Cerebral Venous Sinus Thrombosis in Adults with Prothrombotic Conditions: A Systematic Review and a Case from Our Institution.

Cerebral venous sinus thrombosis (CVST) is a rare condition characterized by elevated intracranial pressure due to impaired cerebral venous drainage, potentially leading to life-threatening consequences. We searched the PubMed electronic database for 'cerebral venous sinus thrombosis' and 'prothrombotic' cases reported in adults (19+ years) and conducted a systematic review for the published literature in the English language pooled with a case from our institution. Data were analyzed regarding patient demographics, risk factors, clinical features, treatment modalities, and outcomes when available. Thirty cases of CVST were identified (29 case reports, of whom two were described in a case series, and the one case from our institution). The patients' mean age was 39 years (range: 19 - 65). The male: female ratio was 1.14:1. The majority (73.3%) had at least one preexisting risk factor, with prescription drug use being the most common risk factor (33.3%) shared among all patients. Most patients (83.3%) presented with at least two symptoms. The most common presenting symptoms were headache (70%), gastrointestinal disturbance (50%), and seizures (40%). Focal deficits (36.7%), vision disturbances (30%), and altered consciousness (20%) were the remaining presenting complaints. Twelve cases (40%) commented on papilledema, with 10 (83.3%) having papilledema present. Anticoagulation abnormalities were examined in 26 cases (86.7%), out of which four cases (15.4%) had isolated protein S (PS) deficiency, three cases (11.5%) had isolated antithrombin III (ATIII) deficiency, and one case (3.8%) had isolated protein C (PC) deficiency. The most common initial imaging modality (22 cases, 73.3%), and most commonly used overall (23 cases, 76.7%), was computed tomography (CT). Magnetic resonance imaging (MRI) was the second most common imaging modality for initial use (five cases, 16.7%), diagnosis or confirmation of CVST (eight cases, 26.7%), and overall (21 cases, 70%). Heparin treatment was involved in the treatment of 18 cases (60%), and warfarin treatment was used in 10 cases (33.3%). Heparin-warfarin combination treatment was utilized in eight cases (26.7%). Most patients survived (28 cases, 93.3%), while the two remaining patients died secondary to brain death from the CVST (6.7%). The findings from this study highlight the clinical characteristics of CVST. Therefore, this study aims to increase awareness of this rare entity. Physicians should maintain a high index of suspicion in order to diagnose patients presenting in the proper clinical context, given this case shares various forms of presentations with other common clinical conditions but requires long-term anticoagulation.

Introduction and background

Cerebral venous sinus thrombosis (CVST) is a relatively uncommon, but potentially life-threatening condition, that has variable and non-specific forms of clinical presentations [1-2]. Anticoagulants, mainly heparin agents, are used as first-line therapy, with most patients attaining an excellent response [3]. This study's objective is to review the patient characteristics, risk factors, clinical features, treatment modalities, and outcomes of CVST, a rare and life-threatening condition in patients with prothrombotic states.

Review

Methods

Search Strategy

The present study protocol adheres to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for reporting systematic review protocols. The PubMed database was searched for adults (≥ 19 years old) and case reports in English using the terms ‘cerebral sinus venous thrombosis’ and ‘prothrombotic’ as keywords. Reference lists were also examined to identify relevant case reports. All full-text published cases were selected, and the authors independently assessed cases for inclusion.

Data Extraction and Analysis

All studies evaluating CVST with prothrombotic abnormalities were screened, with the selection of only those reports containing data on demographic information, clinical features, prothrombotic laboratory results, and diagnostic imaging. Unrelated case reports and those without prothrombotic lab results were excluded (Figure 1). Data are expressed in descriptive statistics using central tendency and dispersion measures.

Figure 1

The PRISMA flow diagram for the systematic review detailing the association of CVST with prothrombotic abnormalities

CVST: cerebral venous sinus thrombosis; PRISMA: preferred reporting items for systematic reviews and meta-analyses

Results

A total of 42 case reports of CVST with prothrombotic laboratory results were screened, with 28 publications ultimately included [4-31]. One case series described two cases, both of which were included, yielding 29 cases for this systematic review. With the addition of a case from our institution, a total of 30 case reports were analyzed. The demographics, clinical features, and outcomes of the 30 cases are summarized in Table 1.

