Acute subdural haemorrhage complicating cerebral venous thrombosis in a patient with protein C deficiency

Abstract

Cerebral venous thrombosis (CVT) directly causing subdural haemorrhage (SDH) is a rare entity. We present a case of an 18-year-old female patient who presented with severe occipital headache. Neuroimaging showed acute SDH and CVT. She was eventually discovered to have underlying protein C deficiency. She was treated with anticoagulation and made an uneventful recovery. We aim to highlight the epidemiology, risk factors and aetiopathogenesis of CVT. We have included a literature review of previously described 13 case studies/reports describing SDH associated with CVT and a brief discussion of the dilemmas associated with management.

Background

Cerebral venous thrombosis (CVT) accounts for 0.5%–1% of strokes worldwide.^{1 2} Annually, its incidence varies, with reports suggesting a range of 3–13 cases per million.^3–5 The incidence in children is slightly higher, up to 7 cases per million.^{3 5}

CVT in adulthood is usually encountered in patients aged <50 years, often between 20 and 40 years of age.^{2 6} Data from one of the largest prospective studies on CVT, the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) revealed a female to male ratio of 3:1.⁷ This predilection was thought to be due to gender-specific factors such as pregnancy and oral contraceptive pills (OCP).⁸ This study also revealed that the superior sagittal sinus (SSS) was most affected (62%), followed by the left transverse sinus (TS; 44.7%) and right TS (41.2%), straight sinus (18%) and the cavernous sinuses (1.3%).

Numerous aetiologies have been implicated in the pathogenesis of CVT, broadly classified into local and systemic causes.^{6 9} Local causes include trauma, neurosurgery, spread of infections (eg, mastoiditis) and invasion by neoplasms. Systemic causes comprise prothrombotic risk factors such as severe dehydration, pregnancy, puerperium, medications (eg, OCP, l-asparaginase and epsilonaminocaproic acid) and inherited thrombophilia (eg, factor V Leiden, protein C and protein S deficiencies, polycythaemia vera, and mutations of antithrombin III and prothrombin gene).^9–11 Inflammatory conditions such as inflammatory bowel disease, Behcet’s disease and sarcoidosis are also associated with increased risks of CVT.¹⁰ However, CVT may remain idiopathic in 20%–30% of cases.^{6 10}

The pathophysiological mechanisms following CVT are crucial to understand its imaging findings. Occlusion of a cerebral vein or venous sinus results in retrograde increase in venular pressure, causing reduced capillary and cerebral perfusion. As this progresses, the blood–brain barrier is disrupted (development of vasogenic oedema) with eventual failure of Na+/K+ ATPase pumps (ischaemic injury/cytotoxic oedema). Venous rupture during this stage leads to parenchymal haemorrhage. The occlusion of dural venous sinuses also leads to impaired cerebrospinal fluid resorption via the intrasinus arachnoid granulations, resulting in increased intracranial pressure, an effect that further worsens venular hypertension.^{9 12} In a large study of 220 patients with sinovenous occlusion, 45% patients showed no parenchymal abnormality, while non‐haemorrhagic infarcts, haemorrhagic infarcts and cerebral haemorrhage was noted in 23%, 20% and 12% cases, respectively.¹³

Case presentation

An 18-year-old female patient presented to the emergency department of our hospital with severe occipital headache since 1 day. On clinical interrogation, she claimed a pain score of 10 out of 10. There was no history of antecedent trauma or previous illness, or use of medications. Clinical examination revealed stable vitals, with a Glasgow Coma Score of 15 and no focal neurological deficit. No papilleodema was noted.

Investigations

The patient underwent a non-enhanced CT (NECT) study of the brain which showed hyperdense distension of the left TS suspicious for thrombosis (figure 1A, B). There were also slivers of acute subdural haemorrhage (SDH) along the falx (figure 1C) and left tentorial leaflet without mass effect. There was no acute parenchymal finding. Subsequent CT venogram study confirmed thrombosis of the left TS and sigmoid sinus (SS), as well as the bulb and cranial aspect of left internal jugular vein (IJV) (figure 1D, E). CT angiogram (CTA) was unremarkable (figure 1F).

Figure 1.

