Cerebral Venous Thrombosis Following a Lumbar Puncture in a Patient Using NuvaRing

Introduction

Lumbar puncture (LP) is a pivotal diagnostic procedure crucial for the assessment of numerous pathologies affecting the nervous system, including infections such as meningitis, encephalitis, neurodegenerative diseases, autoimmune disorders, and even certain central nervous system (CNS) malignancies. The most common complications seen with lumbar puncture are post-LP headache (PLPH) found in 25–30% of cases [1] and back pain in up to 30% of cases [2]. Some less common and more serious complications include infection, bleeding, cerebral herniation [3], and, very rarely, cerebral venous thrombosis (CVT) [4]. Several risk factors have been associated with post-lumbar puncture CVT, including thrombophilia, malignancies, pregnancy, recent high-dose steroid use, particularly in the setting of demyelinating disease such as multiple sclerosis (MS) [5], and hormonal therapy. Independent of lumbar puncture, hormonal contraception alone is a risk factor for CVT [6]. Since 2015 at least 4 citations have reported the association of the NuvaRing (a vaginal contraceptive ring containing 15 μg ethinyl estradiol and 120 μg etonogestrel) with CVT [7–10]. We report the first case of a patient who was using the NuvaRing and developed a CVT after a diagnostic LP as part of a workup for altered mental status.

Case Report

A 29-year-old woman, gravida 0 with no significant medical history, on a vaginal hormonal-based contraceptive ring for 3 years, presented to the emergency room (ER) after being found unresponsive at home, arousable with confusion, non-seizure shaking, and urinary incontinence. She had been last been seen in normal condition18 hours prior, but she had been experiencing fevers and body aches 2 days before the ER visit. She had recently returned from Colombia, South America, 3 days before the ER visit. Her initial vital signs revealed a temperature of 38.8°C (101.8°F), heart rate of 94 beats per minute, blood pressure of 111/81 mmHg, respiratory rate of 17 breaths per minute, and oxygen saturation of 98%. During the physical examination, she was nonverbal, opened her eyes spontaneously, and displayed some shaking. She later became more somnolent and was intubated for airway protection. There was no evidence of trauma. A history was obtained from relatives and was confirmed by the patient when her cognitive function was restored. She had a past medical history of using oral contraceptives 5 years earlier for a total of 2 years, without complications. She had no history of thromboembolism. She did not use alcohol, drugs, or tobacco. There was an unconfirmed family history of possible stroke and possible antiphospholipid syndrome. Her initial laboratory results were unremarkable except for a mildly elevated white blood cell count of 11.2×109/L. Computed tomography (CT) scans of the head and entire spine showed no abnormal findings (Figure 1). CT angiogram scans of the head and neck were unremarkable. Magnetic resonance imaging (MRI) of the brain revealed no evidence of intracranial hypotension or other acute pathology. Due to concerns for meningitis or encephalitis, a lumbar puncture was performed, and cerebrospinal fluid (CSF) was sent for cytology and culture. She was started empirically on intravenous ceftriaxone, vancomycin, and acyclovir. Cerebrospinal fluid (CSF) studies were negative for infectious etiologies, leading to quick de-escalation of antibiotics. The toxicology screen was negative. Autoimmune screening was negative, including antinuclear antibodies, antiphospholipid antibodies, anti-double-stranded DNA, and anti-neutrophil cytoplasmic antibodies. An electroencephalogram ruled out seizure activity. Other possible causes for her presenting condition were considered, including dehydration, unspecified medication reactions, subacute central nervous system infectious disorders, Parkinson’s disease, transient ischemic attacks, or even carbon monoxide poisoning. However, the diagnosis of the condition leading to the original admission and workup was never determined.

The patient’s neurological status improved significantly with successful extubation after 48 hours, but she developed a positional headache that worsened upon sitting up. It was felt her presentation was consistent with a post-dural puncture headache (PDPH) due to a CSF leak, and the neurology team opted for conservative management. She continued to have a persistent headache but denied nausea, vomiting, and neck pain or stiffness. Magnetic resonance venography (MRV) was performed, with no abnormal findings, including signs of intracranial hypotension. The decision was made to proceed with a blood patch after 6 days of conservative management and no improvement. Shortly thereafter, she developed a new-onset right-sided facial droop and right-sided arm weakness. An emergency CT (Figure 2) and CT angiography (CTA) of the head revealed a sagittal sinus thrombus (Figures 3, 4). A T2 FLAIR brain MRI showed subarachnoid blood and edema in the left front lobe under the area of the CVT (Figure 5). The patient was started on a heparin drip. Given the reported family history of stroke and possible antiphospholipid syndrome, she underwent further thrombophilia workup, including Factor V Leiden mutation, Factor II (PT G20210A) mutation, antithrombin II level, lupus anticoagulant, beta-2 glycoprotein antibodies, and cardiolipin antibodies. Her workup was unremarkable and she returned to normal neurological function during the observation in the hospital. She was discharged on apixaban after 14 days. The reason for her initial admission was never determined. A 1-week follow-up MRI of the brain showed no evidence of new thrombosis, but there was evidence of chronic venothrombotic changes. At a 2-week outpatient follow-up, her neurologic manifestation had resolved completely. At 3 months after the initial presentation, she received a copper intrauterine contraceptive device. At 4 months, her head MRI was normal, and at 6 months her apixaban, given for the provoked nature of the sinus thrombosis, was discontinued (Figure 6).