Table 1

Summary of the Clinical Characteristics, Risk Factors, Diagnostic, Management, and Outcomes of CVST Case Reports Included in the Systematic Review

AIHA: autoimmune hemolytic anemia; AMS: altered mental status; APLS: antiphospholipid syndrome; aPS: phosphatidylserine; aPS-Ab: antiphosphatidylserine antibodies; ARF: acute renal failure; AT: antithrombin; AT III: antithrombin III; BIW: two times weekly; b/l: bilateral; BRCA: breast cancer; CRP: C-reactive protein; cocci ag: coccidioides antigen; CT: computed tomography; CTA: computed tomography angiography; CVST: cerebral sinus venous thrombosis; DM: diabetes; d/t: due to; DTR: deep tendon reflex; DVT: deep venous thrombosis; EtOH: alcohol; F: female; fr: fracture; GBE: generalized body edema; GCS: Glasgow Coma Scale; GE: gastroenteritis; GTCS: generalized tonic-clonic seizure; HA: headache; HBV: hepatitis B virus; HCV: hepatitis C virus; Hcy: homocysteine; HHcy: hyperhomocysteinemia; HIT: heparin-induced thrombocytopenia; HIV: human immunodeficiency virus; HLD: hyperlipidemia; H/PF4-Ab: human platelet factor 4 antibody; HTN: hypertension; ICH: intracranial hemorrhage; ICP: intracranial pressure; ID: intellectual disability; IDA: iron deficiency anemia; IgG: immunoglobulin G; IgM: immunoglobulin M; ITP: immune thrombocytopenia; IVIG: intravenous immunoglobulin G; L: lumbar; LAC: lupus anticoagulant; LBP: low back pain; LDH: lactate dehydrogenase; LE: lower extremity; LMWH: low-molecular weight heparin; LOC: loss of consciousness; LP: lumbar puncture; LUE: left upper extremity; M: male; Mo: month; MRV: magnetic resonance venogram; MTHFR: methylene-tetrahydrofolate reductase; N: nausea; NR: not reported; NS: nephrotic syndrome; OCP: oral contraceptive use; PC: protein C; PE: pulmonary embolism; PS: protein S; R: right; RAEB: refractory anemia with excess of blasts; STEMI: ST-segment elevation myocardial infarction; TAT: thrombin-antithrombin III complex; T2DM: type 2 diabetes mellitus; TID: three times daily; UC: ulcerative colitis; UE: upper extremity; UFH: unfractionated heparin; US: ultrasound; V: vomiting; VUR: vesicoureteral reflux; w/o: without; Yr: year

Author (Yr)

Age (Yr) / Gender

Medical History

Duration of Symptoms Before Presentation

Risk Factors at Presentation

Presenting Symptoms

Initial Physical Examination Findings

Papilledema Present?

Anticoagulation Abnormality

Diagnostic Imaging

Treatments Provided

Follow-Up Period

Outcome

Complications

Final Diagnosis

Reference

Heistinger [4] (1992)

38 / F

Multiple episodes of UE phlebitis and DVTs post-delivery, appendectomy, tobacco

NR

OCP use x16 yr (interruptions during pregnancy), tobacco

GTCS; frontal cephalgia, N, V

Somnolent, meningism, anisocoria, reduced R corneal reflex, facial palsy, R arm brisk DTR

NR

Normal AT III, normal PC, decreased PS

Initial imaging: CT; Additional imaging: b/l carotid angiography (confirmed)

Heparin Phenprocoumon

NR

Alive

None

CVST d/t hereditary PS deficiency

4

Musio [5]  (1993)

24 / M

UC

NR

UC x 24 mo

Hematochezia, weight loss, b/l frontal HAs, GTCS

Unable to complete full sentences or follow commands, R homonymous lower quadrantanopia, b/l dysmetria, gait disturbance, R LE weak, R foot clonus, R LE Babinski's reflex

