Early Onset of Cerebral Venous Sinus Thrombosis in a 27-Year-Old Woman Receiving Norethisterone: A Rare Case Report

This case demonstrates that even short-term use of norethisterone may potentially contribute to CVST occurrence in susceptible individuals, particularly when combined with additional risk factors such as levothyroxine-induced subclinical hyperthyroidism, family history of VTE, and COVID-19 vaccination. The rapid onset of symptoms within 1 month of therapy initiation contrasts with previous reports and suggests that individual thrombotic susceptibility may significantly modify the temporal profile of progestin-related CVST. Clinicians should maintain a high index of suspicion for CVST in patients receiving norethisterone who present with neurological symptoms, regardless of treatment duration. This case underscores the importance of comprehensive risk assessment before initiating hormonal therapy and highlights critical knowledge gaps regarding drug interactions between progestins, thyroid medications, and vaccine-related thrombotic risks. Further research is needed to better understand these complex pharmacological relationships and optimize preventive strategies for at-risk populations.

CVST is a relatively rare form of stroke, accounting for approximately 0.5%–1% of all stroke cases [ 1 ]. It disproportionately affects women of reproductive age, who comprise nearly two-thirds of those diagnosed [ 4 ]. Clinically, CVST may present with a range of distinct syndromes, such as elevated intracranial pressure, focal neurological deficits, diffuse encephalopathy, and cavernous sinus syndrome [ 5 ]. Multiple risk factors (genetic and acquired) have been associated with CVST. Female sex remains the most prominent, accounting for approximately 75% of cases. Common contributing factors include the use of hormonal contraceptives, inherited or acquired thrombophilic disorders, pregnancy, and the postpartum period. Other risk factors include infections, genetic mutations, cerebral neoplasms, and myeloproliferative disorders. Hormone replacement therapy has been reported as a contributing factor in 3%–4% of cases. Despite thorough investigation, approximately 10% of CVST cases are idiopathic, with no identifiable underlying cause [ 5 ]. Less frequently, CVST may be linked to conditions such as heparin-induced thrombocytopenia, dysfibrinogenemia, sickle cell anemia, malignancies, vasculitis, sarcoidosis, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, and VITT. Extremely rare causes include systemic and metabolic disorders such as diabetes mellitus, thyrotoxicosis, uremia, nephrotic syndrome, heart failure, and cardiomyopathy [ 6 ]. Thrombophilia denotes a hypercoagulable state that predisposes individuals to VTE, including deep vein thrombosis, pulmonary embolism, and CVST. The occurrence of VTE at a young age is frequently associated with hereditary thrombophilias – such as factor V Leiden, the prothrombin G20210A mutation, the MTHFR C677T polymorphism, and deficiencies in protein C or protein S – as well as with acquired conditions like antiphospholipid syndrome [ 7 ]. However, CVST is rarely attributable to a single factor and is widely recognized as a multicausal disorder arising from the interplay between genetic susceptibility and acquired triggers [ 8 , 9 ]. In many instances, transient environmental factors serve as a “second hit,” precipitating thrombotic events in individuals with an underlying prothrombotic tendency. Indeed, the International Study on Cerebral Vein and Dural Sinus Thrombosis found that over 44% of patients presented with multiple concurrent risk factors at diagnosis [ 10 ]. For example, individuals harboring the factor V Leiden mutation may remain asymptomatic until an additional trigger – such as dehydration, pregnancy, or hormonal therapy – initiates thrombosis [ 11 ]. The thrombotic risk in carriers of dactor V Leiden can increase up to 30-fold when combined with oral contraceptive use, underscoring the synergistic effect of overlapping risk factors [ 8 , 12 ]. In the context of the present case, access to comprehensive diagnostic and therapeutic interventions remains severely constrained. Testing for inherited thrombophilic mutations (including factor V Leiden, prothrombin G20210A, and MTHFR C677T), as well as acquired mutations such as JAK2 V617F – and advanced interventions for CVST, including thrombolysis, mechanical thrombectomy, and stenting – is critically limited in low-resource healthcare settings like Afghanistan. A systematic evaluation of acquired and some inherited thrombotic risk factors was undertaken in this patient. Echocardiography revealed no cardiac abnormalities, effectively ruling out a cardioembolic source, and the patient had no clinical signs or symptoms suggestive of cardiac disease. Pregnancy and surgical intervention are well-established provocative risk factors that can trigger thrombotic events in individuals with an underlying predisposition [ 7 ], and it is notable that the patient had undergone two prior pregnancies and cesarean deliveries without any thrombotic complications. This clinical history suggests that these factors alone were insufficient to provoke thrombosis. Laboratory investigations further narrowed the differential diagnosis. Assays for protein C, protein S, and antiphospholipid antibodies were all within normal ranges, effectively excluding deficiencies in these natural anticoagulants and antiphospholipid syndrome as contributory etiologies [ 7 ]. The absence of these common inherited and acquired thrombophilias, coupled with the lack of cardiac or obstetric triggers, directed clinical suspicion toward alternative, less common prothrombotic mechanisms. In this context, a confluence of potential prothrombotic factors was identified. These included exogenous hormonal therapy with norethisterone, biochemical thyrotoxicosis resulting from unsupervised levothyroxine use (as evidenced by suppressed TSH), a documented family history of VE, and COVID-19 vaccination. Although the available thrombophilia panel was negative, the