release of procoagulant substances like cancer procoagulant and tissue factor by the cancer cells as well as by the inflammatory response of the body. This in turn increases thrombin generation and forms fibrin-rich clots.¹¹ Around 10% of malignancy-associated stroke also have associated venous thromboembolism and elevated D-dimer levels which support this postulation.  This hypercoagulable state is linked to activation of coagulation cascade by cancer cell-derived hematogenous extracellular vesicles, and increased neutrophil extracellular traps (NETs) which activates platelets and thrombin-antithrombin complex formation. Cancer-related stroke patients also exhibit abnormal platetet function and aggregation. Malignancy is also associated with increased soluble thrombomodulin and vascular cell adhesion molevcule-1 (VCAM-1) levels and endothelial injury. These result in in situ thrombosis within cerebral vessels.⁴ Lung and pancreatic cancers cause this coagulopathy commonly.⁶ Hypercoagulability also results in the formation of NBTE which could dislodge and contribute to embolic stroke or ESUS. Paradoxical embolism through PFO is also reported in around 25% of these patients.¹³ Cancer is also linked to acute or chronic disseminated intravascular coagulation (DIC). Low-grade DIC is often associated with solid tumors, whereas acute DIC is often observed in myeloid and lymphoid leukemia, which manifest as marked bleeding.¹⁴ Pancreatic cancer and adenocarcinoma have been reported to be at exceptionally high risk of DIC. Acute promyelocytic leukemia is also strongly associated with DIC resulting in severe hemorrhagic manifestations.¹⁵

Nonbacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, refers to non-infectious, sterile valvular platelet-fibrin vegetations with negative blood cultures.¹⁶ NBTE is most commonly caused by an underlying malignancy, usually as a late complication. However, NBTE with ischemic stroke could rarely be the initial presentation of an underlying malignancy. In a previous study, NBTE was identified as the leading mechanism in cancer-associated symptomatic ischemic stroke, and it was observed that NBTE was often undetected during life.¹⁰ Approximately, 30% to 70% of all cancer-associated ESUS involves multiple vascular distributions, which supports the hypothesis that ESUS with cancer are mostly due to NBTE.  NBTE is also often missed on standard transthoracic echocardiography, whereas transesophageal echocardiography remains superior in detecting it. Few autopsy studies have reported NBTE in 9.3% of patients with cancer, and presence of cancer in 59% of patients with NBTE.^17,18 NBTE is most often reported in adenocarcinomas, especially mucin-producing carcinomas of the lung or the gastrointestinal tract, lymphoma, and also in ovarian, pancreatic and biliary carcinomas. Adenocarcinomas are considered to accelerate thrombosis via mucin production.¹⁹

Direct tumor effects include arterial and venous sinus invasion by tumor mass or leptomeningeal infiltrates, vascular compression by the tumor or tumor bed edema, tumor emboli and intratumoral hemorrhage (ITH). Leptomeningeal metastasis is most commonly associated with breast cancer, lung cancer and malignant melanoma and may cause venous sinus occlusion.¹⁹

Tumor embolism is a rare and underrated mechanism where tumor fragments or cancer cells may embolise to cerebral arteries. This is often described in centrally located primary or metastatic lung cancer with invasion of the pulmonary veins or cardiac chambers and embolization to the brain, as well as in atrial myxoma and invasive head and neck cancers.⁴ These patients often develop metastasis at the site of their prior stroke. Tumor emboli may also invade the vessel causing its dilatation, forming a cerebral aneurysm, which may rupture into the brain parenchyma or subarachnoid space.

