Cerebral venous sinus thrombosis in a patient with concomitant Graves’ disease and squamous cell carcinoma of the cervix

Abstract

Cerebral venous sinus thrombosis (CVST) is caused by either acquired or inherited pro-thrombotic states. Hyperthyroidism is a less recognised predisposing factor of CVST, and the causality has been debated. We report a case of a life-threatening CVST in a 40-year-old woman, with uncommon dual risk factors: hyperthyroidism and advanced squamous cell carcinoma of the cervix. CVST should be considered as a differential diagnosis when a patient with hyperthyroidism presents with new-onset headache or other neurological symptoms. Further assessment to elucidate other covert risk factors may need to be continuously carried out, when the causal relationship of one apparent cause has not been well established.

Background

Thrombosis of the dura venous sinus or cerebral veins is an uncommon type of stroke that usually occurs in young individuals. The diagnosis and management of cerebral venous sinus thrombosis (CVST) remain challenging due to the rarity of the disease, very diverse risk factors and lack of strong evidence from large clinical trials. Hyperthyroidism has been postulated to be one of the uncommon risk factors and occurs in 1.7% of CVST cases.¹ However, the pathophysiological mechanism and the causal relationship have not been clearly established.

We report on a patient, with hyperthyroidism as the apparent cause of her CVST, which led to a delay in the diagnosis of another life-threatening risk factor: carcinoma of the cervix. This case report serves as an example of dual or multiple risk factors in CVST. Meticulous evaluation of the predisposing factors can result in a prompt provision of definitive treatment for treatable conditions such as thyrotoxicosis and cervical carcinoma, and further prevention of recurrent CVST.

Case presentation

A 40-year-old woman with underlying Grave’s disease presented with a 2-day history of new-onset headache. The headache was localised at the left temporal region, throbbing in nature and occasionally associated with nausea and vomiting. It gradually worsened over the 2-day period. The patient had no history of fever, neck pain or photophobia to suggest a meningitis. She also did not have other symptoms of intracranial hypertension such as diplopia, blurred vision, seizures or loss of consciousness. Systemic review did not reveal any symptoms of extracranial sources of headache, such as sinusitis, otitis, orbital infection or cervicogenic headache. She had no history of migraine, head trauma or constitutional symptoms such as weight loss or poor appetite.

The patient had been diagnosed with Grave’s disease and thyrotoxicosis in her teenage years, and was put on antithyroid medications for a few months. The treatment had been discontinued more than 10 years ago, as she was euthyroid. She had no recurrence of symptoms since then and had not been on any medications or follow-up. Prior to the current admission, there had been no hyperthyroid symptoms such as heat intolerance, tremor or emotional lability, but she did have intermittent irregular menses, which was slightly heavy at times. Nevertheless, nothing was out of the ordinary. There was no abdominal pain, dysmenorrhoea or abnormal per vaginal discharge. She had no history of taking hormonal therapy or contraceptive pills, no prior miscarriage and no recurrent early fetal loss. She had no family history of thrombo-embolic disease or malignancy.

The patient was brought to the hospital due to persistent headache and worsening speech difficulty. On examination, she was conscious but appeared restless and confused. She was afebrile. Her blood pressure was normotensive but she was tachycardic with a regular heart rate of 110 beats per minute. She had expressive aphasia with intact comprehension. Both pupils were normal, equal in size and reactive to light. There were no signs of intracranial hypertension such as papilloedema, diplopia or abducens nerve palsy. The motor, sensory and cerebellar examinations were normal. No neck stiffness or brisk reflexes were noted. There was a smooth, diffuse goitre with fine tremor of the outstretched hands. The abdominal and pelvic examinations were unremarkable with no palpable masses. Other systems examined were normal.

Investigations

Brain CT imaging was immediately performed and showed left temporal venous infarction and haemorrhagic transformation, with thrombosis noted in the left sigmoid sinus (figure 1). CT venography confirmed the presence of extensive venous sinus thrombosis extending from the left sigmoid to the left transverse sinus and the left internal jugular vein (figure 2). A thyroid function test showed a severe hyperthyroid state with thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels of <0.005 mIU/L (reference range 0.27–4.20 mIU/L) and 44.2 pmol/L (reference range 12–22 pmol/L), respectively. The autoimmune thyroid panel was also positive for antithyroglobulin and antithyroid peroxidase antibodies. Tests for other connective tissue disease and vasculitis, antiphospholipid antibodies and thrombophilia were unremarkable. No atrial fibrillation was noted on the ECG.

Figure 1.

Non-contrast enhanced CT brain shows a dense left sigmoid sinus (red arrow), suspicious of venous sinus thrombosis, with left temporal haemorrhagic venous infarction.

Figure 2.

