Catastrophic primary antiphospholipid syndrome presenting as status epilepticus
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1 Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
2 Harris Neuromedical Intensive Care Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
3 GKT/GST Dept of Pathology, St Thomas’ Hospital, Lambeth Palace Road, London, SE17EH, UK
Correspondence to:
Dr R S Howard
Box 33 Medical Intensive Care Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG; robin.howard@talk21.com
Keywords: antiphospholipid syndrome; status epilepticus; multiple organ failure
Antiphospholipid syndrome (APS) is defined as the occurrence of arterial or venous thrombosis or recurrent miscarriage, with raised titres of antiphospholipid antibodies, namely lupus anticoagulant (LA) or anti-cardiolipin antibodies (aCL). An accelerated form of APS is catastrophic antiphospholipid syndrome (CAPS) or Asherson’s syndrome. Proposed diagnostic criteria for definite CAPS are: multiorgan failure, development of manifestations within 1 week, demonstration of antiphospholipid antibodies and histopathological evidence of microthrombosis (positive predictive value 99.4%).1 Precipitants include infection, surgery, and childbirth. Patients typically develop widespread thrombotic vasculopathy with marked thrombocytopaenia. Clinically apparent cerebral infarction occurs much less frequently than in uncomplicated APS but the major pathological manifestation of CAPS is cerebral microthrombosis at postmortem examination.
Case report
A 30 year old woman delivered her first child following a full term uncomplicated pregnancy. Three weeks later, she developed headache and transient hemiparesis. The following day she had an episode of speech arrest, bit her tongue, and held both arms stiffly in the air for about 1 minute. On admission to hospital, she was pyrexial and developed generalised tonic clonic seizures. There was no relevant previous medical history and she was not taking any medication. Blood tests. including erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). were normal. Computed tomography scan of the brain and analysis of the cerebrospinal fluid (CSF) were normal. Gynaecological examination showed no retained products of conception. The seizures proved refractory to treatment with intravenous lorazepam. She was transferred to a specialist neurological centre that day.
On arrival she was agitated, disorientated and pyrexial (38°C). Generalised tonic clonic seizures continued. Neurological examination was normal except that all limb reflexes were pathologically brisk and plantar responses were extensor. General examination was unremarkable. Despite being given "loading" doses of phenytoin, phenobarbitone, and magnesium sulphate, the seizures continued. She was anaesthetised and intubated, and mechanical ventilation was introduced. Treatment with high dose intravenous aciclovir for presumed viral encephalitis was commenced.
Investigations revealed a normal full blood count and film with a platelet count of 267x109/l. ESR and CRP were mildly raised at 46 mm/h (normal 1–20) and 28.7 mg/l (normal 0–5). Serial measurements of platelet count, ESR, and CRP did not show any significant change throughout the illness. All other blood tests including coagulation screen were normal or negative.
Magnetic resonance imaging of the brain was normal with no evidence of venous sinus thrombosis, cerebral infarction or haemorrhage. A second lumbar puncture revealed an opening pressure of 30 cm H2O. CSF analysis showed clear colourless fluid with 4 lymphocytes/mm3, a red cell count of <1/mm3, total protein of 0.36 g/l and a CSF:plasma glucose ratio of 4.4:8.9 mmol/l. CSF and serum oligoclonal bands were negative. Multiplex PCR for CSF herpes was negative.
EEG confirmed a diffuse encephalopathic process with unequivocal epileptiform activity over the frontal regions bilaterally with some periodic complexes more prominent on the left. A thrombophilia screen was performed during her illness but results were not available until after her death, and revealed the presence of lupus anticoagulant. Immunological assay for aCL was negative.
Whenever anaesthesia was reduced, seizure activity returned and her pyrexia persisted with no identifiable microbiological source. On day 7 her condition suddenly deteriorated with marked acidosis (base deficit of –14), renal failure, and haemodynamic instability. She
A postmortem examination revealed small vessel fibrin thrombi in the brain (fig 1). There was no evidence of large vessel cerebral thrombosis. The heart showed multifocal haemorrhages with surrounding muscle degeneration, and the lungs showed widespread small vessel thrombosis and shock lung. There was acute tubular necrosis of the kidneys, bilateral adrenal haemorrhage, and hepatic centriacinar degeneration.
Figure 1 Cerebral white matter small vessel showing necrosis and perivascular microgliosis following occlusion by thrombus.
Discussion
This patient developed a thrombotic microangiopathy (TMA) 1 month after a normal term delivery. The premortem laboratory investigations and postmortem examination revealed she was suffering from APS. The alternative postpartum TMA diagnosis of thrombotic thrombocytopaenic purpura was excluded by the fibrin nature of the thrombi and the normal platelet count.