Systemic infections have also been strongly associated with stroke. The systemic inflammatory response induced by the causative pathogen may damage the vascular endothelium and result in intracerebral hemorrhage. Infective endocarditis with cerebral embolization and mycotic aneurysm with septic embolization are other predominant causes.²⁰

Chemotherapy has also been associated with stroke in cancer patients.²¹ Certain chemotherapeutic agents like cisplatin and 5-fluorouracil can damage the vascular endothelium and disrupt the coagulation pathways, leading to thrombosis. L-asparaginase, commonly used in the treatment of acute lymphoblastic leukemia has a well-documented association with thrombosis and stroke. Raloxifene, a selective estrogen receptor modulator is also linked to stroke and thromboembolic events due to its anti-estrogenic action.  Anthracyclines can cause acute and chronic cardiomyopathy, which may lead to ESUS. Chemotherapy-induced immunosuppression increases susceptibility to infections which may trigger systemic inflammatory responses leading to stroke risk. Chemotherapy can cause thrombocytopenia and increase risk of bleeding, including hemorrhagic stroke.¹¹

Radiation therapy to the neck has been related to vessel wall thickening, atherosclerotic plaque formation and vascular damage. Radiation to the thorax can cause injury to the coronary arteries, cardiac valves, myocardium, and pericardium, which can lead to ESUS.⁴ Immunotherapy has also been associated with myocarditis and vasculitis.²² Surgical treatment of cancer can also cause ESUS through direct arterial injury, tumor emboli and secondary cardiac arrhythmias.

The risk of malignancy-associated stroke also correlates with the aggressiveness of the underlying cancer type. The risk was highest among lung, pancreas, and colorectal cancer patients who often presented with advanced stage disease, and lowest among breast and prostate cancer patients who had localized tumor.¹¹ A nationwide analysis in the United States identified that among patients with acute ischemic stroke, 0.12% had a concomitant diagnosis of renal cell carcinoma (RCC). This indicates that while RCC-associated strokes are relatively rare, they are clinically significant. Patients with RCC-related acute ischemic stroke were found to have higher in-hospital mortality rates and longer hospital stays.²³

The temporal relationship between stroke and cancer diagnosis is also complex. Stroke can occur either before or after the diagnosis of cancer. Research indicates that the risk of ischemic stroke increases in the few months preceding the cancer diagnosis. It was also reported that around 1.8% of patients who had an ischemic stroke without a cancer diagnosis were subsequently diagnosed with cancer within a year.²⁴ These are often occult malignancies at the time of stroke presentation.

The latter two cases reported here are of middle-aged women, diagnosed with adenomyosis and a history of ischemic young stroke. They did not have any usual cerebrovascular risk factors. Their CA 125, CA 19-9, and D-dimer levels were elevated. Even though elevated CA 125 and CA 19-9 levels were observed, there was no evidence of malignancy. They were detected to have a high prothrombotic tendency with one patient developing NBTE and venous thrombosis, while the other had a history of recent acute myocardial infarction. Their previous ischemic stroke would have been the result of cardioembolism from NBTE which could not be visualized in echocardiography since it had already embolised, or in situ thrombosis of cerebral arteries.

Cancer antigen 125 (CA 125) is a member of the mucin family glycoproteins. Elevated levels of serum CA 125 are commonly seen in epithelial ovarian tumors, endometrial carcinoma, or pancreatic carcinoma but also in benign conditions like endometriosis, adenomyosis, or acute pelvic inflammatory disease. It is suggested that increased serum CA 125 levels might produce a hypercoagulable state in these patients, leading to the development of NBTE and increased aggregation of white and red blood cells.²⁵ Besides, patients with adenomyosis also have menstruation-induced activation of the tissue factor coagulation pathway which may play a role in the increased risk of thrombotic disorders.²⁶ Serum CA 125 level varies at different phases of the menstrual cycle with a peak during menstruation, even in healthy women which is thought to be related to shedding of endometrial cell surface antigen into the systemic circulation or peritoneal irritation. Therefore, patients with adenomyosis are more likely to develop cerebral infarction during menstruation.²⁷ These two patients with ischemic stroke also had adenomyosis and high CA 125 and CA 19-9 levels resulting in a prothrombotic state with the development of NBTE and venous thrombosis in one of them, and recent myocardial infarction in the other, during menstrual phase.

