Seizures, headache and thrombocytopenia: diagnosis and treatment do not always come in a standard sequence

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1 Intern Emerg Med (2007) 2: DOI /s CASE RECORD A. Iorio M.C. Vedovati E. Filippucci G. Agnelli Seizures, headache and thrombocytopenia: diagnosis and treatment do not always come in a standard sequence Published online: 28 September 2007 Case description Dr. Alfonso Iorio, Prof. Giancarlo Agnelli: A 49-yearold woman was admitted to our department after partial seizure, described as paraesthesia and tonic clonic movements of the left hemisoma. On admission the neurological examination evidenced left arm and facial weakness. The patient s clinical history included systemic arterial hypertension and hypothyroidism secondary to a previous autoimmune thyroiditis. A cerebral computed tomography (CT) scan showed two small cortical haemorrhages on the right hemisphere (Fig. 1). A cerebral magnetic resonance angiography (MRA) showed a cerebral vein thrombosis (CVT) with total occlusion of the superior sagittal sinus and of the left lateral sinus, and a reduced perfusion of the rectum sinus (Fig. 2). Unfractionated heparin (UFH) was started and replaced after 48 h by low-molecular-weight heparin (LMWH). A CT scan performed 8 days later showed a reduction of the haemorrhagic lesions. On the 10th day after the beginning of treatment the patient had a A. Iorio ( ) M.C. Vedovati E. Filippucci G. Agnelli Medicina Interna e Vascolare-Stroke Unit Dipartimento di Medicina Interna Ospedale S. Maria della Misericordia Perugia, Italy iorioa@unipg.it severe headache with no other new neurological signs; the blood count showed a decrease in the platelet count (from a baseline value of /mmc to /mmc). No clinical objective symptoms were suggestive of a possible extension of CVT and the severe headache could have been interpreted as a predictable complaint of cerebral thrombosis. Alternatively, anticoagulation could have prompted the extension of the haemorrhagic infarction. A follow-up cerebral CT scan was performed, and no new signs were found. As a third hypothesis, the exposure to heparin, the entity and the timing of occurrence of thrombocytopenia, the new neurological symptoms and the absence of an alternative explanation for thrombocytopenia were all conditions strongly suggestive of heparininduced thrombocytopenia (HIT). As usually happens when the suspicion of HIT arises, the clinician must cope with the difficult decision of stopping a life-saving treatment of proven efficacy to start another unfamiliar drug, aimed at treating the baseline disease and at halting the tumultuous and dangerous phenomenon of heparininduced systemic platelet aggregation. Furthermore, in many cases there is no time to wait until the laboratory confirmation of the clinical suspicion: all cases, but particularly cardiosurgical and neurological patients, like our one, require immediate management strategies. Thus, due to the high suspicion of HIT, treatment with LMWH was stopped. The following step is to start an alternative anticoagulant treatment as quickly as possible. In Italy no drug is specifically approved for the treatment of uncomplicated HIT, i.e. HIT without occurrence of new arterial or venous thrombosis. Dermatan sulphate, a glycosaminoglycan and indirect (HC II) selective inhibitor of thrombin, successfully used in previous cases of HIT [1], was started on a compassionate use basis. Dermatan sulphate was started at the dosage of 12 mg/kg/day and incremented by steps of 4 mg/kg/day up to 24 mg/kg/day, and an aptt ratio between 1.3 and 1.7 was reached within 12 h. Meanwhile, an ELISA test for HIT (PF4 ENHANCED

2 IM A. Iorio et al.: Seizures, headache and thrombocytopenia 203 Fig. 1 Cerebral CT: two small cortical haemorrhages on the right hemisphere Fig. 3 Follow-up cerebral MRA, performed 14 days after diagnosis: restored venous blood flow in the superior sagittal sinus and in the rectum sinus Fig. 2 Cerebral MRA: total occlusion of the superior sagittal sinus, of the left lateral sinus and reduced perfusion of the rectum sinus Solid Phase ELISA, GTI Diagnostics) was positive. Unfortunately, the treatment with dermatan sulphate was not effective: the platelet count fell down to /mmc two days after the beginning of the drug and the patient had a new partial tonic clonic seizure. HIT was still there and active, and the symptoms