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.