Axial (A) and coronal (B) non-enhanced CT (NECT) images reveals hyperdensity and distension of the left transverse sinus (arrows). Axial NECT slice at the level of the centrum semiovale (C) shows a sliver of acute falcine subdural haemorrhage (arrowhead). Axial slice (D) and maximum intensity projection of the CT venogram (E) confirms occlusion of the left transverse sinus as well as the left sigmoid sinus (dotted arrows). CT angiogram (F) revealed no significant abnormality.

MRI study of the brain performed 3 hours later demonstrated the left-sided TS and SS thrombosis (figure 2A). No acute infarct or acute parenchymal haemorrhage was detected. There was, however, new acute SDH over the left cerebral convexity (figure 2B, C) and increase in the parafalcine SDH, with minimal mass effect (figure 2C).

Figure 2.

MRI of the brain performed 3 hours after the non-enhanced CT revealed loss of flow void in the left transverse sinus (arrow) and sigmoid sinus on axial T2-weighted image (A) concordant with the known acute thrombosis. Axial T2-weighted image at the level of the basal ganglia (B) shows a new shallow subdural haemorrhage (SDH) over the left cerebral convexity (dotted arrows). Axial gradient-recalled echo image (C) at the level of centrum semiovale shows a thin sliver of left parafalcine SDH (black arrowhead) and shallow acute SDH (black dotted arrows) over the left cerebral convexity.

Treatment

In view of the positive imaging findings of CVT, the patient was started on intravenous heparin infusion on a sliding scale, which was changed to subcutaneous clexane 70 mg two times per day on the fourth day of admission. She remained well during her stay and was discharged on the seventh day of admission with an initial dose of 2.5 mg of warfarin on alternate days, to be subsequently titrated on an outpatient basis. A NECT brain study performed on the day of discharge showed persistent hyperdensity of the left TS and SS, as well as the left superior internal jugular bulb (figure 3A). A stable small parafalcine SDH was also noted (figure 3B). Prothrombotic workup showed underlying protein C deficiency, with a protein C activity of 12%. The rest of the prothrombotic workup including protein S, factor V Leiden, prothrombin, antinuclear antibody, anti-dsDNA, anticardiolipin IgM/IgG, lupus anticoagulant, HIV and syphilis markers were negative.

Figure 3.

Axial non-enhanced CT study (day 7) shows stable hyperdense appearance of left sigmoid sinus and transverse sinus (arrow in A) and residual trace left parafalcine subdural haemorrhage (SDH) (arrowhead in B). The previously seen SDH over the left parietal convexity has resolved.

Outcome and follow-up

A follow-up MRI performed 3 months later showed complete resolution of previously seen SDH (figure 4A) and partial recanalisation of the thrombosed left-sided venous sinuses (figure 4B). The patient remains well on prophylactic warfarin as of her last follow-up at the coagulation clinic in April 2020. The clinical team intends to keep the patient on lifelong anticoagulation.

Figure 4.

Follow-up MRI after 3 months. Axial gradient-recalled echo image (A) shows complete resolution of previously seen subdural haemorrhage. Phase-contrast MR venogram maximum intensity projection image (B) shows partially recanalised left transverse and sigmoid sinuses (arrow).

Discussion

Extra-axial haemorrhage, especially SDH as a complication of acute CVT is a rare phenomenon. Data from the 624 patients enrolled in the ISCVT, revealed subarachnoid haemorrhage in 0.8% patients; however, none had SDH.⁷ In our extensive literature review on PubMed (between 1970 and 2020), we found 13 cases of CVT complicated by SDH (table 1).

Table 1.

Review of literature describing CVT complicated by SDH (without a secondary pathology to account for SDH)