simultaneous presence of these heterogeneous risk factors likely created a synergistic “multi-hit” effect that collectively precipitated the development of CVST in this patient. Norethisterone, a first-generation synthetic progestin, is widely used in clinical practice for various indications, including endometriosis management, hormonal contraception, treatment of abnormal uterine bleeding, and hormone replacement therapy. While demonstrating a relatively lower VTE risk compared to newer-generation progestins, norethisterone’s thrombogenic potential remains dose-dependent and is significantly potentiated by coexisting risk factors such as smoking, hypertension, or familial thrombophilia. A 2017 meta-analysis quantified this risk, reporting thrombosis risk ratios of 3.2, 2.8, and 3.8 for first-, second-, and third-/fourth-generation progestins, respectively [ 13 ]. The association between norethisterone and CVST is supported by several case reports in young women, demonstrating variable latency periods. CVST occurred in a 19-year-old and a 22-year-old after 2 years of norethisterone (10 mg daily) [ 3 , 14 ]. However, shorter durations have also been implicated. A 24-year-old with polycystic ovarian syndrome and hyperhomocysteinemia developed CVST after just 50 days of treatment (5 mg thrice daily), while a 41-year-old presented after 90 days of use [ 15 , 16 ]. Another case involved a 23-year-old woman on bi-monthly norethisterone enanthate injections for 2 years [ 17 ]. These cases highlight that while long-term exposure carries risk, CVST can manifest rapidly, particularly in patients with underlying prothrombotic comorbidities. Our case presents distinct clinical features, including a more rapid symptom onset after norethisterone use (1 month versus 50 days to 2 years in prior reports) and a unique combination of risk factors encompassing familial VTE history, iatrogenic hyperthyroidism secondary to excessive levothyroxine dosing, and COVID-19 vaccination history. This case highlights the complex interplay of pharmacological, genetic, and metabolic factors in CVST pathogenesis, particularly emphasizing how norethisterone may act as a precipitating factor in susceptible individuals with multiple concurrent risk factors. Emerging evidence suggests COVID-19 vaccination may rarely predispose to CVST through vaccine-induced immune thrombotic thrombocytopenia [ 18 ]. The patient’s iatrogenic hyperthyroidism represents an additional noteworthy risk factor, as thyroid dysfunction may promote thrombogenesis through multiple mechanisms, including altered hemodynamics, dehydration, and venous stasis [ 19 ]. MR venography represents the gold standard for CVST diagnosis, with thrombosed sinuses typically appearing hyperintense on T1-/T2-weighted magnetic resonance imaging (MRI). Signal characteristics evolve with thrombus age: isointensity on T1 appears during acute (≤5 days) and chronic (≥1 month) phases. Diagnosis requires correlating MRIs intraluminal signal abnormalities with MRVs absent venous flow. When MRI is unavailable, non-contrast CT can exclude other acute pathologies and detect secondary signs of CVST, although early cases may appear normal [ 1 ]. CT venography directly visualizes thrombi as hyperdense filling defects (“cord sign” or “dense triangle sign”). For diagnostically challenging cases, cerebral angiography provides a definitive venous anatomy assessment [ 20 ]. In this case, the patient was treated with low-molecular-weight heparin (enoxaparin). Follow-up brain CT imaging demonstrated partial recanalization of the dural sinus thrombosis compared to prior scans. Clinical improvement in the patient was achieved with low-molecular-weight heparin, with no requirement for escalation to endovascular interventions. After a 6-day hospitalization, the patient was discharged on oral anticoagulation therapy (apixaban). At the 30-day follow-up, complete resolution of symptoms was observed. Anticoagulation with apixaban was continued for the recommended duration of 6 months. Low-molecular-weight heparin is the preferred treatment for CVST due to its practicality and efficacy; however, in cases of clinical deterioration – such as persistent seizures, declining consciousness, or progression of neurological deficits – endovascular interventions, including catheter-directed thrombolysis, mechanical thrombectomy, or venous sinus stenting, should be considered as adjunctive therapies [ 4 ] which are currently not available in Afghanistan. Under recognition of CVST is widespread in resource-limited settings, driven by insufficient access to advanced neuroimaging modalities (MRI/MRV), low clinical suspicion among providers, and inadequate thrombophilia-screening infrastructure. Compounding these challenges are cultural, geographic, and socioeconomic barriers to healthcare access, which contribute to frequent misdiagnosis of CVST as more common neurological disorders (e.g., migraine, ischemic stroke). Additionally, CVST is poorly represented in local medical literature, reflecting a paucity of regional epidemiological data and dependence on international case reports for clinical decision-making. This systemic under detection delays time-sensitive therapies, exacerbates preventable complications, and increases mortality, disproportionately impacting high-risk groups such as women of reproductive age receiving hormonal therapies or those in the postpartum period. Accurate diagnosis of CVST requires detailed clinical evaluation, given its nonspecific and highly variable symptomatology. Critical knowledge gaps remain regarding (1) the pharmacodynamics interactions between norethisterone and levothyroxine and (2) the possible thrombotic potentiation between norethisterone therapy and COVID-19 vaccination, warranting targeted investigation. This case highlights that norethisterone, though commonly prescribed by gynecologists, may precipitate cerebral venous sinus thrombosis in women with concurrent risk factors. A thorough pretreatment assessment for thrombotic risk is essential to prevent life-threatening complications.

