Prevalence, clinical presentation, and treatment-management of cerebral venous thrombosis associated with spontaneous intracranial hypotension: A combined case-series and systematic literature review approach

Abstract

Background

Cerebral venous thrombosis (CVT) is a rare complication of spontaneous intracranial hypotension (SIH). Therefore, its correct diagnosis and the corresponding optimal treatment-management identification remains challenging.

Methods

Over the last 10 years, 300 patients received a definite SIH diagnosis at our stroke center. Through thorough review of the database, we identified all patients with SIH-related CVT. In addition, we performed a systematic literature review including all publications on SIH-related CVT.

Results

Five out of our 300 SIH patients showed CVT (F/M:2/3, mean age: 51.8 ± 15.7). Through the literature search, 72 additional cases were identified. Overall, the prevalence was 1.3% and main clinical presentations were orthostatic headache, nausea, and vomiting. The CVT was predominantly located at the superior sagittal sinus. Treatment strategies included anticoagulants (ACs) (43%), epidural blood patch (EBP) (19.4%), and combined AC + EBP (33.3%). In our cohort, all but one patient received combined EBP and AC. The mean clinical and radiological follow-up were 2 years and 1.5 years, respectively. Complete clinical recovery was reported in 96% of the cases, whereas 56% showed complete radiological CVT resolution. Among patients without radiological resolution (26.4%), 57% received AC-only, while 43% received combined AC + EBP. Of our five cases, all but one patient received combined AC + EBP.

Conclusion

The overall prevalence of SIH-related CVT was 1.3%. AC and combined AC + EBP were the most used treatment-management strategies. CVT resolution was more commonly achieved after the combined strategy. Overall, the rate of complete clinical recovery was 96%.

Introduction

Spontaneous intracranial hypotension (SIH) is currently diagnosed according to the International Classification of Headache Disorders—3rd edition (ICHD-3), ¹ and unsurprisingly, its main symptom is a headache. In 75–80%, the headache is orthostatic, being relieved by recumbency and worsened by Valsalva-type maneuvers. Other common symptoms include tinnitus, auditory disturbance, and dizziness (50% of patients); nausea, vomiting, photophobia, and meningism (20% of patients). ²

The incidence of SIH is estimated around 4–5:100.000 people per year in the Western countries, concerning most frequently women between 35 and 55 years old^2,3 but this number is probably underestimated by a great number of misdiagnosed cases. SIH can be caused by spinal leakage of cerebrospinal fluid (CSF) out of ventral dural tears (type I), by nerve root diverticula (type II), or through a cerebral spinal fluid venous fistula (CSFVF) leading directly into the periradicular veins (type III). Still, in up to 30% of the patients diagnosed with SIH, the CSF leak remains unidentified. ⁴

Cerebral venous thrombosis (CVT) is a rare complication of SIH with an estimated prevalence around 1–2%. ⁵ This prevalence is significantly higher than the general populations’ CVT prevalence, that is about 0.0005%. ⁶ SIH-associated CVT may cause important neurological complications, as subarachnoid hemorrhage and dural arterio-venous fistula. Yet, currently there is no consensus about its treatment-management. Therefore, we aim to perform a comprehensive and updated analysis of all CVT cases described in the literature, in addition to a full rapport of our institution's experience of CVT in a cohort of patient diagnosed for SIH including imaging data, clinical characteristics, and treatment-related outcomes. This unique combination offers us a large pool of SIH-related CVT patients, allowing the identification of most used treatment strategies, in association with complications and recovery levels, aiming to improve the management of this rare, but devastating neurological phenomenon.

Methods

case-series

First, to identify all SIH-related CVT cases treated at our institution, we reviewed 10 years (2013–2023) of medical records and imaging studies of patients admitted with a clinical or radiological SIH diagnosis. All radiological examinations were reviewed for the presence of SIH brain signs using the Bern SIH score was used to depict the most important SIH MRI signs: pachymeningeal enhancement, venous sinus engorgement, suprasellar cistern ≤ 4 mm; subdural fluid collection, prepontine cistern ≤ 5 mm, and mamillopontine distance ≤ 6.5 mm. ⁷ Only patients with a definite diagnosis of SIH were included in the final cohort. All patients with SIH-related CVT underwent at least one brain MRI with gadolinium injection to confirm the SIH-related CVT and at least one brain MRI with gadolinium 6 months after the last treatment. All brain MRIs were reviewed by two neuroradiologists with experience in SIH. Initial brain MRIs were used to: (1) confirm the diagnosis of SIH and (2) to verify the presence of CVT. In case of disagreement, a third senior neuroradiologist solved discrepancies. Patients with intracranial hypotension due to lumbar puncture, surgery, or related to post-traumatic causes were excluded. Follow-up MRIs were used to (1) verify CVT resolution and (2) evaluate the ongoing presence of SIH signs. Collected data included: age, sex, type of symptoms, duration of symptoms, CVT site as identified on MRI, risk factors of CVT (e.g. thrombophilia, oral contraceptives, paraneoplastic syndromes) treatment management, CVT treatment-associated complications, clinical and radiological outcome, and clinical and radiological recurrence.

