Case of cerebral venous thrombosis on a patient with background of nephrotic syndrome

Background

Nephrotic syndrome is a rare disease, with an incidence of about 3 per 100 000 children per year.1 It is usually diagnosed in children, but can affect adolescents and young adults. It is usually classified in idiopathic nephrotic syndrome, where biopsy findings are usually suggestive of minimal changes, focal segmental glomerulosclerosis or mesangial proliferation.2 These are further classified in steroid responsive and steroid resistant forms.3 The other category is secondary nephrotic syndrome, which is usually secondary to systemic diseases, such as systemic lupus erythematosus, hepatitis B infection, postinfectious glomerulonephritis or vasculitides. According to the International Pediatric Nephrology Association guidelines,4 the definition of nephrotic syndrome in children is by gross proteinuria, urinary albumin: creatinine ratio ≥200 mg/mmol, 3+ on urine dipstick with associated hypoalbuminaemia (<30 g/L) or oedema. It is also suggested that urine dipstick can be used for screening at home to monitor proteinuria and then move on to suggest treatment option for both steroid responsive and non-responsive patients. Two uncommon complications associated with nephrotic syndrome are bacterial and viral infections5 and thromboembolic events, which can be potentially debilitating.6 We want to present a case with a rare complication of nephrotic syndrome, a thromboembolic event in the sagittal sinus. The uncommon site of thromboembolism coupled with the long period from diagnosis to having this complication make our case unique. We also believe that the non specific presentation and outcome provides an important learning point for the doctors in the front line. The fact that the patient responded to direct oral anticoagulants, instead of heparinoids or warfarin, may also be the starting point of further research in management of thromboembolism in unique situations.

Case presentation

A man in his 20s with long-standing nephrotic syndrome, which he was used to self-manage with short courses of corticosteroids, presented with 3 weeks of being generally unwell and with periorbital and leg oedema, when the symptoms failed to settle with the usual corticosteroid therapy. Additionally, he developed a headache with vomiting and an episode of light-headedness 2 days before the admission. He also had occasional visual blurring. He did not have any other medical history and was a non-smoker, with no history of excessive alcohol intake. His medication history included Mycophenolate mofetil as immunosuppression to prevent relapses, and prednisolone prescription on a weaning regime to use when he had a relapse. He did not take any other prescribed or over the counter medication. Importantly, there were no medication adherence concerns.

On admission to hospital, relapse of nephrotic syndrome was confirmed with high proteinuria on urianalysis with evidence of microscopic haematuria. He had pitting oedema of his lower extremities and periorbital oedema. His Glasgow Coma Score (GCS) was 15. The tone, reflexes and power on all peripheral extremities were normal. There was no abnormality in cranial nerve examination, although visual acuity was not checked. His plantar reflexes were normal, and he had normal coordination and sensation. His cardiovascular and respiratory examination was also normal. His initial observations were normal, with oxygen saturations of 98%, blood pressure of 116/82 mm Hg and heart rate of 71 beats per minute. Opthalmological examination which showed flame haemorrhages of his left retina suggestive of subhyaloid haemorrhages.

Investigations

His initial blood tests showed normal kidney function, urea and electrolytes, elevated neutrophils to 13.6×1000/cmm, haemoglobin of 175 g/L, C reactive protein of 3.7 mg/L and cholesterol of 10.8 mmol/L. Significant hyponatraemia developed during his admission of sodium 116 mEq/L without any new neurological signs. In view of the significant headache with nausea, vomiting and syncope, an urgent CT of his brain was requested. This showed hyperdense superior sagittal sinus cortical vein (figures 1 and 2). A contrast CT of his head was subsequently performed that confirmed a superior sagittal sinus thrombosis (figures 3 and 4). A MR venography was also performed (figure 5). After hyponatraemia developed, thyroid function tests were done that showed subclinical hypothyroidism. His urine sodium was <10 mEq/L, serum osmolality of 284 mOsmol/kg and urine osmolality was 793 mOsm/kg. His serum albumin was 23 g/L at presentation.

