Associations of Refractory Spontaneous Intracranial Hypotension and Chronic Subdural Hematoma with Factor XIII Deficiency: A Case Report

Abstract

The co-occurrence of spontaneous intracranial hypotension (SIH) due to thoracic dural tear and factor XIII deficiency (FXIIID) is rare and may result in chronic subdural hematoma (CSDH). CSDH often recurs and is difficult to treat, despite appropriate treatment. However, there is no definitive knowledge on the optimal timing of factor XIII (FXIII) supplementation or therapeutic interventions, such as epidural blood patch (EBP) and burr hole drainage (BHD). We present a case of refractory SIH and CSDH associated with FXIIID. Considering an ineffective initial EBP, we performed a second EBP after observing sufficiently high FXIII activity; SIH was cured subsequently. The patient experienced SIH recurrence after 14 months and was treated with a combination of EBP and BHD, with sufficient FXIII supplementation. CSDH disappeared and did not recur for more than 12 months. During the treatment of SIH and CSDH associated with FXIIID, surgical treatment such as EBP appeared ineffective due to low FXIII activity. This necessitates intravenous supplementation of FXIII to maintain sufficient FXIII activity. Regular monitoring of FXIII activity is also necessary to prevent CSDH recurrence.

Keywords

spontaneous intracranial hypotension - chronic subdural hematoma - factor XIII deficiency - factor XIII activity

Introduction

Spontaneous intracranial hypotension (SIH) is defined as an orthostatic headache of spontaneous onset because of low cerebrospinal fluid (CSF) pressure or CSF leak. It is usually accompanied by nuchal pain, tinnitus, auditory disturbances, phonophobia, and nausea.[1] [2] SIH is diagnosed by CSF leakage findings on head magnetic resonance imaging (MRI), spinal MRI, myelography, or myelography with computed tomography (CT). However, the site of CSF leakage is often not reliably identified on imaging studies, and it was reported that only 50% of cases were identified on imaging studies about the site of dural defects.[3] Thus, the presence of bone spurs or pleural effusions is also an important finding to support the detection of the site of CSF leakage.[3] [4] The first step of treatment involves hydration and bed rest. An epidural blood patch (EBP) is applied when no improvement in symptoms is observed. Moreover, an operative closure of the spinal CSF leak may be an option in some cases.[1] Chronic subdural hematoma (CSDH) may also be associated with SIH. Burr hole drainage (BHD) is performed in cases refractory to conservative treatment. Factor XIII deficiency (FXIIID) is a rare bleeding disorder associated with recurrent miscarriages, intracranial hemorrhage, and impaired wound healing. It can also cause other subdural and epidural hematomas.[5] [6] [7] [8] Notwithstanding the rare co-occurrence of SIH and FXIIID, it is associated with CSDH,[8] [9] [10] which often recurs and is difficult to treat despite appropriate treatment.[9] [10] Treatment options include EBP for SIH and BHD for CSDH. In addition, researchers recommend intravenous FXIII administration for low FXIII activity.[11] [12] [13] [14] However, there is no definitive knowledge on the optimal timing of intravenous FXIII administration or therapeutic interventions such as EBP and BHD. Herein, we report a case of recurrent CSDH associated with FXIIID-related SIH, which showed good outcomes by performing EBP and BHD after intravenous FXIII administration.