Literature review

Second, we performed a systematic literature review on PubMed Medline conform the PRISMA guidelines (Figure 1), including all the case reports and case series of patients with SIH complicated by CVT between January 2004 and December 2023. Search syntax terms included “spontaneous intracranial hypotension,” “intracranial hypotension,” “cerebral venous thrombosis,” “cortical vein thrombosis,” and “CVT.” Reference lists of included publications were hand-checked. Series reporting CVT associated with iatrogenic intracranial hypotension were excluded. From each study, we collected age, sex, symptoms, thrombophilia screening, CVT site on MRI, treatment, complications before and after treatment, clinical and radiological outcome, clinical and radiological recurrence.

Figure 1.

PRISMA flow chart.

Statistical analysis

Categorical data were described by their frequency of appearance, whereas quantitative data were described by their mean and standard deviation (± SD). All analyses (descriptive and inferential) were performed with SPSS v.28.

Results

In this section, we will first describe the findings of our institutional case series analysis. Second, we will describe the results of the literature review. Both will follow a similar structure starting with the epidemiological and clinical features, followed by treatment management and complications, and ending with the clinical and or radiological follow-up.

Case-Series results

Epidemiological and clinical features

Three hundred patients were identified with a definite diagnosis of SIH. Of those, five showed CVT (F:2, M:3; mean age: 51.8 ± 15.7), with a related estimated prevalence of 1.6%. Patient’ characteristics are reported in Table 1. At the first MRI scan, all patients had a Bern SIH score of at least six out of nine, for a mean score of seven. In line, they all scored positive of the major criteria to know pachymeningeal enhancement, engorgement of venous sinus, and suprasellar cistern ≤ 4 mm. The mamillopontine distance was ≤ 6.5 mm in four patients, and three showed SDH and had a prepontine cistern ≤ 5 mm.

Table 1.

Case-series overview: SIH-related CVT patients’ characteristics.

Patient	1	2	3	4	5
Age	35	69	35	68	47
Sex	F	M	M	M	F
Symptoms duration	8 days	14 days	4 days	10 days	14 days
Orthostatic hedeache	No	No	Yes	Yes	Yes
Other symptoms	Intracranial hypertension symptoms, neck pain, nausea	Non orthostatic hedeache	Neck pain, nausea, left hemihypesthesia, tinnitus, diziness	Right ataxia, right ptosis	-
CVT location	SSS, RTS, LTS, RJV	SSS, cortical veins	RJV, LJV, cortical veins	SSS, LTS, LSS	Cortical vein
SIH type	-	-	-	-	1
Bern score (xx/9)	7	6	9	8	8
Thrombophilia screening	Negative	Negative	High homocystein level	Negative	Negative
Treatment	AC + EBP	AC	AC + EBP	AC + EBP	AC + EBP
Complications	SDH	-	SDH + SAH	SDH	-
Clinical remission	Chronic hedeache	Yes	Yes	Yes	Yes
Radiological resolution	Complete resolution	Complete resolution	Complete resolution	Complete resolution, persistent SIH IRM signs	Complete resolution
Recurrence	No	No	No	No	No

SSS: superior sagittal sinus; RTS: right transverse sinus; LTS: left transverse sinus; LSS: left sigmoid sinus; RJV: right jugular vein; LJV: left jugular vein; AC: anticoagulant; EBP: epidural blood patch; SDH: subdural hematoma; SAH: subarachnoid hemorrhage; CVT: cerebral venous thrombosis.

At the time of diagnosis, the main symptoms included orthostatic headache (60%), neck pain (40%), and nausea (40%). The mean symptom duration before the hospitalization was 10 days. One patient showed an isolated cortical vein thrombosis, the others (80%) had multiple occlusion sites, including: the superior sagittal sinus (SSS) in 3/5, the left transverse sinus (LTS) in 2/5, the left sigmoid sinus LSS in 1/5, right transverse sinus (RTS) in 1/5, right jugular vein in 2/5, left jugular vein in 1/5, and cortical veins in 3/5 patients.

All patients were screened for thrombophilia (homocysteine level; protein S and C; factor IX; mutation of factor V Leiden, prothrombin, V617F and JAK2; antibodies anti-DNA, anti-cardiolipin, anti-B2GP1, anti-phospholipid). However, only one case showed a high level of homocysteine. Finally, none of the female patients had a history of oral contraceptive assumption.

Treatment-management and complications

In all cases, CVT was treated by anticoagulant (AC) therapy with administration of Enoxaparin. Four patients received an epidural blood patch (EBP) for SIH that needed to be repeated in three patients due to clinical SIH symptom persistence. Nevertheless, complete SIH symptom and MRI signs remission was achieved in all-but-one patient. This patient demonstrated a persistent non-orthostatic headache at 2-year clinical follow-up that did not improve with pharmacological treatment including Topiramate and Venlafaxine administration.

Three patients showed AC therapy-related complications, marked by the development of bilateral subdural hematomas, and in one case the appearance of a cortical subarachnoid hemorrhage on the brain MRI. In all cases, the AC therapy was stopped immediately, and an EBP was performed. Two days later the AC therapy was resumed. At 1 month follow-up, one patient showed a subdural hematoma growth that required a neurosurgical evacuation.

