Reversible cerebral vasoconstriction syndrome in the context of recent cerebral venous thrombosis: Report of a case

Introduction

Cerebral venous thrombosis (CVT) is an infrequent disorder characterized by a wide clinical spectrum, which includes headaches in 80–90% of cases.

Reversible cerebral vasoconstriction syndrome (RCVS) is a probably under-recognized condition characterized by the association of acute severe headaches, often of the thunderclap type, with or without additional neurological symptoms, and multifocal constriction of cerebral arteries, that resolve spontaneously in 1–3 months (1–3). More than half the cases of RCVS occur in special circumstances, such as exposure to vasoactive substances or postpartum (4).

We report the clinical and radiological findings in a patient who had a RCVS during the course of a recent CVT and discuss the hypothetical mechanisms linking both venous and arterial disorders.

Case report

A 24-year-old woman was admitted in our institution with a new onset severe progressive headache.

Past medical history revealed that, one year before, she had been evaluated in another French institution for a right-sided headache progressively worsening on several weeks, associated with pulsatile tinnitus, nausea, blurred vision due to a paresis of the left 6th nerve and bilateral papilledema. Cerebral magnetic resonance imaging (MRI) showed normal brain parenchyma and bilateral stenosis of the lateral venous sinuses without thrombosis. The opening pressure of cerebrospinal fluid (CSF) measured by lumbar puncture was 500 mm H₂O. Given the clinical and radiological presentation, the high body mass index (BMI) (27 kg/m²) and the absence of another cause, idiopathic intracranial hypertension was diagnosed. After failure of initial medical treatment and given the risk of secondary optic atrophy, an endovascular treatment was performed, with stenting of the left lateral sinus (for technical reasons the right sinus could not be stented). Headaches totally resolved during the following week. The patient received double anti-platelet therapy (aspirin and clopidogrel) for three months. Control fundoscopy showed normal papillae.

There was no other history of primary or secondary headache.

One year later, the patient presented to our institution with severe progressive occipital headache worsening over 10 days, associated with horizontal binocular diplopia and nausea. Examination showed a left 6th nerve paresis. Cerebral CT angiography and MRI revealed a venous thrombosis occluding the stented portion of the left lateral sinus (Figure 1). A lumbar puncture, performed on the day of admission, showed an opening pressure of 300 mm H₂0 in left lateral decubitus. CSF was clear with normal cell count, glucose and proteins levels. A volume of 8 mL CSF was taken. D-dimers were within normal range (184 ng/mL). All blood tests for thrombophilic conditions were negative or normal, including antinuclear antibodies, anti-DNA antibodies, C protein, S protein and genetic screening for mutation G1691A of factor V, mutation G20210A of factor II, mutation V617F of JAK2 and mutation of MTHFR. Questioning revealed that the patient was an active smoker (6 pack-years of cigarette smoking (6 PY)) and had taken an emergency contraception (levonorgestrel 1.5 mg) four days before headache onset. The patient did not take any other medication before admission. OPEN IN VIEWER

Anticoagulation was initiated the day of admission with subcutaneous enoxaparin 7000 UI twice daily. Pain was treated with intravenous paracetamol. On day 1 after admission, conventional 4-vessels angiography confirmed the venous thrombosis limited to the left lateral sinus (Figure 1) and showed a global low speed of blood flow in cortical arteries bilaterally. Headaches remained severe from day 0 to day 5, without any postural component and without any modification after the lumbar puncture and then started to improve.