were likely to be attributed to cerebral ischaemia. The functional test for heparininduced antiplatelet antibodies (heparin-induced platelet aggregation, HIPA) showed a cross-reactivity of dermatan sulphate to antiplatelet factor 4 (PF4) antibodies. Administration of dermatan sulphate was stopped and lepirudin was started (bolus of 0.4 mg/kg, followed by continuous intravenous infusion of 0.15 mg/kg, adjusted to maintain an aptt ratio of times the baseline value). The platelet count increased the day after the start of lepirudin. When the platelet count reached /mmc, warfarin was started and lepirudin was discontinued when INR was stable in the therapeutic range. The patient presented an excellent complete clinical recovery and the follow-up MRA performed after 14 days from diagnosis showed a restored venous blood flow in the superior sagittal sinus and in the rectum sinus (Fig. 3). On discharge the platelet count was /mmc and the INR The patient continued on oral anticoagulation and phenytoin for six months, without residual neurological defects. During a follow-up visit ten months later no new events were reported by the patient. Discussion of CVT diagnosis and treatment Dr. Maria Cristina Vedovati, Dr. Alfonso Iorio: CVT represents 1% of all strokes and its incidence in the adult population is about 3 4/ people/year. Incidence peak is in the third decade of life and the male:female ratio

3 204 A. Iorio et al.: Seizures, headache and thrombocytopenia is 1:4 in adults. This high rate of CVT in young women is associated with elevated levels of circulating oestrogens as in pregnancy, puerperium or with the use of oral contraceptives [2]. Seventy-four per cent of the 624 patients with CVT included in the International Study on Cerebral Venous and Dural Sinuses Thrombosis (ISCVT) were female (mean age 39 years). The natural history of CVT varies from complete recovery to severe neurological deficit or death. During the past decade mortality decreased from 30% 50% to 10% 15% and to 8.3% in the recent ISCVT registry. However the combination of mortality and disability is still high (22%) [3]. CVT is associated with many pathological conditions (i.e., pregnancy, puerperium, trauma, infections); yet, it remains idiopathic in 15% of cases. A causal event is often associated to a genetic predisposition. Congenital thrombophilia is reported in 1/3 of patients with CVT [4]. A recent meta-analysis [5] shows that there is an increased risk of CVT in patients using oral contraceptives and in patients with factor V Leiden, mutation G20210A of prothrombin or hyperhomocysteinaemia. Our patient had no known or highlighted risk factors, since admission to discharge. CVT is characterised by a great clinical variability due to the site and number of the sinus or vein involved and to the presence of concomitant diseases. Symptoms may have an acute (37%, <48 h), subacute (56%, 48 h 30 days) or chronic (7%, >30 days) presentation. Headache is the most frequent yet non-specific symptom (88.8% in ISCVT population) [3]. Despite the polymorphic clinical manifestations of CVT, two main syndromes can be identified: thrombosis of the venous sinus and thrombosis of the cortical veins. The clinical features of thrombosis of venous sinus are a consequence of the cerebral hypertension: headache, papilloedema, deficit of cranial nerves, behavioural and cognitive impairment, and coma. The clinical features of thrombosis of cortical veins are a consequence of the venous congestion, secondary oedema and haemorrhages: stroke-like or tumour-like presentation; epilepsy; severe headache. The fluctuation of clinical symptoms in our patient could be interpreted as one of the predictable polymorphic manifestations of CVT. The key to the diagnosis is the imaging of the thrombus or the occluded vessel (i.e., the absence of flow). Angiography has been the gold standard for establishing the diagnosis of CVT for a long time, but nowadays magnetic resonance imaging (MRI) and MRA are regarded as the best tools for both the diagnosis and the follow-up of CVT. However, the sensitivity of conventional MRI sequences to detect clots in the sinuses or veins is suboptimal and largely depends on the time elapsed since thrombus formation to MRI performance. Furthermore, as all the other angiographic techniques, MRA does not differentiate thrombosis and hypoplasia, a frequent diagnostic dilemma for the lateral sinuses. In