Yes

Normal AT III, elevated PC, normal PS

Initial imaging: CT; Additional imaging: MRI (confirmed) SPECT scanning

IV methylprednisolone & oral sulfasalazine (for acute UC); phenytoin, anti-platelet therapy ,(aspirin) acetazolamide; recanalization of thrombosed venous sinus

NR

Alive

Hematochezia 2/2 acute UC, anemia requiring blood transfusion

CVST associated with UC

5

Tuite [6] (1993)

24 / M

Chronic LBP

NR

None

R arm focal motor seizures; HAs, neck pain, photophobia, N, V

Moderate expressive dysphasia, R facial palsy, R hemiparesis, unilateral sensory loss

NR

Decreased AT III, normal PC, normal PS

Initial imaging: CT brain; Additional imaging: b/l carotid angiogram (confirmed)

IV mannitol and dexamethasone, IV furosemide

NR

Brain dead, life support terminated

Elevated ICP, ARF

CVST d/t hereditary AT III deficiency

6

Vayá [7] (1995)

42 / M

Anemia

6 days

Anemia

AMS, pulsatile holocranial HA

No neurological deficits

Yes

Normal AT III, normal PC, normal PS

Initial imaging: CT; additional imaging: MRI (confirmed)

LP, corticoids, & mannitol (anti-edema), heparin

NR

Encephalic death

On 5th day of hospitalization patient developed mixed aphasia, b/l papilledema, supranuclear R facial palsy, and R UE hemiparesis b/l decerebration and Coma

CVST d/t RAEB

7

Akatsu [8]  (1997)

65 / F

Appendectomy, lipoma removal, former tobacco

6 days

Daly PO estrogen, monthly IM medroxyprogesterone, former tobacco

GBE, R-sided HA, N, b/l arm w/t/n

b/l LE and UE pitting edema, L hand weak

No

Decreased AT III, normal PC, normal PS

Initial imaging: CXR; additional imaging: CT, MRI & contrast angiogram (confirmed)

AT III supplementation, warfarin, LMWH, cyclosporin

NR

Alive

None

CVST d/t NS

8

Lefebvre [9] (1998)

32 / F

Chonic HAs, mild ID

7 days

OCP x1 mo

N, hypersomnia, bifrontal HA

AMS, global hypotonia, b/l LE, reduced DTR, R LE Babinski's sign

Fundoscopy showed venous dilatation and blurring of nasal edge of optic disc. No specific report on papilledema

Normal AT III, decreased PC, decreased PS. Positive LAC, increased CRP, D-dimer, and LDH

Initial imaging: CT head (confirmed dx after it was re-examined after performing cerebral arteriography); additional imaging: cerebral arteriography MRI

Heparin oral anticoagulation

NR

Alive

Coma (prior to transfer), PE (10 days following admission), DVT R temporo-occipital hemorrhage

CVST d/t PC and PS deficiency

9

Singhal [10] (1999)

44 / M

Cirrhosis from HCV and EtOH use

NR

Cirrhosis

Generalized tonic-clonic seizure

Icteric

NR

Decreased AT III, decreased PC, decreased PS

Initial imaging: CT head; additional imaging: MRI with gadolinium CTV (confirmed)

Phenytoin Sodium LMWH Liver transplant

NR

Alive

None

CVST d/t AT III, PC, PS deficiencies d/t cirrhosis

10

Boulos [11] (1999)

42 / M

3000 meters high altitude hike one day prior

1 day

Recent high altitude hike

Several tonic-clonic seizures R facial droop R-sided hemiplegia Aphasia

R facial palsy, R hemiplegia, aphasia

Yes

Normal AT III, decreased PC, normal PS

Initial imaging: CT head Additional imaging: MRI (confirmed)

Heparin Valproate

NR

Alive

NR

CVST d/t isolated PC deficiency precipitated by high altitude

11

Akdal [12] (2001)

40 / F

BRCA post-radical mastectomy, tamoxifen

10 days

Tamoxifen

HA, L-sided weakness

L hemiparesis, positive Babinski sign

NR

Normal AT III, normal PC, normal PS

Initial imaging: CT; additional imaging: MRI (confirmed)

