J. Paediatr. Child Health (2005) 41, 221–224 Cerebral thrombosis in childhood nephrosis Arun Gangakhedkar,1 William Wong2 and Lydia A Pitcher3 Kidz First Community Health, Otahuhu, 2 Renal Unit, Starship Children’s Hospital, and Department of Haematology and Oncology, Starship Children’s Hospital, Auckland, New Zealand 1 3 Abstract: Sinovenous thrombosis is an uncommon but serious complication associated with nephrotic syndrome in children. We describe a 9-year-old Caucasian boy who presented with dehydration, vague neurological symptoms and seizures. A diagnosis of nephrotic syndrome was made during the course of hospitalization. The serum antithrombin III level was decreased and brain imaging showed cerebral sinovenous thrombosis. Anticoagulant therapy with heparin was commenced and the patient made a slow but gradual clinical, as well as radiological recovery. We describe this case and review available literature to highlight the importance of suspecting and recognizing this potentially life threatening complication and initiating early treatment. Key words: children; nephrotic syndrome; sinovenous thrombosis. Cerebral venous sinus thrombosis is a rare event in children with nephrotic syndrome.1 It may have a non-specific and highly variable presentation and the diagnosis can be difficult without appropriate imaging. The diagnosis must be considered in any child with nephrotic syndrome having neuropsychiatric symptoms. We report a 9-year-old boy presenting with dehydration and vague neurological symptoms who subsequently was diagnosed with nephrotic syndrome. CASE REPORT A 9-year-old Caucasian boy presented to a regional centre with moderate dehydration following vomiting for 3 days. He had no history of any recent diarrhoea, haematuria, fever or rashes. Examination revealed a lethargic but rousable boy who had a Glasgow Coma Scale score (GCS) of 15. He was afebrile and his blood pressure was 133/90 mmHg. Urine analysis showed 3+ proteinuria and his serum albumin was 16 g/L. He had no oedema. He was haemoconcentrated (haemoglobin 195 g/L and haematocrit 0.52 L/L). The blood urea was elevated to 9.5 mmol/L and sodium (138 mmol/L), potassium (4.2 mmol/L) and creatinine (0.06 mmol/L) were normal. On the day of admission he developed three brief generalized tonic seizures lasting less than 2 min in duration, which were associated with deterioration in his sensorium (GCS of 7). An emergency non-contrast computed tomography (CT) scan of brain was done and this revealed hyperdense changes consistent with sinovenous thrombosis involving the sagittal and straight sinus and the internal cerebral veins (Fig. 1). He had mild impairment of renal function on the second day of admission with elevation in serum creatinine (0.09 mmol/L) and urea (18.9 mmol/L). On the third day of his illness he was transferred to a tertiary centre where he was admitted to the paediatric intensive care unit (PICU) and treated with intravenous fluids for dehydration and an albumin infusion was given. A thrombophilia screen was done which showed a reduced antithrombin III 53% (80–120) but normal Protein C 107% (70–120) and Protein S 130% (70–130) levels. Anti-cardiolipin antibodies were normal (IgG <5GPL, IgM <5MPL). A weak lupus anticoagulant was detected within 24 h and this was negative by the tenth day of hospitalization. He was anticoagulated with heparin infusion that was later changed to subcutaneous low molecular weight heparin. Serial magnetic resonance (MRI) scans of brain were performed (on days 4, 6 and 10 of hospitalization (Figs 2–4)) and the dose of heparin was adjusted according to anti-Xa antibody levels (therapeutic range 0.4–0.7 units/mL). Within 24 h of admission the patient developed a dense rightsided paresis of his upper and lower limbs along with a rightsided VI cranial nerve palsy and facial weakness. His limb and facial weakness improved over the next few weeks but he was left with a diplopia from his abduscens nerve palsy. The child made a complete neurological recovery except for a mild rightsided convergent squint requiring refractory glasses by 1 year after his presentation. He was switched over to warfarin from heparin within the first 3 months and he is being monitored with regular International Normalized Ratio (INR). During the last 2 years he has had frequent relapses of nephrotic syndrome, remains steroid dependent and is on anticoagulant medication with no recurrence of thrombosis. DISCUSSION