Cerebral venous sinus thrombosis (CVST) is a rare manifestation of venous thromboembolism (VTE) and stroke, occurring at an estimated incidence of approximately 3–4 cases per million individuals and 0.5–1% of all stroke occurrences [ 1 ]. Unlike other forms of VTE, such as deep vein thrombosis and pulmonary embolism, which predominantly affect older adults and males, CVST is more commonly observed in younger populations and females [ 1 , 2 ]. Diagnosing CVST is challenging due to its variable and often nonspecific clinical presentation, compounded by its low prevalence. Established risk factors include the use of combined oral contraceptives, thrombophilia, and certain hematologic disorders. Recent studies have identified additional risk factors, elevated BMI, COVID-19 infection, vaccine-induced thrombotic thrombocytopenia (VITT), spontaneous VITT, and polycystic ovarian syndrome [ 1 , 2 ]. This case report describes a young female patient who developed CVST following treatment with norethisterone – a progestogen with documented thrombogenic potential [ 3 ] – during concurrent levothyroxine therapy. The patient’s positive family history of VTE represented an additional prothrombotic risk factor. This presentation underscores the importance of recognizing hormonal therapies as potential thrombogenic triggers during CVST evaluation, especially in patients with additional risk factors.

The authors declare that they have no competing interests.

We thank Ariana Medical Complex for supporting and providing opportunity for this case report. ChatGPT was used to improve the clarity and fluency of the text.

No funding was received for this work.