Anticoagulation

NR

Alive

NR

CVST d/t tamoxifen use

12

Rizzato [13] (2002)

24 / F

Puerperal

NR

Puerperal

Epileptic seizure; diffuse HA, R ear ache, N, V, mild L hemiparesis

NR

NR

Decreased AT III, MTHFR mutatation

Initial imaging: cerebral MRI, MRV

Anticoagulants, empiric antibiotics

NR

Alive

None

CVST d/t puerperium, AT III deficiency, and MTHFR mutation

13

Yilmaz [14] (2004)

19 / M

ITP, AIHA, splenectomy, chronic HBV, ICH

3 days

Evans syndrome (diagnosed at 5 years age)

Headahe, V, generalized convulsive seizure

Negative neurologic exam

NR

Normal AT III, normal PC, normal PS; normal factor VIII levels; positive prothrombin, G20210A heterozygous gene mutation

Initial imaging: CT; additional imaging: MRA (confirmed)

UFH, coumadin; anti-epileptic therapy; dexamethasone, acetazolamide

NR

Alive

NR

CVST d/t Evans Syndrome

14

Muthukumar [15] (2004)

38 / M

Motorcycle accident 24 days prior, brief LOC, two V episodes

NR

Recent closed head injury

Blurred vision Double vision on lateral gaze

Visual acuity 6/6, enlargement of blind spots on visual field exam, b/l lateral rectus (CN6) paresis

Yes

Normal AT III, decreased PC, decreased PS

Initial imaging: CT; additional imaging: MRA/MRV, digital subtraction angiography (confirmed)

Acetazolamide, phenindione

NR

Alive

NR

CVST d/t thrombophilia

15

Rufa [16]  (2007)

57 / M

DVT, thrombosed hemorrhoids, episode of GE 1 hour prior to symptoms. Sildenafil use BIW for 1 year. Patient had prior episodes of thrombosis, occurred within 24 hours of Sildenafil use.

14 days

None

b/l blurred vision, occipital HA

Negative neurologic exam

Yes

Decreased AT III, normal PC, decreased PS. Increased fibrinogen, D-dimer

Initial imaging: carotid doppler; additional imaging: MRI brain (confirmed)

Sildenafil stopped, heparin, warfarin, acetazolamide

NR

Alive

NR

CVST d/t Sildenafil use

16

Ogata [17] (2008)

55 / M

IDA, melena

14 days

IDA

Melena, generalized seizures

L hemiparesis

NR

Normal antithrombin III, normal PC, normal PS, elevated D-dimer, TAT

Initial imaging: CT head; additional imaging: MRI (confirmed), cerebral angiography; upper GI endoscopy - open ulcers in stomach and duodenum; CT abdomen and chest, gallium scintigraphy MRV (4 weeks after dx - showed resolution of CVST)

Phenytoin Medical therapy for peptic ulcer, Iron supplementation

NR

Alive

None

CVST d/t IDA

17

Nayak [18] (2008)

36 / M

Single ectopic kidney with VUR leading to kidney transplantation 3 years prior. Immunosuppressive therapy - prednisolone, cyclosporine, azathioprine

2 days

Steroids

Continuous, diffuse HA worse in recumbent position and with coughing, blurred vision, V

Slightly irritable

Yes

Normal AT III, decreased PC, decreased PS

Initial imaging: MRV (confirmed)

Cephalosporin,  dicoumarol

NR

Alive

NR

Idiopathic CVST after renal transplantation with preserved graft function

18

Sharpe [19] (2011)

25 / F

Inherited type 1 AT deficiency

4 days

3rd trimester pregnant, AT deficiency

HA, V

Negative neurologic exam

NR

Decreased AT III

Initial imaging: CT; additional imaging: MRI without gadolinium MRV (confirmed), Doppler US b/l LE (negative for DVT)

UFH antithrombin concentrate, C-section

NR

Alive

None

CVST d/t pregnancy, inherited type 1 AT deficiency

19

Nagesh Kumar [20] (2011)