Follow-up

Patients were radiologically followed for 18 months on average. In concordance with the MRI signs and SIH symptoms remission, radiological CVT resolution was also obtained in all-but-one patient (Figures 2 and 3). This patient showed a persistent pachymeningeal enhancement, as well as a venous sinus engorgement with a Bern Score of 4/9. Because of the absence of a visible spinal extradural fluid collection, a bilateral decubitus dynamic myelography (DSM) was performed in search of a CSFVF that could possibly explain the SIH persistence. As no leak could be identified, this patient is still under investigation. A second DSM is planned to search for a possible tiny CSFVF. Finally, there were no cases of clinical or radiological recurrence.

Figure 2.

(a–c) T1-weighted MRI brain with gadolinium showing brain sagging: by cisterns effacement (a), pachimeningeal enhancement (c), venous sinuses engorgement, and a cortical left parietal vein thrombosis, marked by the white arrow (a,b); (d–f) control MRI after treatment showing isolated cerebral vein thrombosis resolution (d,e) with persistence of cistern effacement (d) and pachymeningeal enhancement resolution (f).

Figure 3.

(a–c) T1-weighted MRI brain with gadolinium showing SIH-signs with CVT at the superior sagittal sinus, as marked by the white arrow; (d–f) control MRI after treatment showing CVT and SIH-signs resolution.

CVT: cerebral venous thrombosis.

Systematic review results

Epidemiological and clinical features

Through a systematic search of the literature, 45 articles were selected. These were divided in case reports (38/45) and case series (7/45). A total of 72 patients with confirmed SIH and CVT (mean age 40.8 ± 11.47 years; 37 males) were included (Figure 1).

The patients’ clinical presentation is reported in Table 2. Clinical symptoms were described in 62/72 patients. Of those, the main symptom reported was orthostatic headache (87%), followed by nausea (56.4%), vomiting (37.1%), and neck pain (22.5%). Thrombophilia screening was performed in 38 patients, being negative in 30 cases (62.5%) and positive in 8 patients (16.6%). Data for venous site occlusion were available for 66 patients. In 42 cases (58%), multiple CVT locations were identified. The main site of occlusion was the SSS (59%) followed by the cortical veins (30.3%), the LTS (28.8%), and the RTS (24.2%) Table 3.

Table 2.

Systematic literature review: patients’ clinical, radiological and treatment variables.

Variables	Systematic review results	CI (95%)	Number of studies
Total number of articles	45
Case series	7
Case report	38
Clinical variables
Total number of patients	72
Age (years)	Mean = 40.8 SD ± 11.47		44/45
Sex			44/45
M	37
F	34
Not specified	1
Symptoms			39/45
Orthostatic hedeache	54/62 (87%)	0.7629 to 0.9357
Neck pain	14/62 (22.5%)	0.1384 to 0.3452
Nausea	35/62 (56.4%)	0.4409 to 0.6806
Vomiting	23/62 (37.1%)	0.2613 to 0.4956
Diarrhea	1/62 (1.6%)	<0.0001 to 0.0941
Seizures	10/62 (16.1%)	0.0880 to 0.2741
Photophobia	4/62 (6.4%)	0.0208 to 0.1590
Diplopia	4/62 (6.4%)	0.0208 to 0.1590
Phonophobia	3/62 (4.8%)	0.0112 to 0.1383
Tinnitus	9/62 (14.5%)	0.0760 to 0.2557
Other uditive symptoms	7/62 (11.3%)	0.0528 to 0.2182
Diziness	7/62 (11.3%)	0.0528 to 0.2182
Ataxia	1/62 (1.6%)	<0.0001 to 0.0941
VI nerve palsy	1/62 (1.6%)	<0.0001 to 0.0941
Limb weakness	5/62 (8%)	0.0310 to 0.1792
Hemiparesis/Hemiplegia	3/62 (4.8%)	0.0112 to 0.1383
Thrombophilia sceening			27/45
Negative	30/38 (78.9%)	0.6340 to 0.8918
Positive	8/38 (2%)	0.1082 to 0.3660
Radiological variables
SIH type			19/45
I	22/27 (81.5%)	0.6284 to 0.9228
II	5/27 (18.5%)	0.0772 to 0.3716
III	-	-
CVT location			44/45
SSS	39/66 (59%)	0.4704 to 0.7014
ISS	1/66 (1.5%)	<0.0001 to 0.0888
SS	2/66 (3%)	0.0022 to 0.1101
LTS	19/66 (28.8%)	0.1921 to 0.4070
RTS	16/66 (24.2%)	0.1542 to 0.3590
LSS	14/66 (21.2%)	0.1296 to 0.3263
RSS	8/66 (12.1%)	0.0602 to 0.2239
RJV	2/66 (3%)	0.0022 to 0.1101
LJV	1/66 (1.5%)	<0.0001 to 0.0888
ICVT	11/66 (16.6%)	0.0939 to 0.2761
Cortical veins	9/66 (13.6%)	0.0712 to 0.2415
PFV	1/66 (1.5%)	<0.0001 to 0.0888
Treatment			45/45
AC	31/72 (43%)	0.3225 to 0.5456
EBP	14/72 (19.4%)	0.1183 to 0.3016
AC + EBP	24/72 (33.3%)	0.2350 to 0.4485
Neurosurgical treatment	3/72 (4.1%)	0.0094 to 0.1203
Mechanical thrombectomy	2/72 (2.7%)	0.0019 to 0.1015
Complication			45/45
No	36/72 (50%)	0.3875 to 0.6125
Subdural hematoma	20/72 (27.7%)	0.1870 to 0.3911
Intraparenchimal hematoma	10/72 (13.8%)	0.0753 to 0.2391
Subarachnoid hemorrhage	4/72 (5.5%)	0.0177 to 0.1384
DAVF	5/72 (6.9%)	0.0264 to 0.1561
Death	1/72 (1.4%)	<0.0001 to 0.0818
Clinical remission			42/45
Yes	64/67 (95.5%)	0.8713 to 0.9897
No	3/67 (4.5%)	0.0103 to 0.1287
Radiological resolution			34/45
Partial resolution	10/53 (18.8%)	0.1039 to 0.3156
Complete resolution	27/53 (50.9%)	0.3788 to 0.6388
Chronic occlusion	1/53 (1.5%)	<0.0001 to 0.1088
No resolution	14/53 (26.4%)	0.1634 to 0.3968
Thrombosis progression	1/53 (1.5%)	<0.0001 to 0.1088
Recurrence			37/45
Clinical + Radiological	7/72 (9.7%)	0.0356 to 0.1733
Clinical	6/72 (8.3%)	0.0356 to 0.1733