CT venography showed filling defect in the left sigmoid sinus indicating thrombosis, which extends down to the left internal jugular vein (red arrows).

Differential diagnosis

In a patient presenting with new-onset, unilateral headache, there is a variety of differential diagnoses that need to be considered, such as a new-onset primary headache or a secondary headache disorder. The most important step is to exclude sinister causes of headache, which primarily arise from the intracranial structures such as intracranial hypertension, bleeding, mass lesion or vascular diseases. In this patient, the presence of expressive aphasia was a red-flag sign, that is consistent with an intracranial structural lesion. Other common extracranial sources of headache in the head and neck region were excluded based on the patient’s history and physical examination. There was no history of recurrent headache to suggest a benign cause such as migraine.

Thyrotoxicosis can manifest with various neurological symptoms involving both central and peripheral nerves. In most instances, the neurological manifestations occur together with the systemic features of the disease. It can also be a presenting symptom, as seen in our patient.

Migraine should be considered in hyperthyroid patients presenting with unilateral headache. Hyperthyroidism is found to be more common in female patients with migraine headache.²

A hyperthyroid state can be associated with daily persistent headache or progressive symptoms of increased intracranial pressure that resolve on correction of the hyperthyroid state.^{3 4}

Acute ischaemic stroke due to cardio-embolism can occur in a patient with thyrotoxicosis- induced atrial fibrillation. In this patient, the presence of sudden-onset aphasia could be a presentation of ischaemic stroke. Studies suggest that, stroke may be more frequent in the context of hyperthyroidism than non-thyrotoxic atrial fibrillation.⁵ CVST is a rare form of stroke that has been reported in association with hyperthyroidism, due to pro-thrombotic effect.

Hyperthyroid encephalopathy is also not uncommon as a presenting feature of thyrotoxicosis. Behavioural and personality changes with less activity on presentation may indicate an apathetic type of thyrotoxicosis. In thyroid storm or crises, seizures may accompany encephalopathy with more fulminant neurological presentations. The patient may progress from agitated delirium to somnolence and coma.⁶

Patients with Graves’ disease are also at risk of developing other concomitant immune-mediated illnesses that predispose them to intracranial vasculitis, antiphospholipid antibody syndrome, demyelinating disease or immune-mediated encephalitis.⁵

The diagnosis of extensive CVST in this patient was confirmed by CT venography. Apart from thyrotoxicosis, other possible causes of hypercoagulable state that can manifest with extensive CVST in a young woman include malignancy, usage of oral contraception and antiphospholipid syndrome. Although this patient had very subtle history of irregular menses, gynaecological malignancies still need to be considered. Inherited thrombophilia is less likely as this patient had no family history to suggest the disease.

Treatment

CVST was presumed to be the consequence of hyperthyroidism as no other apparent causes were identified. The patient was immediately treated with a therapeutic dose of low-molecular weight heparin, carbimazole and propranolol. However, she deteriorated at 2 days after hospital admission. Her consciousness level dropped abruptly, and she exhibited stupor. She developed left Hutchinson’s pupil and right hemiplegia with Medical Research Council (MRC) grade 1/5 indicating uncus herniation syndrome. Further brain CT imaging showed worsening mass effect with midline shift from the intraparenchymal haemorrhage and vasogenic oedema. She subsequently underwent left decompressive hemi-craniectomy and external ventricular drainage insertion.

Outcome and follow-up

The patient was extubated 3 days after the surgery. Anticoagulant therapy was resumed. Two weeks into intensive rehabilitation, the aphasia and muscle weakness were improving, with a right-sided muscle strength of MRC grade 4/5. At this time, she was euthyroid. She was referred to a gynaecology team due to a history of irregular menses. She was given an outpatient clinic appointment at a later date, because there were no active pelvic symptoms at that point in time, and the hyperthyroid state could have been the reason for the irregular menstruation. She was discharged with dabigatran at 150 mg two times per day.

Two weeks after hospital discharge, the patient was readmitted with menorrhagia and symptomatic anaemia. Dabigatran was withheld and the patient was referred to the gynaecology team for pelvic examination. Examination under anaesthesia revealed an exophytic growth of the cervix with extensive necrotic tissue that bleed on contact. Histopathological examination of the fungating cervical mass indicated moderately differentiated squamous cell carcinoma. Staging CT scan showed a heterogeneously enhancing mass with infiltration of the surrounding nodes, urinary bladder and rectal wall. The patient was diagnosed with FIGO (International Federation of Gynaecology and Obstetrics) stage IVA cervical carcinoma. The cervical carcinoma was not apparent in the initial presentation and was only detected much later after the patient developed bleeding complication from the anticoagulation therapy. Concurrent chemoradiotherapy was planned as part of the standard treatment for locally advanced cervical carcinoma.