35 / M

None

NR

None

Drowsy R-sided focal seizures; loss of consciousness

Unsteadiness

NR

Normal PC, decreased PS, normal Hcy

Initial imaging: CT brain; additional imaging: MRI brain, MRV (confirmed)

Phenytoin, LMWH, warfarin

NR

Alive

NR

CVST d/t PS deficiency

20

Skeik [21] (2012)

65 / M

Congenital hearing loss; obesity, former tobacco use

3 days

None

R-sided HA, flashing visual disturbance, imbalance L-sided neglect, disorientation, N, V

Extremities weakness, L facial palsy, LUE, and LE, brisk DTR, decreased L-sided sensation, L-sided body neglect, GCS 15

NR

Decreased AT III, decreased PC, normal PS

Initial imaging: CT head; additional imaging: MRI/MRA (confirmed), conventional angiogram, CTA

Primary venous mechanical thrombectomy (x2), heparin, aspirin (2/2 to possible HIT, so heparin stopped and started on aspirin)

NR

Alive

ICH, persistent mild amnesia

CVST complicated by ICH and mastoiditis with associated decreased AT III and PC

21

Kolacki [22] (2012)

28 / F

None

3 days

Vaginal NuvaRing (etonogestrel/ethinyl estradiol) started 18 days prior to onset of HA, previously intermittently used NuvaRing from 2002-2006 without complications

Severe, persistent b/l frontal HA Photophobia, N, V, posterior neck pain, stiffness

Stiff neck

NR

Normal AT III, normal PC, normal PS

Initial imaging: CT head; additional imaging: MRA (confirmed)

NuvaRing discontinued

18 days later - CT head showed resolution of hemorrhage and thrombosis

Alive

None

Acute hormone-induced CVST d/t NuvaRing use

22

Verma [23] (2012)

38 / M

None

14 days

None

HA, V, altered sensorium, L-sided body weakness

AMS, DTRs brisk

NR

Normal AT III, normal PC, decreased PS

Initial imaging: MRI, MRA; additional imaging: MRV (confirmed)

Enoxaparin, decongestive therapy; shifted from enoxaparin to warfarin

15 days later- repeat MRV showed recanalisation

Alive

None

CVST d/t PS deficiency

23

Sohoni [24] (2013)

36 / M

T2DM, migraine

4 days

Poorly controlled T2DM

Persistent L hemicranial HA

Unremarkable

No

Normal AT III, normal PC, normal PS

Initial imaging: MRI brain; additional imaging: MRV (confirmed)

UFH, LMWH

NR

Alive

None

CVST d/t uncontrolled T2DM

24

Costa [25] (2014)

30 / F

Chronic LBP, lumbar spine anatomic defects with transpedicular screw L4-L5-S1 fixation

NR

OCP, spinal surgery complicated by accidental durotomy

Severe HA, N, photophobia, R paresthesia

Wound dehiscence/infection, and CSF leakage, motor aphasia

Yes

Prothrombin G20210A heterozygosity, MTHFR homozygosity, HHcy

CT (confirmed)

Oral contraceptive pill stopped, warfarin

NR

Alive

NR

CVST d/t accidental durotomy during spinal surgery

25

Giraldo [26](2014)

47 / F

Tobacco

1 hour

Tobacco

HA behind R eye, unilateral extremity numbness

R hemiparesis, extremities motor deficits, R hemisensory loss to light touch

NR

Normal AT III, normal PC, normal PS, heterozygous prothrombin G20210A gene mutation

Initial imaging: CT head; additional imaging: MRI brain, gradient echo, MRA, MRV, catheter angiogram (diagnosed)

UFH, warfarin

6 weeks later - normal neurologic exam

Alive

NR

CVST d/t isolated thrombosis of L vein of Labbe associated with prothrombin G20210A gene mutation

26

Sugie [27] (2015)

41 / F

Migraine, obesity

8 weeks

None

b/l temporal HA, N, impaired vision, photophobia, extremity weakness

b/l abducens nerve palsy

Yes

Normal AT III, normal PC, elevated PS, elevated ESR, CRP

Initial imaging: MRI brain w/ gadolinium MRI aniography (MRA); additional imaging: MRV (confirmed), internal carotid angiogram