Note that patients can receive multiple treatments and show multiple complications. SSS: superior sagittal sinus; ISS: inferior sagittal sinus; SS: straight sinus; LTS: left transverse sinus; RTS: right transverse sinus; TS: transverse sinus; LSS: left sigmoid sinus; RSS: right sigmoid sinus; PFV: persistent falcine vein; RJV: right jugular vein; LJV: left jugular vein; AC: anticoagulant; EBP: epidural blood patch; DAVF: dural arteriovenous fistula; CVT: cerebral venous thrombosis.

Table 3.

Systematic literature review: overview of clinical and radiological characteristics of the 72 SIH-related CVT patients from 45 studies.

AUTHORS-YEAR	No OF PATIENTS	TOTAL OF PATIENTS	SEX, AGE	ORTHOSTATIC HEADACHE	OTHER SYMPTHOMS	SIH TYPE	SITE OF THROMBOSIS	TRHOMBOPILIA SCREENING	PATOLOGIES ASSOCIETED	AC	EBP	NT	MT	RADIOLOGICAL RESOLUTION	CLINICAL REMISSION	COMPLICATIONS PRE-TREATMENT	COMPLICATIONS POST-TREATMENT	CLINICAL RECURRENCE	RADIOLOGICAL RECURRENCE
LI ET AL. 2023 16	1	-	M, 37	-	Neck pain, left upper and lower limbs weakness/ numbness, seizure, lost consciousness	1	SSS cortical veins	-	-	Yes	Yes	No	No	CR	Yes	No	No	No	No
ZHANG ET AL. 2018 17	1	-	M, 35	+	Nausea, vomiting, photophobia	-	SSS	Negative	-	Yes	No	No	No	PR	Yes	SDH		No	No
GABAY MOREIRA ET AL. 2023 18	3	-	F, 15	+	?	1	-	-	-	No	Yes	No	No	-	Yes	No	No	No	No
			F, 35	+	Photophobia/ phonophobia, nausea, vomiting, dizziness, diplopia, excessive somnolence	1	SSS, SS, RTS, LTS, RSS, RJV	-	-	No	No	Yes	No	-	Yes	No	No	No	No
			F, 27	+	Photophobia/phonophobia, nausea, vomiting	1	-	-	-	No	No	Yes	No	-	Yes	No	No	No	No
FUJII ET AL. 2018 19	1	-	F, 33	+/-	Nausea, vomiting, vertigo	1	SSS, LTS	Negative	-	Yes	No	No	No	CR	Yes	No	No	No	No
PAN 2023 20	1	-	F, 29	+	Neck pain, nausea, vomiting	-	SSS right parietal cortical veins	Negative	-	Yes	No	No	No	CR	Yes	No	No	No	No
ZHANG ET AL. 2018 21	4	374	M, 34	+	Tinnitus, neck pain, tonic-clonic seizures	2	SSS, LTS, LSS	-	-	No	Yes	No	No	CR	Yes	SDH		No	No
			F, 43	+	Nausea	2	SSS, LTS, LSS, LJV	-	-	No	Yes	No	No	CR	Yes	No	No	No	No
			F, 37	+	Nausea, vomiting	2	RTS, SS, ISS	-	-	No	Yes	No	No	-	Yes	SDH		No	No
			M, 38	+/-	Neck stiffness, nausea, vomiting	2	SSS, RTS	-	-	No	Yes	No	No	No	Yes	No	No	Yes	Yes
TAN ET AL. 2008 22	2	-	F, 46	+/-	-	-	LTS, LSS	Reduction C protein	-	Yes	No	No	No	CR	Yes	SDH		No	No
			M, 40	+/-	Vertigo	-	SSS, left cortical vein	Abnormal protein C	-	Yes	No	No	No	-	Yes	SDH		No	No
ALBAYRAM ET AL. 2007 23	1	-	M, 45	+	-	1	SSS	-	-	Yes	Yes	No	No	CR	Yes	No	No	No	No
LAN ET AL. 2007 24	1	-	M, 36	+	Nausea, vomiting	-	Right parietal cortical vein	Negative	-	No	Yes	No	No	CR	Yes	DAVF, IH		Yes (epilepsy)	No
ADE AND MOONIS 2013 25	1	-	F, 54	+	Nausea, vomiting	-	SSS, left cortical veins	-	Right ophthalmic artery aneurysm	Yes	Yes	No	No	CR	Yes	SDH, SAH		No	No
KIM ET AL. 2020 26	1	-	M, 35	-	Headache after a mild head trauma, neck stiffness, tonic-clonic seizures	-	SSS	Negative	-	Yes	Yes	Yes (SDH)	No	CR	Yes	No	SDH	No	No
KATAOKA ET AL. 2007 27	1	-	M, 36	+	Nausea, auditory distortion	1	SSS	Negative	-	Yes	Yes	No	No	No	Yes	No	SDH	Yes	Yes
LAI ET AL. 2007 28	1	-	F, 45	+	Nausea, vomiting	-	cortical vein	Negative	-	Yes	Yes	No	No	CR	Yes	SDH, IH		No	No