Case Report

A 36-year-old woman was admitted to our hospital because of an orthostatic headache. CT revealed a right CSDH ([Fig. 1A]). There was no history of trauma, and the symptoms of orthostatic headache were typical of SIH. Contrast-enhanced MRI of the head displayed dural contrast ([Fig. 1B]), thus indicating SIH-associated CSDH. The platelet count, fibrinogen level, prothrombin time international normalized ratio (PT-INR), and activated partial thromboplastin time (APTT) were within reference levels, and screening with coagulation tests revealed a decrease in FXIII activity to 46.3%; therefore, she was diagnosed with FXIIID. FXIII measurements were performed with a synthetic substrate method (Berichrom FXIII, Sysmex Corp., Japan) and a latex-enhanced immunoturbidimetric assay (LPIA F-XIII, LSI Medience, Japan). The former reflects the activity of FXIII, while the latter the antigen level of FXIII. These levels correlated well, suggesting type I FXIIID. We administered intravenous plasma-derived FXIII concentrate, followed by EBP the day after admission, for an FXIII activity of 78.4% ([Fig. 2]). Whole spine MRI did not identify the site of CSF leakage, but the MRI showed bilateral pleural effusions, especially at the Th7 level, which led us to speculate the presence of CSF leak from the thoracic spine ([Fig. 3]). Subsequently, she had EBP at the Th7–8 level performed by an anesthesiologist. Following the first EBP, headache symptoms did not improve, which was considered a treatment failure because of insufficient FXIII activity improvement. FXIII supplementation was continued again, and then the FXIII activity reached 133.5%. The second EBP at the Th7–8 level was performed on the eighth day of admission, and the headache improved. Thereafter, the right CSDH spontaneously disappeared within 4 months, and outpatient visits were terminated. Approximately 14 months following the first admission, she redeveloped orthostatic headache. A CT scan displayed a left CSDH, following which the patient was admitted to our hospital. The symptoms of orthostatic headache were typical of SIH. Contrast-enhanced MRI of the head revealed dural contrast and a hematoma under the left cerebellar tent, thus suggesting a CSDH associated with recurrent SIH. Whole spine MRI did not identify the site of CSF leakage; however, the pleural effusions were observed, especially at the Th7 level same as before. It was speculated that the CSF was leaking from the thoracic spine. The FXIII activity decreased to 62.6% during admission. Following intravenous FXIII supplementation, the anesthesiologist performed EBP at the Th7–8 level on the sixth day of admission when the FXIII activity reached 137.6%. Immediately following EBP, the headache improved. However, she experienced nightly headaches that worsened when she lowered her head. Considering that the CSDH remained untreated, headache symptoms were supposedly caused by increased intracranial pressure. Moreover, the left CSDH displayed a gradual worsening trend on the CT scan during hospitalization. BHD was performed the following day when FXIII activity was 133.2%. Postoperatively, the headache improved. Moreover, the SIH findings improved on contrast-enhanced MRI. Thereafter, the hematoma did not recur, and the patient was discharged. In the outpatient clinic, the hematoma disappeared and did not relapse for more than 12 months. FXIII activity of the patient is being monitored.

Fig. 1 Imaging findings on first admission. CT scan displays a right CSDH (A). Contrast-enhanced MRI of the head displays dural contrast (B). CDSH, chronic subdural hematoma; CT, computed tomography; MRI, magnetic resonance imaging.

Fig. 2 The time course of FXIII activity, CSDH imaging, and treatment. The patient was admitted with right CSDH. FXIII supplementation was initiated on day 5 of admission. EBP was performed on day 6 of admission and was ineffective. After continuing FXIII supplementation, EBP was performed on day 13 of admission and improved SIH. Right CSDH disappeared within 4 months after EBP. Fourteen months later, the patient was admitted to the hospital with left CSDH. FXIII supplementation and EBP were performed; however, the headache and CSDH worsened. Thus, BHD was performed on day 8 of second admission. Postoperatively, SIH improved and CSDH did not recur for more than 12 months. BHD, burr hole drainage; CSDH, chronic subdural hematoma; EBP, epidural blood patch; FXIII, factor XIII; SIH, spontaneous intracranial hypotension.

Fig. 3 Chest MRI at initial treatment. Bilateral fluid accumulation at the Th7 level (arrow heads) was observed (A), and it was considered to be pleural effusion because of fluid transfer (arrow) in the lateral recumbent position (B). It was diagnosed that the CSF was leaking from the thoracic spine. CSF, cerebrospinal fluid; MRI, magnetic resonance imaging.

Discussion

FXIIID is reportedly related to wound healing and is generally defined as <70% activity.[15] This blood coagulopathy is classified as congenital or acquired form,[5] with an incidence of 1 in 2 million individuals. Moreover, it is associated with recurrent miscarriages, intracranial hemorrhage, and impaired wound healing, and can also cause other subdural and epidural hematomas.[5] [6] [7] [8] The causes of acquired FXIIID are varied and may be idiopathic or related to autoantibodies or other factors.[5] [14] Its consumption may also decrease with surgical treatment or disseminated intravascular coagulation.[16] [17] [18] In the aforementioned case, it was not clear if the mechanism of FXIIID was congenital or acquired. The FXIIID in this patient is less likely to be caused by consumptive decline in CSDH because FXIIID activity decreased after the hematoma disappeared. Further differentiation would require additional analysis like autoantibody testing.