A 27-year-old female presented to the emergency department with chief complaints of severe headache, nausea, vomiting, imbalance, and blurred vision for the past 3 days. She had no history of head trauma, hypertension, or smoking, and her BMI was within normal range (24.3 kg/m 2 ). There was no history of head trauma or hypertension. Furthermore, the patient had a family history of thromboembolism. She was under hormonal therapy (norethisterone, 5 mg once daily) for 1 month. She received levothyroxine (100 μg once daily) for hypothyroidism without medical consultation for more than 6 months. She had a history of COVID-19 vaccination 2 years ago, one dose. The patient has been misdiagnosed with acute gastritis and was treated for 3 days before being admitted. The patient was alert and fully oriented during the physical examination, with a Glasgow Coma Scale (GCS) score of 15/15. Speech was normal, without dysarthria or aphasia. Pupils were equal, round, and reactive to light. Plantar reflexes were flexor (negative Babinski sign bilaterally), and no motor weakness was observed in the upper or lower extremities. Vital signs at admission were within normal limits. Initial laboratory investigations revealed a normal complete blood count and preserved renal function. Liver function tests were within normal limits, except for a mildly elevated alkaline phosphatase level (114 U/L). The coagulation profile demonstrated a prolonged activated partial thromboplastin time of 46.1 s; however, this test was performed after administration of a single emergency dose of enoxaparin. The D-dimer level was markedly elevated at 4,100 ng/mL. Thyroid function testing showed marked suppression of thyroid-stimulating hormone (TSH <0.005 µIU/mL) with a normal free thyroxine (FT4) level. A thrombophilia workup, including antiphospholipid antibodies (IgG and IgM) as well as protein C and protein S levels, was unremarkable ( Table 1 ). Laboratory tests results HCT, hematocrit; TLC, total leukocyte counts; aPTT, activated partial thromboplastin clotting time; PT, prothrombin time; INR, international normalized ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TSH, thyroid-stimulating hormone; ALP, alkaline phosphatase. Abdominal/pelvic ultrasonography was normal. Brain computed tomography scan (CT scan) revealed hyperdense signals in the superior sagittal, straight, and transverse sinuses, raising suspicion for CVST ( Fig. 1 ). Subsequent MR venography confirmed extensive thrombosis involving the superior sagittal sinus, torcular Herophili, bilateral transverse sinuses, and partial involvement of the straight sinus ( Fig. 2 ). Additional diagnostic workup included transthoracic echocardiography, which showed normal function and structure. Carotid Doppler ultrasound revealed normal bilateral carotid artery and both vertebral arteries. Non-contrast axial brain CT demonstrates marked hyperdensity within the superior sagittal sinus, straight sinus (arrowhead), and bilateral transverse sinuses, representing the “cord sign” of acute cerebral venous sinus thrombosis. Note the absence of parenchymal hemorrhage or edema at this stage. MR venography demonstrates extensive thrombosis with flow void involving: superior sagittal sinus, torcular Herophili, bilateral transverse sinuses, and proximal straight sinus. Note the absence of normal venous flow signals in affected segments. Based on comprehensive clinical evaluation and confirmatory radiological findings, a definitive diagnosis of CVST was established. The patient was subsequently transferred to the intensive care unit for close neurological monitoring and initiation of targeted therapy. The treatment regimen consisted of therapeutic anticoagulation with subcutaneous enoxaparin (1 mg/kg every 12 h), seizure prophylaxis with intravenous levetiracetam (500 mg every 12 h), analgesia with scheduled intravenous acetaminophen (500 mg every 6 h), and as-needed antiemetic therapy with intravenous ondansetron (8 mg PRN) for nausea control. Following 24 h of intensive monitoring and treatment, the patient showed marked clinical improvement with the resolution of visual disturbances and a significant reduction in headache intensity. Based on this positive response, therapeutic anticoagulation with subcutaneous enoxaparin was continued for five additional days. During the hospitalization, levothyroxine therapy was discontinued after biochemical confirmation of drug-induced subclinical hyperthyroidism. Serial neuroimaging demonstrated a favorable course of thrombus resolution. A follow-up CT scan on day 3 of treatment revealed incomplete reduction in thrombus density within the superior sagittal, straight, and transverse sinuses, representing early partial recanalization ( Fig. 3 ). Subsequent clinical assessment after 3 days confirmed continued improvement in all presenting symptoms, including headache, balance disturbances, and visual acuity, as well as d-dimer (2,400 ng/mL). After 6 days of hospitalization, the patient was discharged on oral apixaban (2.5 mg twice daily), following a transition from enoxaparin, for the secondary prevention of CVST. Follow-up non-contrast brain CT demonstrates persistent hyperdensity in the superior sagittal sinus, straight sinus, and transverse sinuses, consistent with partial recanalization of previously documented dural sinus thrombosis. Note the interval reduction in thrombus burden compared to initial imaging. At the 1-month follow-up, repeat CT imaging showed near-complete resolution of the previously noted thrombotic changes, with significant reduction in density observed in the superior sagittal, straight, and right transverse sinuses, indicating successful recanalization ( Fig. 4 ). This radiographic improvement correlated well with the patient’s complete resolution of neurological symptoms, confirming the effectiveness of the instituted anticoagulation therapy. The patient maintained good functional status throughout the recovery period with no residual neurological deficits. A follow-up brain MRV at 3 months showed complete resolution of the CVST. Follow-up non-contrast brain CT demonstrates near-complete resolution of hyperdensity in the superior sagittal sinus, normalization of density in the straight sinus, and partial residual hyperdensity in the right transverse sinus.

This study protocol was reviewed and approved by the Institutional Review Board of Ariana Medical Complex, approval No. 002-23/04/2025, and written informed consent was obtained from the patient’s caregiver. The patient’s caregiver provided written informed consent for the publication of patient’s personal and clinical information, including any identifying images. The CARE checklist has been provided as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552250 ).

Mohammad Pazhman Sediqi, MD, PGD: conceptualization, clinical management/patient care, supervision, project administration, and writing – critical review and editing; Diana Jamalzai, MD: conceptualization, data collection, case investigation, resources, visualization/imaging, patient consent, ethics approval, and writing – original draft; Elaha Esmat, MD: data collection, case investigation, resources, and writing – original draft; Mohammad Ramin Hamidi, MD: data collection, case investigation, and writing – original draft; Abdul Wahed Sidiqi, MD, MSc, FECS: clinical management/patient care and writing – critical review and editing; Nommanudien Naibkhil, PharmD, MSc: writing – original draft and writing – critical review and editing; Mohammad Sharif Sediqi, MD, MPH: writing – critical review and editing.