SAVOIARDO ET AL. 2006 29	2	-	M, 31	+	Neck stiffness, nausea, vomiting	1	SSS, LTS, LSS	Negative	-	Yes	No	No	No	PR	Yes	No	No	No	No
			F, 40	+	Neck stiffness	-	-	Negative	-	Yes	No	No	No	PR	Yes	No	No	No	No
FERRANTE ET AL. 2021 30	8	445	F, 72	-	Cognitive/ motor slowing, gait ataxia	-	SSS	Negative	-	Yes	No	No	No	PR	Yes	IH	No	No	No
			M, 69	-	Nausea, vomiting, tinnitus	-	RTS, RSS, SS	Negative	-	Yes	Yes	No	No	CR	Yes	No	No	No	No
			F, 43	-	Nausea, bilateral tinnitus	-	LTS, LSS	Negative	-	Yes	Yes	No	No	PR	Yes	No	No	No	No
			M, 45	-	Diplopia, drowsiness, cognitive/ motor slowing, ack of inhibition	-	SSS, LTS, LSS	Negative	-	Yes	Yes	No	No	CR	Yes	SDH		No	No
			M, 59	-	Bilateral tinnitus, ear fullness	-	LTS, LSS	Negative	-	Yes	Yes	No	No	CR	Yes	DAVF	No	No	No
			F, 54	-	Nausea, vomiting	-	SSS	Abnormal Protein C	-	Yes	Yes	No	No	No	Yes	No	No	No	No
			M, 51	-	Dizziness	-	RTS	Negative	-	Yes	Yes	No	No	No	Yes	SDH	No	No	No
			F, 36	-	Nausea, vomiting, ear fullness, bilateral tinnitus	-	LTS	Negative	-	Yes	Yes	No	No	CR	Yes	No	No	No	No
PERRY ET AL. 2018 31	1	-	M, 43	-	Dizziness, nausea	1	SSS cortical veins	Negative	Antiphospholipid Syndrome	Yes	Yes	Yes (hematoma)	No	-	Yes	IH	No	Yes	No
WANG ET AL. 2007 32	1	-	F, 33	-	Occipito-nuchal pain, nausea, vomiting, simple partial seizures	1	Cortical vein (right vein of Trolard)	Negative	-	No	Yes	No	No	CR	Yes	SAH	No	No	No
RICHARD ET AL. 2007 33	2	-	M, 38	+	Orthostatic headache after a minor cranial trauma	-	SSS, RTS, LTS, bilateral parietal cortical veins	Negative	-	Yes	No	No	No	PR	Yes	SDH, SAH	No	No	No
			F, 60	+	Bilateral tinnitus, right hemiplegia, severe cephalalgia	-	Right parietal cortical vein	-	-	Yes	No	No	No	CR	Yes	SDH, IH	No	No	No
GE ET AL. 2023 34	3	-	M, 40	+/-	Seizures	-	-	-	-	Yes	No	No	No	No	Yes	No	No	No	No
			F, 38	+	Nausea, vomiting	-	-	-	-	Yes	No	No	Yes	No	Yes	No	No	No	No
			M, 20	+/-	Limb weakness	-	-	-	-	Yes	No	No	No	No	Yes	No	No	No	No
DANGRA ET AL. 2011 35	1	-	M, 35	+	Vomiting, diarrhea	1	SSS, RSS, LSS	Negative	-	Yes	No	No	No	ChrO	Yes	SDH	No	No	No
YAMAMOTO ET AL. 2020 36	1	-	F, 52	+	Left-sided hemiparesis, tonic-clonic seizures	1	LTS, LSS	-	-	Yes	Yes	No	No	CR	Yes	SDH	No	No	No
BERROIR ET AL. 2004 37	2	-	F, 46	+	Neck pain, auditory distortion	-	SSS, RTS	Negative	Benign mastopathy treated by norethisterone	Yes	No	No	No	PR	Yes	No	No	No	No
			F, 32	+	Nausea, vomiting, hyperacusia, tinnitus	-	SSS, LTS	High homocysteine level, homozygous C677 T, MTHFR gene mutation, heterozygous G20210A prothrombin gene mutation.	-	Yes	No	No	No	-	Yes	No	No	No	No
YOON ET AL. 2011 9	1	-	M, 26	+	?	1	SSS	-	-	Yes	Yes	No	No	-	Yes	No	No	No	No
GULER ET AL. 2013 38	1	-	M, 40	+/-	Weakness at right side, tonic-clonic seizure	-	SSS, RTS, RSS	Negative	-	Yes	No	No	No	PR	Yes	No	No	No	No
TIAN AND PU 2012 39	1	-	F, 41	+	Nausea, vomiting	-	SSS, RTS, LTS, RSS, LSS	-	-	Yes	No	No	No	-	Yes	No	No	No	No
SCHIEVINK AND MAYA 2008 5	3	141	F, 26	-	Occipital and posterior neck pain, nausea	1	LTS, LSS	-	-	Yes	Yes	Yes	No	-	Yes	No	No	No	No
			M, 32	-	Occipital and posterior neck pain, nausea	1	SSS, TS, cortical vein	-	-	No	Yes	No	No	TP	Yes	SAH	No	Yes	Yes
			M, 43	+	Posterior neck pain, transient horizontal diplopia, generalized tonic-clonic seizure	1	SSS, RTS, RSS	-	-	Yes	Yes	No	No	No	Yes	IH	No	Yes	No