On day 7 after admission, while eating, the patient suddenly had a bilateral excruciating headache with nausea, vomiting and photophobia. Maximal intensity was reached in less than one minute, thus consistent with a thunderclap headache. Examination disclosed neck stiffness. A new cranial MRI showed the already known thrombosis of the left lateral venous sinus on T2* weighted images and venography, a convexity subarachnoid haemorrhage restricted to the left frontoparietal cortical surface on FLAIR sequences, symmetrical hyper-intense lesions of both cerebellar lobes on diffusion-weighted sequences with diminished apparent diffusion coefficient, consistent with bilateral recent cerebellar infarcts, and multiple alternating segments of constriction and dilation of cerebral arteries on MR-angiography (Figure 2). OPEN IN VIEWER

Arterial vasoconstriction was confirmed the same day by transfemoral angiography (Figure 3) showing diffuse segmental irregularities of both posterior cerebral arteries, both posterior–inferior cerebellar arteries and both middle cerebral arteries and their branches. The venous thrombosis had significantly reduced and was limited to the proximal third of the left lateral sinus. OPEN IN VIEWER

Nimodipine was started at the dose of 1 mg/hour intravenously and anticoagulation was stopped.

From day 7 to day 11 after admission, intense headaches, nausea and vomiting persisted without improvement. Transcranial Doppler on day 8 (i.e. 24 hours after the thunderclap headache) showed increased mean intracranial velocities with 130 cm/s on both middle cerebral arteries, 120 cm/s on the right and 100 cm/s on the left anterior cerebral artery, 70 cm/s on the right and 65 cm/s on the left carotid siphon. On day 9, 48 hours after nimodipine treatment, the patient had one other thunderclap headache while resting, less intense than the first episode. A new MRI showed the extension of the venous thrombosis to the torcular, the proximal third of the superior sagittal sinus and the right lateral sinus. The convexity subarachnoid haemorrhage was stable. There was no new ischaemic lesion. MRA was stable. Blood tests on day 9 showed that D-dimers had raised to 785 mg/mL. Anticoagulation was started again. On day 11, headache and associated symptoms started to improve and resolved progressively over one week. Nimodipine was continued orally (60 mg every 4 hours with progressive decrease over six weeks). The patient was discharged 30 days after admission under nimodipine (30 mg every eight hours) and oral anticoagulants (coumadine). On the day of discharge, she was headache free and without any focal deficit.

A transcranial Doppler and a CT angiography performed three months after discharge showed a complete normalization of cerebral arteries and a recanalization of all venous sinuses including the stented lateral venous sinus. At four years of follow-up, the patient is headache-free, otherwise asymptomatic and remains under oral anticoagulants.

Discussion

The patient had a RCVS in the setting of a CVT, which had developed within the stent placed in her left lateral venous sinus one year before in order to treat an idiopathic intracranial hypertension. The clinical presentation was dominated by severe headaches, which unusual and changing patterns led to serial cerebral imaging and angiography that allowed us to diagnose both venous and arterial disorders. Progressive headache with paralysis of the sixth nerve led to the diagnosis of CVT; this headache fulfilled the ICHD-III diagnostic criteria for 6.6 Headache attributed to cerebral venous thrombosis (1). One week after, a thunderclap headache led to the diagnosis of RCVS and fulfilled all diagnostic criteria for 6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome (RCVS) (1).

The patient had a rare complication of venous sinus stenting. Endovascular treatment is performed by some teams in cases with idiopathic intracranial hypertension as a second line treatment after failure of medical management (5). To our knowledge, venous stent thrombosis has not been reported during follow-up in such patients. Antiplatelet therapy is usually recommended for 3 months after the procedure, based on the estimated time for stent endothelialization (5). In our patient, overweight (BMI 27 kg/m²), tobacco smoking and emergency contraception with a progestin (levonorgestrel), might have contributed to the in-stent venous thrombosis.