FXIII supplementation is effective for refractory CSF leak following craniotomy.[12] A previous study reported that SIH was cured by the intravenous administration of FXIII concentrate[13]; thus, FXIIID can be considered a cause of SIH. Patients with SIH-associated CSDH have lower FXIII activity than those without, in addition to a greater risk of postoperative CSDH recurrence.[10] Low FXIII activity may interfere with the repair of CSF leakage sites and cause refractory CSDH.[13] Therefore, the pathogenesis of this case involved FXIIID, which led to the development of SIH and CSDH.

Since coagulation disorders may coexist with chronic subdural hematoma,[18] it is important to screen for coagulation disorders, especially in refractory CSDH. Despite the rare occurrence of FXIIID, cases of CSDH with FXIIID have been reported.[19] Furthermore, coagulation disorders such as von Willebrand factor deficiency and hemophilia have been reported to be associated with spontaneous subdural hematoma.[19] [20] Therefore, although FXIII may not be the routine checklist for SIH, in the setting of SIH with CSDH, screening for FXIII should be performed in addition to other coagulation factors such as factors II, V, VIII, IX, X, and XI, and fibrinogen.[8] [21] [22]

Shimogawa et al. previously reported five patients with recurrent FXIIID-mediated SIH successfully treated with FXIII supplementation.[10] In all cases, the patients were treated with a combination of EBP and BHD, and their FXIII activities were <70%. However, the activity following FXIII supplementation has not been specified. Our case is the first report to corroborate FXIII activity and treatment response in a case of CSDH associated with FXIIID-mediated SIH, with multiple follow-ups of FXIII activity before and after supplementation. The failure of the first EBP treatment and the relapse following the first admission may be attributed to low FXIII activity. The treatment success in the first and second admissions can be attributed to high FXIII during the invasive procedures, namely EBP and BHD. Although the recurrence occurred after an interval of 14 months in this case, which means that the second procedure may not be an ultimate success, CSF leakage could be stopped certainly by EBP because of the marked improvement in orthostatic headache during the hospitalization. Despite no definite opinion on the optimal timing of treatment or the target of FXIII activity, we recommend invasive procedures when the FXIII activity is at least 100%.

In this case, the patient was cured after the first hospitalization. However, she experienced a recurrence owing to no follow-up for FXIII activity in the outpatient setting. FXIII activity is reportedly low in non-traumatic CSDH. Since postoperative recurrence is common when FXIII activity is low,[9] if BHD had been performed without increasing FXIII activity in this case, there would have been a high probability of recurrence. In addition, FXIII activity can be a predictor of postoperative recurrence.[9] Previous reports have demonstrated an association between FXIII and a higher risk of recurrence, with a cutoff of 68.5%.[9] Nonetheless, this value is an outcome of FXIII activity at the onset. There is no definite opinion on the target level of FXIII activity following treatment or a guideline for supplementation. Considering that low FXIII activity may lead to recurrence, its activity should be assessed periodically in FXIIID-mediated SIH. A follow-up study with a larger cohort is necessary for generalization of our hypothesis.

Conclusion

In the treatment of FXIIID-associated SIH and CSDH, surgical treatments such as EBP may be ineffective due to low FXIII activity. This warrants treatment with intravenous FXIII supplementation. Moreover, regular monitoring of FXIII activity is necessary to prevent recurrence.

Conflict of Interest

None declared.

Authors' Contributions

S.M. designed the study, the main conceptual ideas, and the proof outline. T.T., S.Y., K.S., and M.S. collected the data. K.E., M.N., M.K., and Y.Y. aided in interpreting the results and worked on the manuscript. M.S. performed EBP. N.S. supervised the project. T.T. wrote the manuscript with support from S.M. All authors discussed the results and commented on the manuscript.

Patients' Consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Publication History

Article published online:
23 June 2025