PARIS ET AL. 2020 40	1	-	M, 40	+	Neck pain, nausea, vomiting	-	LTS, LSS	-	-	Yes	Yes	No	No	CR	Yes	No	No	No	No
LEE ET AL. 2021 41	1	-	M, 34	+/-	-	1	SSS, RTS	-	-	Yes	No	Yes (SDH)	No	-	Yes	No	SDH	Yes	No
RICE ET AL. 2013 42	1	-	M, 75	-	Status epilepticus, GCS 3	-	SSS	-	-	Yes	No	No	Yes	No	No	IH	IH, Death	No	No
NARDONE ET AL. 2010 43	1	-	M, 44	-	Sensory disturbances in the left upper limb and occasional left visual field defects (transient homonymous hemianopsia)	-	Cortical veins	Negative	-	Yes	No	No	No	-	Yes	SDH	No	Yes	No
MAO ET AL. 2011 44	1	-	M, 34	-	-	-	SSS, ISS, SS	Negative	-	Yes	No	Yes (SDH)	No	CR	Yes	SDH	No	No	No
TAKEUCHI ET AL. 2007 45	1	-	M, 32	+	Nausea	-	SSS	-	-	No	Yes	No	No	CR	Yes	No	No	No	No
GARCIA- CARREIRA ET AL. 2014 46	2	-	F, 29	+	Photophobia/phonophobia,	1	SSS cortical veins	High homocysteine level	-	Yes	Yes	No	No	No	Yes	No	No	Yes	Yes
			M, 54	+	Left hemiparesis and hemihypesthesia, left hemianopsia	-	Cortical vein (right vein of Trolard)	-	-	Yes	Yes	No	No	-	Yes	SAH, IH	No	No	No
COSTA ET AL. 2012 47	1	-	F, 48	+	Neck pain, plugged ear, nausea	1	LTS	Negative	Previous diagnosis of mediastinal large B-cell lymphoma with no evidence of activity	Yes	No	No	No	No	Yes	No	No	No	No
HARITANTI ET AL. 2007 10	1	-	M, 42	+	Dizziness, nausea, tinnitus, horizontal diplopia	-	SSS, RTS	Negative	-	Yes	No	No	No	PR	Yes	No	No	No	No
IVANIDZE ET AL. 2010 48	1	-	F, 33	-	Neck pain, nausea, vomiting	-	SSS	Protein S defect	-	Yes	No	No	No	No	Yes	No	No	No	No
SINNAEVE ET AL. 2017 49	1	-	F, 21	+	Nausea, photophobia	-	Cortical veins	Factor V Leiden, HT mutation	-	Yes	Yes	No	No	-	Yes	No	No	No	No
SOPELANA ET AL. 2004 50	1	-	M, 56	+	Nausea, vomiting	-	SSS	Negative	-	Yes	No	No	No	PR	Yes	No	No	No	No
OIEN ET AL. 2022 51	5	563	M, 43	+	Nausea, right-sided weakness	1	SSS cortical veins	-	-	Yes	Yes	No	No	CR	Yes	IH	No	Yes	Yes
			M, 49	+/-	Intermittent pulsatile and non-pulsatile tinnitus	-	RTS, RSS	-	-	No	Yes	No	No	CR	Yes	DAVF	No	No	No
			F, 39	+	-	-	PFV (persistent falcine vein)	-	Chiari 1 malformation, Klippel- Trenaunay- Weber Syndrome	Yes	No	No	No	No	Yes	No	No	Yes	Yes
			F, 68	+	Nausea, vomiting	Suspicious fistula	SSS, RTS, LTS	-	-	Yes	No	No	No	No	No	DAVF	No	Yes	Yes
			M, 40	+	-	-	SSS, RTS, LTS, RSS, LSS	-	-	No	Yes	No	No	CR	Yes	No	No	No	No
FLEMMING AND LINK 2005 52	1	-	F, 31	+	Nausea, no pulsatile noise	-	SSS, RTS	Negative	-	Yes	No	No	No	CR	No	DAVF	No	Yes	No
ZHANG ET AL. 2022 53	3	735	F, 34	+	Neck pain	-	Cortical veins	Protein S defect	-	No	Yes	No	No	-	-	SDH	No	No	No
			F, 32	+	Nausea, neck rigidity	-	Cortical veins	-	-	No	Yes	No	No	-	-	No	No	No	No
			M, 44	+	-	-	Cortical veins	-	-	No	Yes	No	No	-	-	SDH	No	No	No
GULUR ET AL. 2013 54	1	-	M, 41	+	Sixth-nerve palsy	1	Left parietal cortical vein	-	Syndrome of inappropriate antidiuretic hormone secretion (during hospitalization)	Yes	Yes	No	No	CR	Yes	SDH	No	No	No
SEILER AND HAMANN 2009 55	1	-	F, 48	+	Epileptic seizure	-	SSS	-	-	Yes	No	No	No	-	-	No	No	No	No
SUGIURA ET AL. 2019 56	1	-	F, 41	+	Right ear fullness, dizziness, numbness	1	cortical veins	Negative	-	Yes	Yes	No	No	-	Yes	SDH, SAH	No	No	No
ROZEN 2013 57	1	-	-	-	-	-	SSS, RTS, RSS, RJV	Negative	-	Yes	No	No	No	CR	-	No	No	No	No