No	Authors	Age/sex	Risk factors	Clinical features	Imaging findings	Treatment and outcome
1	Chu et al14	40/F	Oxymetholone for aplastic anaemia	Headache, vomiting, blurring of vision. B/L CN6 palsy.	MRI and MRV: Lt tentorial SDH with CVT of SSS, Lt TS and Lt sylvian vein.	Oxymetholone discontinued. No anticoagulation due to thrombocytopenia. Recovered.
2	Singh et al19	33/F	None	Nuchal pain and occipital headache.	CT and MRI: B/L chronic SDH with occlusion of straight sinus, Lt TS, SS and SSS.	Treated with intravenous unfractionated heparin, followed by acenocoumarol. Recovered.
3	Mathew et al15	40/M	None	Headache, vomiting, Lt hemiplegia.	MRI: Rt parietal parenchymal haemorrhage, B/L SDH, Lt parietal SAH. MRV: CVT of SSS and B/L TS.	Treated with heparin. Recovered
4	Sirin et al24	77/M	JAK2 V617F mutation (PV)	Headache and back pain.	CT: Acute Rt temporal parenchymal haematoma and SDH. MRI: Spinal SDH. CA: CVT of SSS, Rt TS and SS.	Anticoagulation withheld. Lt hemiparesis better after 4 months.
5	Takahashi et al16	55/M	Possible dehydration	Headache, weightlifting.	CT: Acute right cerebral convexity and falco-tentorial SDH. MRI and CA: occlusion of the SSS.	Treated with intravenous heparin sodium. Recovered.
6	Zupan et al20	26/F	Puerperium, epidural anaesthesia	Persistent headache.	CT: B/L parietal-occipital subacute/chronic SDH. MRV: CVT of the Rt TS, Rt parietal cortical veins and partial CVT of SSS.	Treated with intravenous low-molecular heparin. Recovered
7	Akins et al11	38/F	OCP	Headache and difficulty in speech.	CT and MRI: Lt frontal SDH, Lt temporal venous infarct and Lt TS thrombosis.	Treated with intravenous heparin. Recovered
8	Akins et al11	68/F	JAK2 V617F mutation (PV)	Headache, coma.	CT: Lt acute SDH. Craniotomy, evacuation of the SDH showed an engorged cortical vein. CTV and MRV: SSS occlusion.	Treated with hydroxyurea, hydration and aspirin. Poor outcome.
9	Akins et al11	60/F	None	Bifrontal headache.	CT: Lt isodense SDH. Mini-craniotomy, evacuation. Recurrent SDH, needing burr hole drainage. MRV: CVT of left TS, SS and IJV.	Treated with endovascular thrombectomy and venoplasty. Recovered.
10	Alboudi et al25	30/F	Systemic lupus erythematosus	Headache associated with projectile vomiting.	CT: CVT of straight sinus, VOG, ICVs, Lt TS and Lt SDH.	Unsuccessful mechanical clot removal. Treated with IV heparin followed by warfarin. Spastic quadriparesis and incontinence.
11	Sahoo et al17	60/F	None	Right-sided weakness and seizure.	CT: Left frontal subacute SDH. Contrast-enhanced MRI: CVT of Rt TS, SS and SSS.	Treated with low-molecular-weight heparin, followed by oral warfarin. Recovered.
12	Bansal et al18	40/F	OCP	Rt hemiplegia, headache.	CT: Lt fronto-temporo-parietal acute SDH, SAH of Lt parietal and occipital sulci, and cerebral oedema. CTV: CVT of SSS and Rt TS.	Underwent decompressive craniectomy. Deceased on post op day 1.
13	Alharshan et al26	23/M	Down’s syndrome-related thrombogenesis	Headache, confusion.	CT: Subacute Lt SDH, craniotomy evacuation. F/U MRV: CVT of Rt TS and SS.	Treated with heparin. F/U recurrent Lt SDH, recanalisation of CVT. Repeat craniotomy. Recovered.

B/L, bilateral; CA, cerebral angiogram; CTV, CT venogram; CVT, cerebral venous thrombosis; F/U, follow-up; ICV, internal cerebral vein; IJV, internal jugular vein; Lt, left; MRV, magnetic resonance venogram; OCP, oral contraceptive pills; PV, polycythaemia vera; Rt, right; SAH, subarachnoid haemorrhage; SDH, subdural haemorrhage; SS, sigmoid sinus; SSS, superior sagittal sinus; TS, transverse sinus; VOG, vein of Galen.

In most of these studies, SDH was presumed to be a complication of CVT. The authors postulated the cause of SDH to be a rupture of the cortical or bridging veins secondary to increased back-pressure/venous hypertension induced by CVT.^{11 14–18} Akins et al demonstrated conclusive evidence in support of this theory.¹¹ In their study, one patient (case number 9 in the above table) with occlusion of the left TS, SS, and IJV underwent pre-endovascular and post-endovascular manometric measurements. These demonstrated venous stasis and reversal of flow, increased venous pressure and delayed drainage of the vein of Labbe. This is the only study till date that objectively demonstrated the mechanism of SDH in patients with CVT-associated SDH.