In the presence of clinical signs of dehydration and absence of oedema on presentation the diagnosis of nephrotic syndrome was delayed in our case. A CT scan of the brain was performed as the patient became drowsy and developed seizures and focal neurological deficits. The CT scan revealed sinovenous thrombosis. He has made a full recovery but remains at risk for recurrence of thrombosis due to frequent relapsing nephrotic syndrome. Cerebral venous thrombosis in children is a serious but uncommon diagnosis that can be associated with several underlying systemic conditions. Deficiencies of physiological anticoagulants such as antithrombin, protein C or protein S have been considered as being associated with childhood venous thrombosis. The frequency of protein C and protein S deficiency is 3.8% and 3%, respectively in selected patients with venous thrombosis and that of antithrombin deficiency is reported to be between 0.5% and 4.9%.2 Our case had low antithrombin III and a transient lupus anticoagulant was detected. Anti-phospholipid antibodies (anti-cardiolipin (aCL) and lupus anticoagulant (LA)) Correspondence: Dr W Wong, Renal Unit, Starship Children’s Hospital, Private Bag 92024, Auckland, New Zealand. Fax: +64 9 307 8977; email: wwong@adhb.govt.nz Accepted for publication 29 March 2004. 222 Fig. 1 A non-contrast CT scan of brain in coronal section done on admission showing hyperdense changes consistent with sinovenous thrombosis involving the sagittal and straight sinus. Fig. 2 T1 weighted MRI of the brain in midline sagittal section showing a high signal consistent with thrombus in the superior sagittal sinus and straight sinus. can be transient in children and it is the persistence of positive tests that is considered to be significant.3 Thromboembolic events are known to complicate nephrotic syndrome.4 Membranous glomerulonephritis is the commonest lesion causing nephrotic syndrome in adults and is most commonly associated with thrombosis.4 Compared with adults minimal change nephrotic syndrome is the commonest lesion in childhood and has the least risk of thrombosis.4 Thromboembolic complications occur in 2–5% of children with nephrotic syndrome.5,6 The most commonly affected vessels are deep leg veins, followed by inferior vena cava, renal veins and pulmonary vessels. Involvement of cerebral vessels has been rarely reported in this condition.6–8 Sinovenous thrombosis is probably less A Gangakhedkar et al. Fig. 3 T1 weighted MRI midline sagittal section of the brain showing a high signal in the region of straight sinus consistent with a thrombus. Fig. 4 T1 weighted MRI of brain in coronal section showing a high signal in the region of sagittal sinus consistent with a thrombus. recognized or remains an under reported disorder in children with nephrotic syndrome.8–13 Fatal neurological symptoms with sagittal sinus thrombosis,14 and non-fatal thalamic stroke with sagittal sinus thrombosis15 and sinovenous thrombosis with associated iron deficiency11 have been reported in children with nephrotic syndrome. Multiple risk factors are common and the incidence of cerebral venous sinus thrombosis in children with nephrotic syndrome is not known (Table 1). Factors involved in the development of venous and arterial thromboemboli include events leading to dehydration, renal loss of anticoagulant factors, reactive haematological changes and autoimmune factors. Reactive haematological changes such as thrombocytosis, increased levels of fibrinogen and coagulation factors, and alpha2-anti-plasmin (a major fibrinolytic inhibitor) 223 (−) not present or information unavailable, NS, nephrotic syndrome; PC, protein C; PS, protein S; ATIII, antithrombin III; deficits,CT, computed tomography; MRI, magnetic resonance imaging; X, residual speech deficit. †our case. child – – – – – – – – – – died 3 years – – – – – – – – CT yes improved 2 years male – – – – – – – CT/MRI yes improved 7 years male – yes – yes – – – CT/MRI yes improved 5 years – – yes yes yes – – – CT yes X 7 years male yes yes yes yes PC/PS – – CT/MRI yes improved 2 years 6 months male – – – – – – – CT no improved 2 years 4 months female yes – – – – – – CT/MRI – – child – – – – – – yes – – – – 12 years male yes – yes yes – – – CT – improved 3 years male – – yes yes – – gastro CT yes improved Case 411 Case 312 Case 28 Case 1† 9 years male yes yes yes yes ATIII no no CT/MRI yes improved Age Sex Encephalopathy Headache Seizures Neurological