SSS: superior sagittal sinus; ISS: inferior sagittal sinus; SS: straight sinus;| LTS: left transverse sinus; RTS: right transverse sinus; TS: transverse sinus; LSS: left sigmoid sinus; RSS: right sigmoid sinus; PFV: persistent falcine vein; RJV: right jugular vein; LJV: left jugular vein; AC: anticoagulant; EBP: epidural blood patch; NT: neurosurgical treatment; MT: mechanical thrombectomy; SDH: subdural hematoma; SAH: subarachnoid hemorrhage; DAVF: dural arteriovenous fistula; IH: intraparenchymal hemorrhage; CR: complete resolution; PR: partial resolution; ChrO: chronic occlusion; TP: thrombosis progression; CVT: cerebral venous thrombosis.

Treatment-management and complications

Treatment-management was classified into four groups: (1) AC therapy (43%); (2) EBP (19.4%); (3) combined AC + EBP (33.3%), and (4) neurosurgical treatment for spinal dural leak repair (4.2%). Concerning the latter, surgery was performed in one patient after unsuccessful EBP, and in two cases neither AC nor EBP was performed before intervention. Finally, two patients, both in the AC-group, also underwent mechanical thrombectomy of the main involved sinus.

Overall, 33/72 patients (45.8%) had SIH and CVT-related complications: the most common complication was the development of a subdural hematoma (51.5%), followed by an intraparenchymal hemorrhage (27.3%), a dural arteriovenous fistula (15.1%), and a subarachnoid hemorrhage (12.1%). Post-treatment complications were observed in four cases (5.5%), of which three showed a subdural hematoma and one an intraparenchymal Hemorrhage. Finally, one patient died.

Radiological and clinical follow-up

The mean clinical and radiological follow-up was 2 and 1.5 years, respectively. We reported two types of outcomes: the rate of clinical recovery and the rate of radiological CVT resolution. Clinical outcome was available for 67 patients: 95.5% reported complete clinical recovery, and 4.5% reported the absence of clinical improvement.

Radiological outcomes were available for 53 patients. Most showed complete (51%) or partial (18.8%) resolution. One patient showed a CVT stability with chronic occlusion, whereas another showed progression of the thrombosis. Finally, 26.4% showed no CVT resolution after either AC (57%) or combined AC + EBP (43%).

In 13/72 patients, intracranial hypotension symptoms’ recurrence occurred after treatment. Among these, the MRI signs showed SIH recurrence in six patients, and both CVT and SIH recurrence in one patient after having stopped with the AC therapy. In all-but-one case, retreatment was specified, leading to complete resolution in at least nine patients. In the other four cases, (the absence of) resolution was not specified.

Discussion

By pooling data from the literature and our institutional experience, we provide a thorough case-series analysis of almost 80 patients with SIH-related CVT. Being a rare, yet potentially severe complication of SIH, an extensive overview of its prevalence, radiological characteristics, treatment-management, and related outcomes was lacking by our knowledge. We observed that (i) the CVT was in more than half of the cases located within the sagittal superior sinus, (ii) was efficiently treated by a combined AC + EBP approach, and (iii) associated with a complete clinical recovery rate of 96%.

Etiology of CVT

Mechanisms underlying SIH-related CVT are still not completely elucidated, but the following hypotheses were proposed in the literature. The first hypothesis, based on the Monro-Kellie doctrine of constant intracranial volume, states that the CSF depletion in SIH leads to an increase in cerebral blood volume, that on its turn increases the diameter of cerebral venous sinuses. ⁸ Since flow velocity is inversely proportional to vessel diameter, this results in greater blood stasis with a related increase in thrombotic risk. ⁹ The second hypothesis suggests that SIH-related brain sagging may cause venal damage through stretching of the venous endothelium and mechanical distortion of the vessel wall that both contribute to a prothrombotic state. ¹⁰ The last hypothesis focusses of decreased CSF absorption into the cerebral venous sinuses because of the increased blood viscosity due to CSF volume depletion. All in all, morphological and dynamic changes of both the brain and the CSF seem to contribute to the CVT risk among SIH patients.

Interestingly, in four out of five of our CVT patients, the underlying SIH leak remained unidentified. And in the literature, it's cause was only mentioned about half of the time. When identified, the most common found leak was a type I leak, i.e. a dural tear (∼80%), with a small proportion of type II leaks and no type III leaks. Although we cannot say with certainty that type III leaks are unrelated to SIH-related CVT. That is, type III leaks related to CSFVFs were only recognized as a separate entity in 2014. In addition, radiological CSFVF detection is challenging,^11,12 requiring a lateral decubitus DSM.^12,13 This procedure has only been integrated into our clinical routing over the last 4–5 years, which was after our patients’ time. ¹⁴ It might thus be possible that our four patients with unknown leak location had a CSFVF that could not be identified of CT myelography.