Glycerol, acetazolamide, LP

Heparin, warfarin, aspirin, rivaroxaban

Alive

NR

CVST-induced secondary intracranial hypertension secondary to APLS

27

Gleichgerrcht [28] (2017)

52 / F

HTN, HLD, fibromyalgia, EtOH, drug abuse

NR

Tobacco, trauma requiring orthopedic surgery 15-day exposure to prophylactic LMWH (leading to HIT and CVST)

Acute onset AMS on postoperative day 15 after T12 fr secondary to a motorcycle accident w/o head trauma

Negative neurologic exam

NR

Normal AT III, normal PC, normal PS Low platelets, positive H/PF4-Ab

Initial imaging: CT head, CTA; additional imaging: MRI brain, MRV (confirmed)

UFH, argatroban (switched from UFH after finding low platelets and positive H/PF4 antibody); dexamethasone (ITP treatment - failed); IVIG (ITP treatment - successfully normalized platelets)

None

Alive

HIT

HIT-induced CVST complicated by ITP

28

Qadir [29] (2017)

40 / F

Menometrorrhagia

3 days

Norethisterone TID for 21 days/month for the past 3 months

Jerky movements in L arm, HA

L UE decreased power

NR

Normal AT III, normal PC, normal PS, Factor 7 deficiency

Initial imaging: CT (confirmed)

Enoxaparin

NR

Alive

NR

CVST d/t Factor 7 deficiency  possibly d/t OCP

29

Ganeshan [30] (2017)

21 / F

C-section (3 weeks prior), DVT (3 years prior)

< 24 hours

Puerperal

GTCS, HA, transient L arm numbness

Somnolent, pupils sluggishly reactive, L UE monoparesis with decreased DTR

NR

Elevated AT III, normal PC, decreased PS Elevated Hcy

Initial imaging: chest XR, echocardiogram, abdominal US; additional imaging: MRA (diagnosed)

Diazepam, phenytoin, methylprednisolone, ceftriaxone, acyclovir, phenobarbitone, mannitol, Fraxiparin, (LMWH) Levetiracetam

3 months later - repeat MRA showed restoration of normal blood flow through cerebral venous sinuses

Alive

Recurrent seizures and status epilepticus

CVST d/t puerperium, HHcy, recent C-section, suspected infection, low PS

30

Ganeshan [30] (2017)

25 / F

Migraine, C-section (3 years prior)

< 24 hours

OCP x2 yr, puerperal

Facial palsy, R arm weakness

Aphasic, R facial palsy, R UE weakness, decreased DTR

NR

Normal AT III, normal PC, normal PS, elevated Hcy

Initial imaging: CXR, echocardiogram, CT brain; additional imaging: MRI brain, MRV (confirmed)

Aspirin, oral contraceptive pills, stopped Fraxiparin, (LMWH), warfarin

4 months later - MRI brain and MRV showed resolution of CVST

Alive

NR

CVST d/t puerperium, HHcy, and OCP

30

Varner [31] (2018)

48 / M

Obesity

NR

None

GTCs, AMS

NR

NR

Normal AT III, normal PC, normal PS, positive IgM aPS

Initial imaging: CT, MRI, MRV, and conventional angiography (confirmed)

Levetiracetam, heparin, endovascular mechanical venous suction thrombectomy

3 months later presented for thrombophilia workup, pt was found to have a STEMI , was admitted and subsequently discharged after 5 days

Alive

None

CVST d/t aPS-Ab

31

Komro (2020) Present Study

61 / M

Essential HTN, pre-DM, obesity, negative cocci ag and IgG ab, negative HIV

7 days

None

Blurry vision

HTN

Yes

Decreased AT III, normal, PC, normal PS, negative prothrombin G20210A gene mutation, factor V Leiden mutation, antiphospholipid antibody

CT, CTV, MRI, MRV

Aspirin, acetazolamide, losartan

NR

Alive

None

Papilledema d/t increased ICP, possibly d/t CVST

Our case

The mean age at presentation was 39 years old (range: 19 - 65), with 24 (80%) being less than 50 years old. There were 16 male (53.3%) and 14 female (46.7%) patients (Figure 2). The majority (73.3%) had at least one preexisting risk factor (Figure 3). Prescription drugs were the most common risk factor (33.3%) shared among all patients. A history of tobacco smoking was reported in four cases (13.3%).