Discussion

This case is unique for 4 reasons. First, a previously healthy reproductive-age woman who had been exposed to contraceptive-level exogenous estrogens through oral contraceptive pills and a vaginal ring for a total of 5 years suddenly developed a central nervous system venous thrombus. In addition, her thrombophilia workup was subsequently negative. Second, she developed the CVT stroke 7 days after a lumbar puncture and 1 day after a blood patch to treat a post-LP headache. Third, the neurological sequence occurred in real-time with brain imaging to document the events. Fourth, this is the first reported case of post-LP CVT in a patient with contraceptive estrogen exposure, and there were no residual objective neurological sequelae after completing anticoagulation treatment. Cerebral venous thrombosis (CVT) is uncommon, with an annual incidence ranging from 1.16 to 2.02 cases per 100 000 population [11]. It is more prevalent in females than males, with a female-to-male ratio of 3: 1 [12]. The median age of patients diagnosed with CVT is 37 years and a study reported that 530 out of 624 patients with CVT had at least 1 identifiable risk factor [12]. There are numerous risk factors associated with CVT. Common risk factors include obesity, oral contraceptives (OCPs), prothrombotic states, drugs, infections, malignancy, and mechanical trauma such as lumbar puncture [13]. Among young females, the use of OCPs is the most frequently observed risk factor [14], with the risk further increased in those with prothrombotic genetic mutations [12]. There are only a few case reports of CVT associated with use of hormonal vaginal rings. Although NuvaRing is applied locally, it has systemic absorption similar to oral contraceptives and carries a comparable risk of inducing a thrombogenic state. The development of CVT after lumbar puncture is thought to be related to a transient change in CSF pressure, possibly leading to stasis, and the loss of volume from the puncture. These mechanical changes can create a pressure gradient that can cause stretching of the vessels, causing injury to the venous endothelium. CVT can have a wide presentation, with headaches being the most common. Seizures, focal deficits, altered mental status, and coma have also been reported [15]. In cases of post-lumbar puncture (LP) CVT, it can be challenging to distinguish between post-dural puncture headache (PDPH) and headaches caused by CVT. PDPH typically worsens when upright and improves when lying down. The development of CVT in post-LP patients should be highly suspected if the headache becomes continuous, or if there are new seizures, new focal deficits, and signs of increased intracranial pressure. The modality of choice is an MRI of the brain with an MR venogram, which can reveal a thrombus or lack of blood flow [13]. Radiographically, CVT presents as a hypointense area in the cerebral sinus, and it can also show indirect signs in the brain, such as edema due to venous obstruction. If MRI is unavailable, a CT head with a CT venogram is an alternative diagnostic method, with high sensitivity and specificity (95% and 91%, respectively) [16]. MRI is often preferred in cases of contrast allergies or pregnant patients. When both CT and MRI with venogram are inconclusive and CVT suspicion remains high, cerebral angiography may be performed. Routine thrombophilia workup in CVT in patients who do not have risk factors such as pregnancy, infection, trauma, OCPs, or malignancy is controversial and unsettled [17]. The first-line treatment for CVT in the acute setting is intravenous (IV) heparin or subcutaneous low-molecular-weight heparin (LMWH), even in the presence of bleeding or infarction secondary to CVT. Two randomized trials demonstrated that anticoagulation resulted in better outcomes without increasing the risk of new bleeding, while patients in the placebo groups experienced new hemorrhages [18,19]. Endovascular treatment, including mechanical or endovascular thrombolysis, is only recommended for patients who do not respond to appropriate anticoagulation, as it carries a higher risk of mortality without providing additional benefits compared to anticoagulation alone [20]. Warfarin or direct oral anticoagulants (DOACs) are a preferred form of anticoagulation to prevent recurrence of CVT. DOACs are increasingly favored due to fewer drug interactions, no dietary restrictions, and less intense monitoring. In specific situations, warfarin is still favored over DOACs, such as in patients with renal insufficiency or antiphospholipid syndrome. In pregnant patients with CVT, low-molecular-weight heparin remains the treatment of choice. The duration of therapy is uncertain due to the limited evidence and recommendations available. For patients with provoked transient CVT caused by factors such as pregnancy, infection, trauma, oral contraceptives, or malignancy, most clinicians recommend 3–6 months of full-dose anticoagulation. In cases of unprovoked CVT, the treatment duration is extended to 6–12 months. Lifelong anticoagulation is required for those with recurrent CVT or a diagnosis of thrombophilia [13].

Conclusions

A previously healthy 29-year-old woman developed CVT following a lumbar puncture during evaluation for acute encephalopathy. An additional risk factor was the use of an estrogen contraceptive ring. Seven days after admission, the CVT was diagnosed with MRV, and the only 2 risk factors were the LP and the contraceptive ring. She had used estrogens for 5 years and would not be considered a candidate for a thrombotic disorder. The blood patch or even the 6-day delay in inserting the blood patch is an unlikely element that increased her risk of CVT higher than the LP alone. What did significantly increase her risk, however, was the combination of estrogens and the LP. The important message from this case is that even when 2 risk factors are present for a CVT, early diagnosis and treatment can result in an objectively normal neurological outcome.