Differential diagnosis

When reviewing a young adult with headache, visual symptoms and nausea, the initial differentials should include migraine, infective causes like meningitis or encephalitis, intracranial neoplasm and idiopathic intracranial hypertension. There was no history of headache and nausea in this male and therefore migraine was highly unlikely to have an onset at this age. Especially the symptoms occurring at a time when nephrotic features were active suggestive of a different aetiology. Additionally, the pain was bilateral and the headache was gradual in onset lasting for over a week, contrary to migraine. The visual symptoms could be explained due to oedema of the optic disc or cranial nerve IV palsy. Usual culprits are mass lesions, potentially causing shift of the midline. Brain neoplasm, either primary or metastatic would be unlikely in a man in his 20s without any predisposing factors, but should be ruled out. Mass lesions of infective origin such as a cerebral abscess would also be plausible. In terms of infective causes for his symptoms, meningitis or encephalitis could present with findings of intracranial hypertension or altered consciousness. The reason for the infective causes to be high in the differential list is due to his inherent risk of bacterial infections due to the nephrotic syndrome and also due to mycophenolate mofetil. Finally, idiopathic intracranial hypertension classically tends to present with positional headache, worse in incumbency and in early morning. It should be included in the list of differentials, as it is a recognised cause of intracranial hypertension in young adults and otherwise could explain the headache and the visual symptoms.7 Intracranial hypertension can be caused by venous sinus thrombosis, which, as a rare entity was unlikely cause of this finding, at least initially. A vascular event, such as a haemorrhagic or an ischaemic stroke involving the occipital lobe would also need to be considered in the absence of visual symptoms. An ischaemic cause, however, would be quite rare in a young adult without any underlying clotting abnormalities, or rare diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) or Fabry’s disease.8 Most of the potential differential diagnoses would require an urgent imaging and this is what pointed the clinicians to the eventual diagnosis, as mentioned above. Hyponatraemia is a common presentation in the acute medical setting and thoroughly described. The presence of peripheral overload, would be in keeping with a hypervolaemic hyponatraemia. The hyponatraemia in the presence of nephrotic syndrome can be explained due to the low intravascular blood volume resulting from the reduced oncotic pressure of low serum albumin. This stimulates the vasopressin secretion which drives the hyponatraemia.9 The high urine osmolality in our patient would be in accordance with the hyperproteinuria and the increased vasopressin that he was suffering due to the nephrotic syndrome. The low normal serum osmolality could be explained by the hyperlipidaemia, which is classically associated with nephrotic syndrome.

Treatment

He was treated initially with high dose of corticosteroids for nephrotic syndrome, and symptomatic management was initiated with antiemetics and analgesics. Following the suspicion of cerebral sinus thrombosis on the CT head, dalteparin was initiated at a therapeutic dose, according to his weight. At the onset of the significant acute hyponatraemia, he was treated initially with hypertonic sodium chloride solution in critical care. Prior to his discharge his anticoagulation was altered to the direct oral anticoagulant apixaban. His subhyaloid haemorrhages were treated conservatively with weekly monitoring.

Outcome and follow-up

He made a good recovery in the subsequent days and his oedema subsided. In terms of the presenting symptoms, his nausea and headache resolved, and his vision gradually improved. He was started on long-term anticoagulation and was followed up as an outpatient by nephrology, ophthalmology and haematology. Ophthalmology follow-up was organised weekly, nephrology follow-up was arranged as routine within 1 month for repeat protein/creatinine ratio.

The man presented again to the hospital with recurrent headache 1 week after discharge. No abnormality was found on this occasion in blood tests and clinical examination. He underwent repeat imaging of his head (magnetic resonance venography) that showed improvement with partial resolution in the previously seen thrombus. He was discharged with follow-up as mentioned before. Following a review of his nephrologist and haematologist it was agreed to commence on prophylactic anticoagulation with low dose rivaroxaban during his relapses. His follow-up imaging on 8 months showed resolution of the thrombus, within superior sagital sinus with CT of the brain (figures 6 and 7) and MRI with venogram (figure 8).