Prevalence and anatomical locations

Previous CVT studies estimated its SIH-related prevalence between one and two percent. ⁶ By pooling the data of five published case series together with our database, we had a large pool of 2000 SIH patients to more precisely estimate the related CVT prevalence, to know 1.3%. At our center only, its prevalence was slightly higher with five patients among 300 SIH cases, or 1.6% (Table 4). In more than half of the patients, CVT occurred at multiple sites (58%). This proportion is quite comparable to what was reported in the VENOST study of patients without SIH (52%). ¹⁵

Table 4.

SIH-related CVT prevalence: overview of the five largest published studies and our case-series analysis.

Authors—Year	CVT/SIH	Prevalence
Schievink et al. (2008)	3/141	2.1%
Zhang et al. (2018)	4/374	1%
Ferrante et al. (2021)	8/445	1.8%
Zhang et al. (2022)	3/375	0.4%
Oien et al. (2022)	5/563	0.8%
Current case-series (2024)	5/300	1.6%

CVT: cerebral venous thrombosis; SIH: spontaneous intracranial hypotension.

Confirm expectation, the diameter of venous sinuses was significantly larger in the SIH population, compared to normal population (dominant transverse sinus 10 ± 1.75 vs 7.52 ± 1.2 mm; straight sinus 4.76 ± 0.92 vs 3.69 ± 0.57 mm; SSS 8.35 ± 1.57 vs 6.37 ± 0.71 mm). ⁵⁸ The largest increase in diameter was found for the SSS, offering a potential explanation of why the CVT occurred most frequently within the SSS. Moreover, cortical vein thrombosis appears also to be more frequent in the SIH population (about 30%) compared to a normal population. This might be explained by the fact that SIH patients may show brain sagging that stretches the cortical veins and increases meningeal blood volume inducing cortical vein dilation.

Clinical features

The age of patient with a SIH-related CVT was higher than that of the general CVT patient’ population (40.8 vs. 32.9 years, respectively).^6,59 In our case-series, the mean age was even higher (51.8 years). The male/female ratio also differed, with a higher prevalence for females in the general CVT population (male/female ratio 2:3), compared to the SIH-related CVT population (about 1:1). ⁵⁹

The most common symptoms at presentation were comparable between the SIH-related CVT population and general SIH population, excepted for seizures, that were only reported in the SIH-related CVT population. ³ Also, nausea and vomiting were very commonly reported in the latter population.^21,30 It is likely that these symptoms are associated with the occlusion of the venous sinus rather than with the SIH, as about 40% of patients with CVT develop intracranial hypertension. ⁶⁰ Accordingly, we reported one patient (patient 1) admitted with MRI signs of intracranial hypotension, with a Bern Score of 7/9, and with papilledema that was associated to a secondary intracranial hypertension due to the occlusion of multiples sinuses. In our literature review, we also identified one case of intracranial hypertension symptoms due to CVT. ⁵¹ Like for CVT, its best treatment-management is still debated. In our case, AC with Enoxaparin was used, resulting in a complete CVT and papilledema resolution, as well as the disappearance of SIH signs, despite the persistence of a chronic headache.

Treatment-management

To date there are no clear treatment-management indications for SIH-related CVT. We observed that the majority of patients were treated with ACs, most often heparin followed by oral anticoagulation. ⁶¹ Results from the systematic review highlighted that in few cases patients received oral AC or urokinase as first treatment; however, this did not result in CVT resolution. Partial resolution on its turn was associated with treatment by AC-only, except for one case of thrombosis progression that received EBP only. More importantly, complete resolution was mainly obtained through the combined AC + EBP approach. In our case-series, this was true for 4/5 patients, and none showed recurrence. Taken together, based on the combined literature and case-series data, we can consider immediate EBP to seal the SIH-leak, followed by AC to resolve the CVT, currently as the best treatment-strategy. Repeated EBP might be necessary some in patients.^62,63 In case of unsuccessful EBP, myelography with fluoroscopy-based or CT-based dynamic techniques should be considered to locate and repair the leak. Mechanical thrombectomy has equally been proposed in patients with major sinus thrombosis, and it might be considered in some cases, especially when SIH is complicated by the development of a subdural hematoma, that makes AC treatment riskier.^64,65 However, to date, there is no data available supporting endovascular treatment in SIH-related CVT patients. Finally, giving the growing body of literature supporting the efficacy of subdural hematoma embolization in hematoma recurrence prevention, this might be a valuable alternative in patients under ACs for SIH-related CVT that developed a subdural hematoma. ⁶⁶

Conclusions

By pooling data from the literature and our institutional experience, the overall prevalence of SIH-related CVT was 1.3%. The CVT was most often located at the SSS (50%) and the transverse sinuses (48%). AC and combined AC + EBP were the most common treatment strategies, with higher CVT resolution achieved by the combined strategy. Despite the complex-treatment management, the overall rate of complete clinical recovery was 96%.

The study was conducted following approval by an ethics committee (IRB-MTP_2023_01_202201315).