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Patients with thrombotic thrombocytopenic purpura (TTP) can present with devastating neurological abnormalities.1Mortality may be as high as 95%, but current treatment has reduced this to about 10% and early treatment improves the rate of recovery.2 We describe two patients who presented with predominantly neurological symptoms and signs who, because of a delay in making a diagnosis of TTP, were referred for treatment at a late stage. Both patients were reviewed by neurological and haematological experts, who considered that the prognosis was poor.
The first case was a 49 year old woman with a longstanding diagnosis of schizophrenia and a previous left sided cerebrovascular accident. She was admitted to her local hospital with a 3 day history of drowsiness, confusion, epistaxes, and spontaneous bruising, having been noted to be increasingly agitated and disoriented over the preceding 6 weeks. Her only medication was trifluperazine and paroxetine. The second case was a 58 year old man, previously fit and well, who presented to his local hospital with a 3 week history of confusion, drowsiness, jaundice, and right upper quadrant pain. He was taking no medication. The initial findings in both patients are summarised in the table. In both a diagnosis of TTP was made, although this was not until 5 days after admission in the first case, and both patients were transferred to the intensive care unit for plasma exchange and further management.
Treatment was started in both cases with five cycles of plasma exchange, each cycle using 3l cryodepleted fresh frozen plasma, and in the first patient this was followed by a course of oral prednisolone and azathioprine. Both made an excellent recovery, with an improvement in conscious level, a rise in platelet count, disappearance of red cell fragments, a fall in LDH and bilirubin concentrations, and normalisation of renal function. The first patient was self ventilating with no neurological deficit at time of transfer back to the referring hospital. The second patient had a Glasgow coma score of 15 by the fifth day of treatment, the only focal neurology being a bilateral internuclear ophthalmoplegia (INO)). Three months later the ophthalmoplegia had resolved and the patient was self caring with minimal disability. Both patients were extensively investigated to look for an underlying cause for TTP, but none was found.
Thrombotic thrombocytopenic purpura is a syndrome comprising a pentad of features—fever, thrombocytopenia, microangiopathic haemolytic anaemia, neurological abnormalities, and renal dysfunction. Not all five features are required to make the diagnosis—often fewer are present—and there is no pathognomonic test, so diagnosis may be difficult. It is often considered along with haemolytic uraemic syndrome (HUS) to form part of a range of diseases called the thrombotic microangiopathies. In these disorders, intravascular platelet aggregation (there is minimal fibrin deposition) leads to obstruction of arterioles and capillaries, causing local ischaemia. Thus TTP is seen when the cerebral microcirculation is affected, and HUS when the renal microcirculation is affected. An episode of TTP may present as a one off illness, may be recurring,1 or may arise in association with drugs, neoplasia, pregnancy, or HIV infection.
Thrombotic thrombocytopenic purpura presents with neurological manifestations in over 50% of episodes, with headache, confusion, and somnolence being most common, leading to focal neurological deficit, convulsions, and eventually coma and death.3 These clinical features are often fleeting and fluctuating and several important points regarding imaging should be made. Firstly, brain CT may be normal or may show multiple hypodense areas indicative of generalised cerebral oedema.4 Secondly, brain MRI may also be normal, although it is likely to show multiple foci of high intensity on T2 weighted images.5 6 Coma has been shown to be a bad prognostic indicator. Of importance is the finding that despite the presence of substantial neurological dysfunction, normal findings on brain CT strongly suggest the potential for full clinical recovery.6 7
Plasmapheresis is now the treatment of choice: plasma infusion alone should not be regarded as an acceptable alternative but as a short term measure only.2 Fresh frozen plasma is the usual replacement fluid, although it remains to be determined whether cryosupernatant or solvent/detergent fresh frozen plasma is more effective. These plasmas lack von Willebrand factor, and since ultralarge von Willebrand factor multimers have been demonstrated in TTP, it is postulated that additional factor exacerbates the disease. Platelet transfusions should be avoided (unless there is life threatening bleeding) as they may worsen the condition.
These two cases illustrate that patients with TTP may present to the intensive care unit with profound coma, such that many clinicians would consider the prognosis so poor that further active management would be inappropriate. In addition, the cases show that patients can survive and even make a full recovery despite a delay in diagnosis and appropriate treatment.