Singh et al (case number 3) described a patient with bifrontal chronic SDH in a patient with occlusion of the deep and dural sinuses. The pathogenesis of the SDH was thought to be slightly different from the aforementioned studies. The clinical and imaging finding of bridging veins between the scalp emissaries and the SSS led them to hypothesise that the patient was suffering from acute-on-chronic CVT; the SDH possibly resulted from the abnormal venous communications between the scalp veins and the SSS.¹⁹ Zupan et al (case number 7) also suggested that CVT associated with SDH may occur in the postpartum period due to raised intracranial pressure, dehydration, venous congestion and hypercoagulability after labour.²⁰

Another feature to consider is that patients with CVT and associated SDH may have an underlying thrombophilic (acquired or inherited) risk factor. Though there has been no data to prove this, Akins et al suggested that SDH complicating CVT needs to be investigated for an underlying thrombophilia.¹¹ In our literature review, we found one case report with idiopathic recurrent thrombophlebitis, two with JAK2 V617F mutation (polycythaemia vera), three on high-risk medications (two on OCP and one on oxymetholone), one pregnant patient, one postpartum, one with possible dehydration, one with systemic lupus erythematosus and one with Down’s syndrome.

In our literature review, we also encountered other reports of CVT with SDH occurring due to a secondary pathology. ¹⁵ Takamura et al in a single case report described the recurrent SDH in patient with extensive CVT.²¹ The cause of the SDH was thought to be either due to chronic disseminated intravascular coagulation (found on laboratory tests) or due to a dural arteriovenous fistula secondary to the CVT.¹¹ Cases of SDH and CVT with underlying intracranial hypotension have also been described. The reduction of intracranial pressure leads to venous engorgement and stasis (Monro-Kellie doctrine), leading to SDH and CVT, respectively. Orthostatic headache is commonly associated with intracranial hypotension, but the change in its character to a more constant headache must raise the suspicion of a complication like SDH.^{11 22}

In this report, we present the clinical–radiological findings in a 18-year-old female patient with CVT involving the left TS, SS and IJV. Acute SDH was seen in this patient primarily along the falx and left tentorium, which progressed along the left cerebral convexity. In our patient, the cause of CVT was linked to an underlying deficiency of protein C, found on laboratory investigations. Given that the patient had no past illness or trauma, we hypothesise that the SDH was a complication of venous hypertension induced by the CVT. In order to ensure that there was no other vascular cause of the SDH, a CTA was also performed, which revealed no abnormality. Also, the patient had no clinical or radiological manifestations that could suggest underlying intracranial hypotension.

Apart from being an uncommon occurrence, CVT-associated SDH poses a unique clinical challenge. Treatment of CVT is usually performed with anticoagulation; however, this poses a potential risk of haemorrhagic transformation of venous infarcts and may increase the risk of extra-axial haemorrhage.⁸ Though the efficacy of anticoagulation in patients with existing parenchymal haemorrhagic complications is well-documented, there is no consensus on its use in concomitant extra-axial haemorrhage. In patients with small SDH not requiring surgical decompression, anticoagulants have been used for the treatment of CVT with good patient outcomes (table 1). Akins et al suggested that anticoagulation (heparin and heparinoids) is best avoided when neurosurgical intervention is indicated—in two out of the three patients who needed surgical evacuation of SDH, anticoagulation was not initiated, though hydration and antiplatelet agents were provided.¹¹ Since our patient only had a thin sliver of SDH and was not a candidate for surgery evacuation, she was treated with IV heparin infusion followed by subcutaneous clexane and finally oral warfarin. Her complete clinical recovery with a normal follow-up MRI was indicative of optimum management. Endovascular mechanical thrombectomy is emerging to be a safe and efficacious treatment alternative for CVT with SDH for the treatment of venous hypertension and avoiding the potential bleeding risks from systemic anticoagulant treatment.^{11 23}

Learning points.

• Cerebral venous thrombosis directly causing subdural haemorrhage is a rare entity.

• The presumptive pathogenesis is venous hypertension, reduced perfusion, breakdown of the blood–brain barrier, venous rupture and consequently venous haemorrhage.

• Patients should be worked up for underlying causes and risk factors should be elicited.

• Management poses a clinical challenge as the benefits of anticoagulation must be weighed against the risk of worsening intracranial haemorrhage.