Spontaneous Spinal Epidural Hematoma in a Patient on Apixaban for Nonvalvular Atrial Fibrillation

Background With the rise in the use of direct oral anticoagulants (DOACs), more hemorrhagic complications are being encountered. Since the first description of a case of spontaneous spinal epidural hematoma (SSEH) related to the utilization of DOACs in 2012, there have been few reports describing a similar association. However, no cases so far have reported an association between SSEHs and apixaban. Case Description: A 76-year-old lady, with a history of nonvalvular atrial fibrillation, presented with a new onset of progressive left lower and upper extremity weakness. She reported back pain and numbness in the left leg up to the knee along with numbness in the left arm up to the shoulder. A CT scan of the neck was suggestive of an epidural hematoma extending from C2-C3 level to C6-C7. As the patient was on apixaban at the time, surgical treatment was delayed for two days to decrease the risk of intraoperative bleeding. Nine days later, she was discharged. Her physical exam was almost unchanged from that on presentation, except for resolution of pain and minimal improvement in motor power in her left lower extremity from 1/5 to 2/5 distally. Conclusions Spinal hematomas represent surgical emergencies with earlier intervention portending better outcome. Based on the few case reports that point to DOACs as a potential culprit, it appears that a high suspicion index resulting in earlier SSEH diagnosis and intervention is crucial for improved neurological outcome and recovery. Prompt diagnosis remains a challenge, especially that SSEH can mimic cerebrovascular accidents.


Background
Since the first description of a case of SH associated with the use of a DOAC (rivaroxaban) in 2012 [1], there have been a total of 10 other reports describing both SSEH and spinal subdural hematomas (SSDHs) in association with different DOACs [2][3][4][5][6][7][8][9]. As the use of DOACs continues to increase [10], more similar cases are expected to complicate treatment with these agents. SSEH represents the vast majority of cases of SH [11]. However, no cases so far have been reported about an association between apixaban and SSEH (Table 1). Despite reports of successful medical management [13,14], surgical decompression remains the cornerstone of management of these patients with earlier intervention correlating with better outcome [15]. However, even with the recent FDA approval of idarucizumab as a reversal agent for dabigatran and andexanet alfa for apixaban and rivaroxaban [16], the limited availability and experience with these agents complicates the timing of surgery. We hope that this case report and literature review will help in establishing a better idea about the optimal management of these patients and raise awareness about the importance of having a high index of suspicion for this condition when encountering a patient on DOACs.

Case Report
A 76-year-old African American lady presented to the hospital with new onset weakness and back pain. Her medical history consisted of essential hypertension, atrial fibrillation, abdominal aortic aneurysm, sick sinus syndrome, asthma, and gout. She reported that her back pain started after she came back from the bathroom at 4 : 00 a.m. while trying to sit down on the bed. e patient described the pain as shooting in nature, severe in intensity, and radiating ere was no history of any urinary or stool incontinence or retention or any previous similar episodes. e patient had been recently diagnosed with atrial fibrillation one month prior to presentation in an outside hospital and had since been maintained on apixaban 1 tablet 5 mg twice daily. Her other home medications included alprazolam, allopurinol, losartan, hydrochlorothiazide, and metoprolol. She reported full compliance with her medications prior to presentation. A dual chamber pacemaker was inserted 11 days before this visit in an outside hospital, and her other surgical history included a hysterectomy several years ago for uterine fibroids. She denied any history of smoking, alcohol abuse, or illicit substances usage. e patient did not have previous bleeding history. e patient's vital signs on presentation were within normal limits, and her neurological exam showed a patient alert and oriented to time, place, and person with intact speech. Her motor power was 5/5 in her right upper extremity proximally and 4/5 distally and 3/5 in her left upper extremity proximally and 1/5 distally. In her lower extremities, the motor power was 5/5 on the right and 1/5 all over on the left. She had decreased sensation to light touch in her left upper and lower extremities. She had no clonus, and Hoffman and Babinski signs were negative bilaterally. Her reflexes were 2+ all over and symmetric.
Initial lab tests were significant for hypokalemia (3.1 mmol/L), leukocytosis (12700 WBCs per microliter), and slight anemia with a hemoglobin level of 9.3 g/dl with unknown baseline. Her other lab tests including liver function and renal function were within normal limits.
Given her presentation of acute focal neurological deficit, a noncontrast head CT scan was ordered and showed signs of chronic vascular ischemic disease only. e patient continued to have severe back pain, and having a history of abdominal aortic aneurysm, an acute aortic dissection was suspected, and hence, a CT angiogram of the abdomen, pelvis, and thorax was ordered. e CT angiogram did not show any signs of aortic dissection. A CT scan of the neck was performed to investigate the cause of the left upper extremity weakness and numbness. It showed an epidural soft tissue density extending along the left aspect of the spinal canal causing compression and marked rightward deviation of the cord concerning for an epidural hematoma extending from C2-C3 level to C6-C7 ( Figure 1).
As the patient was on apixaban at the time, a decision was made to delay surgical treatment for 2 days to decrease the risk of intraoperative bleeding. A C2-C7 laminectomy, hematoma exclusion, and spinal fusion were then performed. On discharge, 9 days later, her physical exam was mostly unchanged from that on presentation except for the resolution of pain and improvement in motor power in her left lower extremity from 1/5 to 2/5 distally.

Discussion and Conclusions
Spinal hematomas represent surgical emergencies with earlier intervention portending better outcome [15]. e acute presentation, however, represents an important diagnostic challenge [15] especially as a mimicker of cerebrovascular accidents [18]. Even though no direct trauma is involved in spontaneous spinal hematomas, some activities have been associated with onset such as stretch exercises [19] and Valsalva maneuvers during trumpet playing [20] and defecation [3], for example, which might have been the case in our patient as well. Even though new reversal agents have been recently approved for dabigatran, apixaban, and rivaroxaban [16], the lack of their widespread use makes it essential to identify the best evidence-supported choice for surgical timing of evacuation. Based on the few case reports that have been published so far, it seems that the benefit of earlier intervention outweighs the risk of surgical bleed.
According to our literature review, 4 patients underwent surgical intervention within 24 hours of symptoms onset, and 3 of these 4 patients (75%) had excellent outcomes with unknown outcome in the third one [2,4,5]. Preceding the emergent surgical interventions, prothrombin complex concentrate was given to one patient and fresh frozen plasma to the other which has been shown in some previous studies to be an effective reversal method for factor X inhibitors [21].
ere was no associated bleeding with either surgical intervention. On the other hand, 5 cases (including this report) had delayed surgical intervention (>24 hours) [5][6][7][8][9]. Among these cases, only 2 had good recovery (40%), and 3 had bad outcomes. No perioperative bleed was reported in any of the cases. e short follow-up period in most of these articles including ours (9 days) represent a major limiting factor in most of these reports. e number of cases reported is insufficient to reach any statistically significant result, but seems to be pointing towards the importance of early surgical intervention for neurologic recovery. With the development of new reversal agents and increased experience with the current ones, earlier surgical intervention is most likely to increase in frequency as surgeons become more comfortable operating on these patients leading hopefully to less neurologic deficit.
is means that a high suspicion index leading to earlier diagnosis is key for timely intervention, and we hope that this article will help in raising awareness about this condition as a potential complication of DOACs use, especially with the significant and continuous increase in their utilization.

Consent
A consent form was obtained and signed by the patient and kept in her medical records.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
AE reviewed the literature, collected and analyzed the data, and wrote the manuscript. LN gathered the history, examined the patient, and reviewed and edited the manuscript. HK reviewed and edited the manuscript.