CAPS occurs in <1% of patients with APS.2 However, it is vital to be aware of the diagnosis as patients rapidly develop severe multisystem failure. A review of the pathogenesis of 80 cases of CAPS noted an excess of women (79%) with an average age at onset of 37 years.3 The majority with multiorgan failure had secondary APS, mostly associated with systemic lupus erythematosis. Obstetric complications are recognised precipitants of CAPS, probably because of increases in levels of natural clotting factors. Two cases of CAPS occurring in the postpartum period have been reported, both following fetal loss.4,5
Cerebral involvement has been reported in around 60% of cases of CAPS.3 However, there are no previous reports of primary antiphospholipid syndrome presenting with status epilepticus. The case was unusual in several other respects. There was no previous diagnosis of APS and no history of miscarriages or thrombotic events. The patient presented with isolated neurological symptoms with no evidence of other organ involvement until 7 days later. Daily blood tests did not raise the suspicion of thrombophilia or blood dyscrasia and, in contrast to a series of 80 patients in whom 98% had high aCL titres,3 this patient had negative aCL.
The optimal treatment for CAPS is uncertain but the rationale is to prevent ongoing thrombosis with anticoagulation and to prevent production of mediators that generate the hypercoagulable state by immunosuppression. A review of data from the international CAPS registry found that patients who
This case emphasises that CAPS may present as an apparently isolated cerebral disorder. It is important to maintain a high degree of suspicion of antiphospholipid syndrome in critically unwell patients, particularly with known precipitating factors for CAPS such as during the postpartum period. Early treatment with anticoagulation and immunosuppression gives the best chance of improving the >50% mortality rate of the condition.
References
Cervera R, Font J, Gomez-Puerta JA, Espinosa G, Cucho M, Bucciarelli S, Ramos-Casals M, Ingelmo M, Piette JC, Shenfeld Y, Asherson RA, members of the CAPS Registry Project Group. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis. 2005; doi: 10, 1136/ard. 2004. 025759 (Epub).
Asherson RA, Espinosa G, Cervera R, et al. Catastrophic antiphospholipid syndrome. Proposed guidelines for diagnosis and treatment. J Clin Rheumatol 2002;8:157–65.
Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001;80:355–77.
Hochfeld M, Druzin ML, Maia D, et al. Pregnancy complicated by primary antiphospholipid syndrome. Obstet Gynecol 1994;83:804–5.
Kupferminc MJ, Lee MJ, Green D, et al. Severe postpartum pulmonary, cardiac and renal syndrome associated with antiphospholipid antibodies. Obstet Gynecol 1994;83:806–7.(L J Coward1,2, D M Kullma)
2 Harris Neuromedical Intensive Care Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
3 GKT/GST Dept of Pathology, St Thomas’ Hospital, Lambeth Palace Road, London, SE17EH, UK
Correspondence to:
Dr R S Howard
Box 33 Medical Intensive Care Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG; robin.howard@talk21.com
Keywords: antiphospholipid syndrome; status epilepticus; multiple organ failure
Antiphospholipid syndrome (APS) is defined as the occurrence of arterial or venous thrombosis or recurrent miscarriage, with raised titres of antiphospholipid antibodies, namely lupus anticoagulant (LA) or anti-cardiolipin antibodies (aCL). An accelerated form of APS is catastrophic antiphospholipid syndrome (CAPS) or Asherson’s syndrome. Proposed diagnostic criteria for definite CAPS are: multiorgan failure, development of manifestations within 1 week, demonstration of antiphospholipid antibodies and histopathological evidence of microthrombosis (positive predictive value 99.4%).1 Precipitants include infection, surgery, and childbirth. Patients typically develop widespread thrombotic vasculopathy with marked thrombocytopaenia. Clinically apparent cerebral infarction occurs much less frequently than in uncomplicated APS but the major pathological manifestation of CAPS is cerebral microthrombosis at postmortem examination.
Case report
A 30 year old woman delivered her first child following a full term uncomplicated pregnancy. Three weeks later, she developed headache and transient hemiparesis. The following day she had an episode of speech arrest, bit her tongue, and held both arms stiffly in the air for about 1 minute. On admission to hospital, she was pyrexial and developed generalised tonic clonic seizures. There was no relevant previous medical history and she was not taking any medication. Blood tests. including erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). were normal. Computed tomography scan of the brain and analysis of the cerebrospinal fluid (CSF) were normal. Gynaecological examination showed no retained products of conception. The seizures proved refractory to treatment with intravenous lorazepam. She was transferred to a specialist neurological centre that day.
On arrival she was agitated, disorientated and pyrexial (38°C). Generalised tonic clonic seizures continued. Neurological examination was normal except that all limb reflexes were pathologically brisk and plantar responses were extensor. General examination was unremarkable. Despite being given "loading" doses of phenytoin, phenobarbitone, and magnesium sulphate, the seizures continued. She was anaesthetised and intubated, and mechanical ventilation was introduced. Treatment with high dose intravenous aciclovir for presumed viral encephalitis was commenced.