The patient developed a RCVS while treated for the CVT. She fulfilled all criteria for a definite RCVS, namely, severe thunderclap headaches, multifocal constriction of cerebral arteries assessed by several angiographies, followed by a complete resolution of arterial abnormalities on the angiographic control performed three months later (1,2). The clinical history of the RCVS was associated with several complications (6). She had a mild convexity subarachnoid hemorrhage, which is the most common haemorrhagic complication of RCVS (25–30% of all cases) (4). She also had an asymptomatic bilateral cerebellar infarction. Parenchymal stroke in RCVS includes ischaemic infarcts (6–39%) and intracerebral haemorrhage (12–20%) (3,4,7). The temporal course of angiographic abnormalities in our patient is in agreement with the hypothesis that arterial abnormalities progress from small distal to larger arteries during the course of RCVS (3,8). Indeed, a global low speed of blood flow was noticed on the first angiogram in small cortical arteries bilaterally, six days before the clinical onset of RCVS with a thunderclap headache. We hypothesize that this reduced blood flow could be the result of vasoconstriction of small cortical arteries not visible on a conventional angiogram. The second angiogram done right after the thunderclap headache on day 6 after admission evidenced diffuse constriction and dilation of proximal parts of intracranial arteries and the third angiography performed 1 week after showed even more severe lesions (Figure 3).

The co-occurrence of CVT and RCVS, two rare conditions, raises the issue of a potential link between them. Although the exact mechanisms of RCVS remain unknown, it is believed that the primum movens is a transient disturbance of intracranial arterial tone regulation with sympathetic over-activity. In about half the cases, RCVS occurs in peculiar settings, such as exposure to vasoactive substances and/or postpartum. Other potential triggers such as intracranial hypotension, head trauma, surgical or endovascular procedures have been described (1,4).

The association between CVT and RCVS has been previously reported in two women during immediate postpartum (9,10). In both cases, the authors concluded that CVT and RCVS were probably distinct pathophysiologically, although Katzin et al. hypothesized that rapid changes in CSF pressure due to CVT may be mechanistically involved in triggering RCVS (10). The clinical and radiological course in our case suggests that CVT preceded RCVS. It is, however, difficult to imagine that a CVT could by itself trigger arterial constriction. Moreover, anticoagulant therapy used to treat CVT was never identified as a possible precipitant for RCVS.

A common risk factor might have played a role in both conditions. Postpartum is a known risk factor for RCVS and CVT (11). Soo and colleagues described a RCVS after oral contraceptive pills (12). Freilinger and colleagues reported a RCVS associated with hormone therapy for intrauterine insemination (13). Both case reports suggested that female hormones could be implicated in RCVS by increasing the cerebral vasoreactivity. Our patient was exposed to a single dose of levonorgestrel. This emergency contraceptive progestin could have played a role in the CVT, although venous thrombosis is mainly favoured by oestrogens, and possibly in the RCVS.

Another link between CVT and RCVS could be the lumbar puncture. Chaves and colleagues reported a patient with intracranial hypotension caused by an iatrogenic CSF leak, who developed a RCVS with multiple cerebral infarcts (14). They proposed that cerebral vasoconstriction was triggered by the downwards displacement of the brain secondary to the loss of CSF volume. Schievink and colleagues reported a patient in whom an asymptomatic transient diffuse multifocal cerebral vasoconstriction developed in the setting of an acute onset spontaneous intracranial hypotension (15). Moreover, several cases of postpartum RCVS, starting during or right after an epidural anaesthesia with iatrogenic dural puncture have also been described (16,17). In our patient, there was no clinical or MRI feature suggestive of intracranial hypotension after the lumbar puncture. However, she presented with a CVT causing an intracranial hypertension syndrome. In such a condition, vasoconstriction is the normal autoregulatory cerebrovascular response. A sudden lowering of the abnormally high CSF pressure might have affected the intracranial arterial tone, which was potentially already modified by the hormonal therapy, and this combination of factors could have contributed to initiate a RCVS.

In conclusion, our patient presented with unusual severe headaches evolving over a few days, which distinct patterns led to serial imaging investigations that disclosed a CVT and then a RCVS. Several vascular causes can be associated in a patient with severe headaches. Diagnosis relies on serial neuroimaging.

Clinical implications

A patient with severe headaches might have two distinct underlying vascular disorders.