Figure 2

Age and gender distribution of adults with CVST. The bar graph represents the number of patients with CVST for the specific age and gender group

Figure 3

Risk factor frequency in 30 patients with cerebral sinus venous thrombosis (CVST)

Among females, 11 (78.6%) reported having gender-specific risk factors. Six (54.5%) were receiving exogenous estrogen hormone therapy (EEHT), four (36.3%) were pregnant or puerperal patients, and one (9.1%) was receiving norethisterone therapy. Three case reports (10%) involved mechanical precipitants. Other disorders, including congenital heart disease, thyroid disease, Evans syndrome, diabetes, and cirrhosis, were reported in three cases (10%). The least common risk factors were a preexisting hematologic condition (two cases, 6.7%) or inflammatory disease (one case, 3.3%).

Of the 20 cases (66.7%) that reported the duration of symptoms, most (55%) had symptoms between two to seven days at presentation. Four patients (20%) presented earlier with symptoms up to one day, while five patients (25%) presented later with symptoms lasting at least eight days. One patient (5%) had symptoms more than two weeks, not presenting until two months after symptom onset (Table 2).

Table 2

The Duration of Symptoms Before the Patients’ Presentation

Duration	The fraction in each category (%)
0 - 1 day	4/20 (20.0%)
2 - 7 days	11/20 (55.0%)
8 - 14 days	4/20 (20.0%)
> 2 weeks	1/20 (5.0%)

Most patients (83.3%) presented with at least two symptoms (Figure 4). The most common presenting symptoms were headache (70%), gastrointestinal disturbance (50%), and seizures (40%). Focal deficits (36.7%), vision disturbances (30%), and altered consciousness / confusion / disorientation (20%) were the remaining presenting complaints. Twelve cases (40%) commented on papilledema, with 10 patients (83.3%) having papilledema present.

Figure 4

The presenting symptoms of cerebral venous sinus thrombosis (CVST)

*The percentage of papilledema out of 12 cases with available data

Anticoagulation abnormalities were examined in 26 cases (86.7%). Four cases were excluded as they did not mention at least one of the following levels: antithrombin III (AT III), protein C (PC), or protein S (PS). AT III, PC, and PS were all normal in 11 cases (42.3%). An abnormality in at least two out of the three anticoagulants was reported in six patients (23.1%). Isolated AT III (three cases, 11.5%), PC (one case, 3.8%), or PS (four cases, 15.4%) deficiency was noted in the remaining cases (Figure 5).

Figure 5

The prevalence of different prothrombotic conditions in patients with CVST

AT III: antithrombin III; CVST: cerebral sinus venous thrombosis; PC: protein C; PS: protein S

Hyperhomocysteinemia (HHcy) was found among three (21.4%) female patients where it was associated with a G20210A prothrombin gene mutation in the first, low PS in second, and normal AT III, PC, and PS in the third patient. Moreover, among females with HHcy, one was puerperal, the second was using EEHT, and one was puerperal and had a two-year history of EEHT use.

The G20210A prothrombin gene mutation was found among three (9.4%) patients overall, out of which one was a male with low AT III and two were females (one with normal AT III, PC, and PS, and the other with no reported data on AT III, PC, and PS testing).

The most common initial imaging modality (22 cases, 73.3%) and most commonly used overall (23 cases, 76.7%) was computed tomography (CT) scan (Figure 6). Magnetic resonance venogram (MRV) was the most common modality that diagnosed or confirmed CVST (10 cases, 33.3%). Magnetic resonance imaging (MRI) was the second most common imaging modality for initial use (five cases, 16.7%), diagnosis or confirmation of CVST (eight cases, 26.7%), and overall (21 cases, 70%).