Discussion

The diagnosis of CVST in this case was straightforward, with typical symptoms of acute onset of headache and neurological deficit, which was confirmed by the brain imaging and CT venography. Identification of the risk factors that potentiated the CVST is a crucial step in the diagnosis for preventing disease recurrence and guiding the duration of anticoagulant therapy. However, the diagnosis of advanced cervical carcinoma in our patient was delayed and unexpected, due to very subtle clinical symptoms and excessive emphasis on the hyperthyroidism as the likely culprit for the illness.

CVST is a rare and frequently unrecognised type of stroke, occurring in only 0.5%–1% of stroke cases.⁷ The predisposing factors of CVST are multifaceted. They can be classified into acquired and genetic risks and are generally attributed to the Virchow triad: stasis of blood, vessel wall changes and hypercoagulable composition of the blood. Common acquired risks include surgery, trauma, pregnancy, puerperium, antiphospholipid syndrome, malignancy and oral contraception. Inherited thrombophilia conditions such as deficiency of antithrombin III, protein C and protein S, and factor V Leiden positivity constitute the genetic risks.⁷

Hyperthyroidism has been implicated as a rare predisposing factor for CVST that occurs in 1.7% of all cases.¹ Although this patient was relatively asymptomatic, she was likely in a hyperthyroid state prior to the current illness, given her suppressed TSH and her presentation with CVST as a result of hypercoagulability. Coagulation abnormalities such as elevated levels of factor VIII have been observed among patients with hyperthyroidism and CVST.⁸ Compared with euthyroid controls, hyperthyroid patients have shown increased fibrinogen, von Willebrand factor and plasminogen-activated inhibitor 1, as well as shorter activated partial thromboplastin time.⁹

There have been more than 30 reported cases concerning patients with hyperthyroidism and CVST. In one review, 14 out of 35 hyperthyroid cases had additional pro-thrombotic risks, which include puerperium, thrombophilia, chronic inflammatory lung disease and heterozygous MTHFR c677T gene mutation.¹⁰ Hence, a causal relationship has not been robustly established between hyperthyroidism and the occurrence of CVST.

Malignancy is another uncommon cause of CVST. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) study, 7.4% of CVST cases were associated with malignancy.¹¹ CVST is postulated to be more frequent among patients with haematological malignancies. Potential mechanisms include usage of chemotherapeutic and hormonal agents, a hypercoagulable state and tumour invasion of cerebral venous sinuses.

In a case–control study involving 593 patients with CVST, a history of malignancy increased the risk of CVST by approximately fivefold, and the risk was markedly higher among patients with haematological types than those with a solid organ malignancy.¹² This observation contrasts with the more common forms of systemic venous thrombo-embolism, for which the risk is similar for both haematological and solid organ malignancy.¹³ So far, there has been no reported case of an association between hyperthyroid state and the risk of cervical carcinoma.

In the management of CVST, anticoagulant drugs are the mainstay of treatment.⁶ Low-molecular weight heparin is a preferred drug in comparison to unfractionated heparin during the acute stage, followed by a vitamin K antagonist to prevent recurrent thrombosis. The duration of treatment is variable within the range of 3–12 months, depending on the underlying risk factors. Treatment can be life long if the risk of recurrence is high. For our patient, dabigatran treatment was commenced for maintenance therapy, although it actually has weak evidence in CVST, based on one case series.⁶ Decompressive surgery is recommended for patients with acute CVST with cerebral oedema or mass effect and impending herniation to prevent death.⁶

As for the risk factor screening for occult malignancy, the European Stroke Organisation guidelines of 2017 recommend against routine screening for occult malignancy in patients with cerebral venous thrombosis to improve outcome.⁶ However, this recommendation is based on low-quality evidences from 11 studies. Our case illustrates an important diagnostic delay, where the continuous assessment and pursuit of the cause of CVST was interrupted, when hyperthyroidism was presumed to be the apparent risk factor. As a result, the diagnosis of an underlying advanced cervical malignancy was only detected later, on the development of bleeding complication from the anticoagulant therapy. Clinicians should consider an alternative or concurrent diagnosis if the patient is not responding as expected.

Learning points.

• Cerebral venous sinus thrombosis (CVST) should be included in the differential diagnosis of new-onset headache in young patients with pro-thrombotic risk factors.

• The association between hyperthyroidism and CVST remains contentious.

• Patients with CVST may have more than one pro-thrombotic risk factors.

• A continuous evaluation to elucidate other non-apparent predisposing factors for CVST should be pursued in symptomatic cases, especially when the causal relationship of the apparent cause has not been well established.

• Malignancy is an important potentially treatable cause that needs to be considered in a case of extensive CVST, even if the symptoms and signs of the disease are subtle.