Investigations revealed a normal full blood count and film with a platelet count of 267x109/l. ESR and CRP were mildly raised at 46 mm/h (normal 1–20) and 28.7 mg/l (normal 0–5). Serial measurements of platelet count, ESR, and CRP did not show any significant change throughout the illness. All other blood tests including coagulation screen were normal or negative.
Magnetic resonance imaging of the brain was normal with no evidence of venous sinus thrombosis, cerebral infarction or haemorrhage. A second lumbar puncture revealed an opening pressure of 30 cm H2O. CSF analysis showed clear colourless fluid with 4 lymphocytes/mm3, a red cell count of <1/mm3, total protein of 0.36 g/l and a CSF:plasma glucose ratio of 4.4:8.9 mmol/l. CSF and serum oligoclonal bands were negative. Multiplex PCR for CSF herpes was negative.
EEG confirmed a diffuse encephalopathic process with unequivocal epileptiform activity over the frontal regions bilaterally with some periodic complexes more prominent on the left. A thrombophilia screen was performed during her illness but results were not available until after her death, and revealed the presence of lupus anticoagulant. Immunological assay for aCL was negative.
Whenever anaesthesia was reduced, seizure activity returned and her pyrexia persisted with no identifiable microbiological source. On day 7 her condition suddenly deteriorated with marked acidosis (base deficit of –14), renal failure, and haemodynamic instability. She
A postmortem examination revealed small vessel fibrin thrombi in the brain (fig 1). There was no evidence of large vessel cerebral thrombosis. The heart showed multifocal haemorrhages with surrounding muscle degeneration, and the lungs showed widespread small vessel thrombosis and shock lung. There was acute tubular necrosis of the kidneys, bilateral adrenal haemorrhage, and hepatic centriacinar degeneration.
Figure 1 Cerebral white matter small vessel showing necrosis and perivascular microgliosis following occlusion by thrombus.
Discussion
This patient developed a thrombotic microangiopathy (TMA) 1 month after a normal term delivery. The premortem laboratory investigations and postmortem examination revealed she was suffering from APS. The alternative postpartum TMA diagnosis of thrombotic thrombocytopaenic purpura was excluded by the fibrin nature of the thrombi and the normal platelet count.
CAPS occurs in <1% of patients with APS.2 However, it is vital to be aware of the diagnosis as patients rapidly develop severe multisystem failure. A review of the pathogenesis of 80 cases of CAPS noted an excess of women (79%) with an average age at onset of 37 years.3 The majority with multiorgan failure had secondary APS, mostly associated with systemic lupus erythematosis. Obstetric complications are recognised precipitants of CAPS, probably because of increases in levels of natural clotting factors. Two cases of CAPS occurring in the postpartum period have been reported, both following fetal loss.4,5
Cerebral involvement has been reported in around 60% of cases of CAPS.3 However, there are no previous reports of primary antiphospholipid syndrome presenting with status epilepticus. The case was unusual in several other respects. There was no previous diagnosis of APS and no history of miscarriages or thrombotic events. The patient presented with isolated neurological symptoms with no evidence of other organ involvement until 7 days later. Daily blood tests did not raise the suspicion of thrombophilia or blood dyscrasia and, in contrast to a series of 80 patients in whom 98% had high aCL titres,3 this patient had negative aCL.
The optimal treatment for CAPS is uncertain but the rationale is to prevent ongoing thrombosis with anticoagulation and to prevent production of mediators that generate the hypercoagulable state by immunosuppression. A review of data from the international CAPS registry found that patients who
This case emphasises that CAPS may present as an apparently isolated cerebral disorder. It is important to maintain a high degree of suspicion of antiphospholipid syndrome in critically unwell patients, particularly with known precipitating factors for CAPS such as during the postpartum period. Early treatment with anticoagulation and immunosuppression gives the best chance of improving the >50% mortality rate of the condition.
References
Cervera R, Font J, Gomez-Puerta JA, Espinosa G, Cucho M, Bucciarelli S, Ramos-Casals M, Ingelmo M, Piette JC, Shenfeld Y, Asherson RA, members of the CAPS Registry Project Group. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis. 2005; doi: 10, 1136/ard. 2004. 025759 (Epub).
Asherson RA, Espinosa G, Cervera R, et al. Catastrophic antiphospholipid syndrome. Proposed guidelines for diagnosis and treatment. J Clin Rheumatol 2002;8:157–65.
Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001;80:355–77.
Hochfeld M, Druzin ML, Maia D, et al. Pregnancy complicated by primary antiphospholipid syndrome. Obstet Gynecol 1994;83:804–5.
Kupferminc MJ, Lee MJ, Green D, et al. Severe postpartum pulmonary, cardiac and renal syndrome associated with antiphospholipid antibodies. Obstet Gynecol 1994;83:806–7.(L J Coward1,2, D M Kullma)