Figure 6

Imaging modalities used when evaluating patients with suspected CVST

Initial (blue): first imaging used to evaluate the patients. Diagnosis/Confirmation (orange): the ultimately used imaging to diagnose or confirm the diagnosis of CVST. Overall (grey): the percentage of cases where imaging used at any point in patients’ evaluation

CVST: cerebral sinus venous thrombosis

Heparin agents were involved in the treatment of 18 cases (60%), and warfarin agents were used in 10 cases (33.3%). A heparin-warfarin combination treatment was utilized in eight cases (26.7%). Ten cases (33.3%) reported using other anticoagulants either with or without the use of heparin and/or warfarin agents (Figure 7). Surgical intervention occurred in three cases (10%).

Figure 7

Treatments used for patients with cerebral sinus venous thrombosis (CVST)

Most patients survived (28 cases, 93.3%), while the two remaining patients died secondary to brain death from the CVST (6.7%). The two patients (100%) that died were administered mannitol and corticosteroids during their treatment course, and neither were given warfarin. One other patient who survived and recovered fully was given mannitol (Table 3).

Table 3

Survival outcome among cerebral sinus venous thrombosis (CVST) patients

Outcome	No. of patients/Total (%)
Alive	28/30 (93.3%)
Dead	2/30 (6.7%)

CVST occurs with similar frequency in males and females, and the symptom presentation often leads to a broad differential diagnosis.

Discussion

In this systematic review of CVST cases, several findings are notable. CVST is a rare condition that represents a unique challenge to physicians. It occurs at a similar frequency in both men and women and has a wide variety of symptoms that are clinically indistinguishable from other common clinical conditions, which most often lead to a broad differential diagnosis [1, 32-33].

Most cases had at least one preexisting risk factor indicating multifactorial etiology with multiple mechanisms involved in its pathogenesis. Prescription drug use was the most common risk factor, including those involved in oral contraceptive use. Among females, 10 (71.4%) reported having gender-specific risk factors. Four (40%) were pregnant or puerperal patients and six (60%) were getting EEHT.

Exogenous hormone therapy, pregnancy, and puerperium were the common risk factors for transient prothrombotic states and present in 78.6% of the female patients [34-36]. Tobacco use being the most common risk factor identified. More than half of the cases had symptoms between two to seven days before the presentation [37-38].

Most patients had symptoms for two to seven days at presentation and had at least two symptoms, with headache, gastrointestinal disturbance, and seizures being the most common presenting symptoms [39]. Normal AT III, PC, and PS were found in 42% of cases. Moreover, at least two of the three anticoagulants were deranged in a quarter of cases with available data [40].

The G20210A prothrombin gene mutation is linked with heightened risk for venous thrombosis, including CVST [40]. In this study, the G20210A prothrombin gene mutation was found in 9.4% of patients overall. Raised serum homocysteine levels are reported in the literature to cause a 4-fold higher risk of CVST [41]. In this study, HHcy was found among three (21.4%) female patients with a mean age of 25 years (range: 21 - 30).

CT scan was the initial modality of choice for most cases and the most commonly used overall, which could be due to its easy accessibility, relatively shorter scan period, and lower cost. MRI and MRV are the second and third most commonly used imaging overall, respectively. MRI and MRV were also the two most common imaging modalities used for diagnosis or confirmation of CVST. Therefore, MRV, in combination with MRI, is a non-invasive, specific modality that has proven reliable in diagnosing CVST [42-43].

Survival rate was 93.3%, and all deceased cases were not given warfarin during their treatment course. Papilledema (optic disc swelling due to high intracranial pressure) was present in 83.3% of the cases with available data. Therefore, looking for papilledema constitutes an essential factor which, unfortunately, was only reported in 40% of the cases.

Conclusions

CVST may present with a variety of clinical presentations, which makes it a diagnostic dilemma and could lead to misdiagnosis or delayed diagnosis. Appropriate physical examination by primary care providers combined with a high index of suspicion, especially in the right context, is crucial in diagnosis. We advise for increased utilization of the direct ophthalmoscope to evaluate for papilledema in patients with suspected CVST. Further well-designed studies are warranted to help determine etiologies, as well as diagnostic and management strategies, for identifying CVST cases and to establish trends in patient outcomes.