addition, these techniques are usually unable to diagnose isolated cortical venous thrombosis definitively. With respect to CT scan, the diagnosis of CVT requires the acquisition of angiographic sequences, as the first-line cranial CT scan without contrast agent does not allow the exclusion of the presence of CVT. Treatment in the acute phase aims to relieve symptoms and prevent cerebral herniation. Herniation is mainly due to the combination of acutely increased intracranial pressure and oedema, due to large venous infarcts. It may be treated by medical (diuretics, corticosteroids) or surgical (decompressive hemicraniectomy) therapy. The aetiologic treatment of CVT is anticoagulation, which reduces the progression of the thrombotic process and favours the dissolution of the clot. The use of anticoagulant treatment raised much concern, because of the high proportion of CVT with complicating cerebral haemorrhage in the site of venous infarct (about 40% of all patients with sinus thrombosis have haemorrhagic infarcts before anticoagulant treatment is started). Only three small, randomised clinical trials on acute treatment of CVT have been conducted [6 8]. A meta-analysis showed the efficacy and safety of anticoagulant treatment with respect to control treatment (reduction of death and disability and no increase of bleeding even in patients with cerebral haemorrhagic infarction) [9]. The guidelines of the American College of Chest Physicians (ACCP) [10] remark on the essential role of anticoagulation in the treatment of CVT: while vitamin K antagonists (target INR 2.5, range ) are the drug of choice for long-term treatment (3 6 months are recommended), UFH or LMWH should be used in the acute phase (1B level of evidence). Currently there is no evidence from randomised controlled trials about the efficacy and safety of either systemic or local thrombolytic therapy in patients with CVT. The use of antiepileptic drugs in patients with CVT is recommended for secondary prophylaxis of seizures. Discussion of HIT diagnosis and treatment Dr. Esmeralda Filippucci, Prof. Giancarlo Agnelli: Following administration of LMWH, the patient developed HIT. HIT is a potentially serious side effect of heparin treatment. HIT is caused by the formation of heparin-dependent, platelet-activating IgG antibodies, directed against PF4/heparin complexes. The overall incidence of clinically overt HIT is approximately 1.2% of all heparin-treated patients [11]. The frequency of HIT is dependent upon: the heparin used (3% in patients receiving UFH and less than 1% in patients receiving LMWH), patients (higher incidence of HIT in surgical patients than in medical ones) and gender (HIT more frequent in female patients than in male ones). Data on the role of heparin dose are controversial, and cases of HIT following expo-

4 IM A. Iorio et al.: Seizures, headache and thrombocytopenia 205 sure to traces of heparin (i.e., after heparin flushing for central venous catheter care) have been described. The mortality rate is about 15%, despite adequate therapy [12]. The classical clinical presentation of HIT is summarised by the 4Ts clinical scoring system: Thrombocytopenia and Thrombosis and Timing, in the absence of other explanation of thrombocytopenia [13]. Thrombocytopenia is defined as a platelet count <150x10 9 /l or a platelet fall of >50% of baseline count. Generally the platelet count does not fall below 20x10 9 /l. Thrombosis indicates the presence of venous or arterial thrombosis. The available evidence indicates that the risk of venous (deep vein thrombosis, pulmonary embolism) and arterial (acute limb ischaemia, stroke, acute myocardial infarction) thrombosis after stopping heparin, in the absence of alternative anticoagulation, ranges from 20 to 50% [11]. It has to be noted that new thrombotic events can occur even with a platelet count above 150x10 9 /l, and that the risk of thrombosis remains high for days to weeks after discontinuation of heparin, even if the platelet count normalises. Timing. In about 70% of HIT cases, the platelet count falls 7 10 days after the beginning of the heparin therapy. Less frequently (about 25% of cases), the fall of platelet count occurs earlier (within hours) if the patient has been previously treated with heparin in a onemonth time span [14]. Finally, in a minority of patients (3 5%) with a high titre of platelet activating antibodies, thrombocytopenia