There are previous reports of systemic embolism in the fingers or kidneys, as well as thrombi in the brachiocephalic trunk and left subclavian artery in adenomyosis patients.²⁸ There are also case reports of cerebral embolism from NBTE associated with adenomyosis.²⁹ Most NBTE is discovered only on autopsy and not antemortem which could be attributed to the difficulty in detecting these small-sized vegetations under the cardiac valves and their high tendency for embolization so that the vegetations have already detached from the cardiac valve at the time of evaluation following the ischemic event.

In the first patient with adenomyosis (case 3), during the stroke evaluation, transesophageal echocardiography showed a small, mobile echogenicity on the posterior mitral valve leaflet which was probably the remnant of vegetation that had already embolised. During present admission, we were able to detect NBTE early, allowing timely intervention before any embolic complications could occur. The patient also had mild thrombocytopenia which was considered secondary to severe iron deficiency anemia which resolved following the correction of anemia. However, NBTE was not identified in the second patient with adenomyosis (case 4), in whom hypercoagulability-related in situ thrombosis was suspected.

The second patient with adenomyosis (case 4) presented with posterior reversible encephalopathy syndrome though she was normotensive and had no elevation in her blood pressure during or after the episode. PRES typically manifests with symptoms such as headache, altered mental status, seizures or visual disturbances. Imaging often reveals hyperintense areas in parieto-occipital lobes, basal ganglia, cerebellum, brainstem involving both white and gray matter on T2 -weighted and diffusion-weighted MRI. Systemic hypertension is a well-established risk factor for PRES which causes hypertension-related cerebrovascular endothelial cell dysfunction and impaired cerebral autoregulation. However, PRES can also occur in patients on immunosuppressive or cytotoxic agents like tacrolimus or cyclosporine, or in patients with connective tissue diseases like systemic lupus erythematosus, or thrombotic microangiopathies like thrombotic thrombocytopenic purpura. PRES has also been reported in a limited systemic sclerosis patient with transient hypercoagulable state induced by infection.³⁰ Although there are no reports linking adenomyosis directly to PRES, some case reports suggest that gonadotropin-releasing hormone (GnRH) therapy and rapid correction of severe anemia in adenomyosis may contribute to development of PRES. These effects may be attributed to hypoestrogenemia attenuating the protective effects on endothelial cells or sudden hyperviscosity leading to cerebral hypoperfusion, blood-brain barrier dysfunction, and vasogenic edema.³¹ In this patient, adenomyosis-related hypercoagulability is considered the likely precipitating factor for PRES.

This case series highlights the diverse and often under-recognised etiologies of ischemic stroke beyond the well-described traditional risk factors. These cases illustrate the importance of considering both malignant and non-malignant hypercoagulable states as potential risk factors for ischemic stroke, especially in younger population or those without conventional cardiovascular risk profiles. A thorough clinical evaluation, including a focused search for occult malignancy or prothrombotic conditions is essential in atypical presentations of stroke. The cases reported here are also noteworthy due to the relative rarity of ischemic stroke associated with renal cell carcinoma and carcinoma of unknown primary. Also, NBTE which is often a post-mortem diagnosis was encountered in two of the patients, allowing timely clinical intervention. There have been few case reports of cerebral infarcts in adenomyosis patients reported mostly in Japan previously. To our knowledge, this is the first Indian report of adenomyosis-associated ischemic young stroke with high prothrombotic tendency in the form of NBTE, myocardial infarction, and venous thrombosis secondary to elevated CA 125 and CA 19-9. Therefore, it is important to be aware of adenomyosis as a rare, less-identified risk factor for ischemic young stroke in women. The potential role of adenomyosis-related hypercoagulability in the pathogenesis of normotensive PRES also warrants further research.

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