deficit ProteinC/S, ATIII def Iron deficiency Other illness Neuro imaging Anticoagulation Outcome Table 1 Cases of sinovenous thrombosis in childhood nephrotic syndrome Case 529 Case 610 Case 715 Case 827 Case 928 Case 101 Case 1130 Case 1231 Cerebral thrombosis in childhood nephrosis and loss or deficiency of anticoagulant factors such as plasma antithrombin III, plasminogen and protein S can contribute to thrombosis.16 The coagulation inhibitors can be broadly divided into two main groups, protein C and its activator protein S on the one hand and antithrombin III on the other. Massive proteinuria contributes to urinary loss of anticoagulant proteins. This results in compensatory increased hepatic synthesis of coagulation inhibitors, and the plasma levels of these proteins are the sum of loss and gain.17 Both elevation and reduction of protein C and protein S concentrations has been reported in nephrotic syndrome.17,15 The risk of thrombosis is higher at the onset of the disease or during a relapse where there may be acute intravascular volume depletion.18 Our patient had significant evidence of volume depletion with impaired renal function and haemoconcentration. Early recognition of signs of hypovolaemia may help prevent complications such as sinovenous thrombosis.18 Cerebral venous thrombosis can have an extremely variable clinical presentation, mode of onset, imaging appearance and outcome. Its prognosis remains largely unpredictable.19 Intracranial hypertension may be the only manifestation if the thrombus is limited to superior longitudinal sinus or a predominant lateral sinus. Thrombosis of cortical veins, alone or in association with a sinus thrombus causes venous infarction. Partial or complete recovery is possible even with a severe initial presentation emphasizing the need for early diagnosis and treatment.20 CT scan is usually the first investigation performed on an emergency basis. Although it sometimes detects the hyperdense thrombosed sinus, it usually shows non-specific changes such as hypodensities, hyperdensities and contrast enhancement and in a third of cases it is normal in the first 3 days after clinical onset.21 MRI has a sensitivity of 90% and MRI and magnetic resonance venography (MRV) together provide diagnosis in all cases.21 For a proper interpretation the radiologist needs to be informed about suspected cerebral thrombosis when a scan is being requested. Specific treatment with anticoagulation is controversial in children, but has been established as appropriate therapy in adults.22 Anticoagulant treatment with heparin is probably safe and beneficial for children with sinus thrombosis, even those with intracranial haemorrhages.23,24 Some studies show that the outcome after sinovenous thrombosis (SVT) may be less favourable than reported previously and may not be significantly influenced by treatment.25 A thrombophilia screen to detect a hypercoagulable state including antithrombin III, protein S, protein C, anti-phospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant), plasminogen, thrombin time or reptilase time and fibrinogen may be helpful.22 Laboratory should be requested to perform urgent analysis for correctible factor deficiencies such as PC, PS and antithrombin III, and preferably a paediatric haematologist should be consulted before initiating therapy with factor replacement using fresh frozen plasma or specific factor concentrate. It is being observed that ATIII level in nephrotic syndrome are decreased due to both increased catabolism and urinary loss.26 Replacement therapy may be helpful in correcting the thrombophilic state, however as this condition is rare, collaborative international studies are required to optimize the therapy in this condition for any specific interventions. In summary the present case report highlights the importance of having a high index of suspicion for cerebral sinovenous thrombosis in cases of nephrotic syndrome with neuropsychiatric manifestations. Multiple factors may predispose to thrombosis. This complication can be seen on initial presentation or during the course of relapsing nephrotic syndrome. Early recognition is important as treatment with anticoagulation may 224 A Gangakhedkar et al. be indicated. Detailed radiographic assessment of the CNS preferably with an MRI scan in all patients in addition to initial CT scan is recommended to ensure a diagnosis. 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