may occur up to 3 weeks after the end of heparin treatment (delayed onset HIT) [15]. When HIT is clinically suspected, it is indicated to test the presence of heparin-dependent antibodies by using functional or serological tests. Functional tests (HIPA, Serotonin Release Assay, SRA) are technically demanding and not available in all laboratories. Serological tests (ELISA) are reliable, simple to perform, sensitive and specific, and feasible in any basic laboratory. Indeed, HIT may be regarded as a clinicopathologic syndrome: its diagnosis relies upon both the suggestive clinical picture and the positivity of the test for PF4/heparin reactive antibodies. As soon as the clinical feature is recognised, heparin administration must be stopped and a rapidly effective alternative non-heparin anticoagulant should be started, without waiting for the laboratory test results. Argatroban and lepirudin, two direct thrombin inhibitors, are currently approved for use in patients with HIT. Argatroban is FDA-approved for use in patients with HIT with or without thrombosis as well as in patients with or at risk of HIT who are undergoing percutaneous coronary intervention [16]. Lepirudin is FDAand EMEA-approved for anticoagulation of patients with HIT and associated thrombosis, to treat and prevent further thromboembolic complications [17, 18]. Limited data support the use of alternative parenteral non-heparin anticoagulants (dermatan sulphate [1, 19] and fondaparinux [20, 21]). General discussion and clinical implications Prof. Giancarlo Agnelli, Dr. Alfonso Iorio: CVT and HIT are potentially life-threatening diseases. Few case reports describe the association of these two conditions. In all the described cases, in contrast to our patient, CVT developed as a complication of HIT. Kyritsis et al. described a case of a woman with a septic superficial thrombophlebitis treated with heparin who developed HIT complicated by CVT. Heparin was stopped and the patient was treated with warfarin, and later on discontinued warfarin for the development of a cerebral haemorrhage. The patient made an excellent recovery [22]. Warkentin and Bernstein described the case of a woman who developed a delayed-onset HIT, complicated by CVT and deep vein thrombosis [23]. In a cohort of 120 patients with HIT, recruited over a period of 11 years and studied retrospectively, 3 patients suffered from cerebral venous thrombosis [24]. Two other fatal cases were reported without details [25, 26]. The peculiarity of our case is the development of HIT during heparin treatment for CVT. The every-other-day platelet count monitoring during anticoagulant therapy (heparin and dermatan sulphate) made a prompt diagnosis of HIT possible in this patient. The clinical course of the CVT-related symptoms (headache and seizures) was swinging and, in our patient, potentially correlated with variation of platelet count. Furthermore, this is the first report in the literature on the use of lepirudin in patients with CVT. As we know, lepirudin has a high rate of haemorrhagic complications (major bleedings 29.4%) [12]. Moderate to severe renal impairment, long duration of lepirudin treatment and mean lepirudin dose greater than 0.07 mg/kg/h are significant predictive factors for major bleeding. It has been observed that the mean lepirudin doses administered in routine practice are usually reduced by about 25% of full dosage [27] and a prospective observational case series demonstrated that the reduction of the drug labelled dose by 1/3 is as effective as the full dose [28]. In our case, lepirudin was administered safely at full dosage: no complications, in terms of new bleeding or worsening of pre-existing cerebral haemorrhage, were observed. In conclusion, we would like to suggest the following items for the routine clinical practice: - considering CVT in differential diagnosis in young adults with first occurrence of severe headache; - treating CVT with heparin even in the presence of cerebral haemorrhage; - assessing efficacy of anticoagulant treatment in CVT patients with a clinical rather than a radiological follow-up; - thinking of HIT in patients treated with heparin and assessing the platelet count periodically; - stopping heparin treatment and starting alternative anticoagulant (lepirudin bolus of 0.4 mg/kg, followed by continuous intravenous infusion of 0.15 mg/kg/h,

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