Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients

J. A. Gómez-Puerta, R. Cervera, L. M. Calvo, B. Gómez-Ansón1, G. Espinosa, G. Claver, S. Bucciarelli, A. Bové, M. Ramos-Casals, M. Ingelmo and J. Font

Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, 1 Department of Neuroradiology, Centre Clínic de Diagnòstic per la Imatge, Hospital Clínic, Barcelona, Catalonia, Spain.

Correspondence to: R. Cervera, Servei de Malalties Autoimmunes, Hospital Clínic, Villarroel, 170, 08036-Barcelona, Catalonia, Spain. E-mail: rcervera{at}clinic.ub.es


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To analyse the clinical and radiological characteristics of patients with dementia associated with the antiphospholipid syndrome (APS).

Methods. Twenty-five patients were identified by a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of dementia associated with APS published in English, Spanish and French from 1983 to 2003. Additionally, we included five patients from our clinics.

Results. There were 21 (70%) females and 9 (30%) males. The mean age of patients was 49±15 yr (range 16–79 yr). Fourteen (47%) of the patients suffered from primary APS, 9 (30%) had systemic lupus erythematosus and 7 (23%) had ‘lupus-like’ syndrome. Ten (33%) patients had Sneddon's syndrome and 2 (7%) had cerebral lesions described as Binswanger's disease. Other APS-related manifestations included thrombocytopenia in 12 (40%) patients, cerebrovascular accidents in 11 (37%), heart valve lesions in 8 (27%), deep vein thrombosis in 7 (28%), migraine in 7 (23%), seizures in 4 (13%); five of the 21 (24%) female patients had nine spontaneous abortions. Lupus anticoagulant was present in 21/29 (72%) patients and anticardiolipin antibodies were present in 24/29 (83%) patients. Cortical infarcts were found in 19 (63%) patients, subcortical infarcts in 9 (30%), basal ganglia infarcts in 7 (23%) and signs of cerebral atrophy in 11 (37%). Anticoagulation was used in 14/25 (56%) patients, steroids in 12/25 (48%), aspirin in 6/25 (24%) and dypiridamole in 5/25 (20%).

Conclusions. Dementia is an unusual manifestation of APS but one which has a high disability impact in a patient's daily life. In order to prevent these consequences, an echocardiographic and cerebral CT or MRI evaluation are recommended in all patients with APS. Furthermore, ruling out APS should be recommended in the clinical approach to dementia, especially in young patients.

KEY WORDS: Antiphospholipid syndrome, Dementia, Vascular dementia, Multi-infarct dementia, Sneddon's syndrome, Binswanger's disease


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Dementia is being increasingly diagnosed in clinical practice and has a high disability impact in a patient's daily life. Alzheimer's disease is the main cause of dementia, followed by vascular multi-infarct dementia, Parkinson's disease, frontal lobe dementia and, less commonly, other metabolic and reversible causes of dementia [1].

The antiphospholipid syndrome (APS) is an autoimmune pro-thrombotic condition characterized by venous and/or arterial thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL), i.e. lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) [2]. Involvement of cerebral large vessels is frequent in APS and patients usually present clinically with transient ischaemic attacks (TIA) and strokes. However, a wide spectrum of other neurological features has been described, including chorea, epilepsy, multiple sclerosis-like lesions, psychiatric features, migraine and also dementia, among others [2, 3].

A relationship between dementia and APS has been proposed by several authors [2–7]. Although most studies have focused on patients with dementia and cerebral vascular lesions, less severe cognitive impairment has also been associated with the presence of aPL in the absence of imaging lesions in the brain [7]. Furthermore, the ischaemic stroke in Sneddon's syndrome may overlap with APS and some of these patients suffer from severe vascular dementia. The objective of this study was to analyse the clinical and radiological features of patients with dementia associated with APS, highlighting the importance of early diagnosis of this condition.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients were identified by a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of APS published in English, Spanish and French from 1983 (when APS was first defined) to December 2003 (keywords used were: anticardiolipin antibodies, lupus inhibitor, cardiolipin, coagulation inhibitor, lupus anticoagulant, antiphospholipid syndrome, antiphospholipid antibodies, multi-infarct dementia, vascular dementia, Sneddon's syndrome, Alzheimer's disease and Binswanger's disease).

Cases having Sneddon's syndrome with dementia but without aPL were not included. Only cases with well-documented clinical summaries and relevant information were included in this review. Data from these cases were summarized using a standardized data form, including gender, age, diagnosis of the underlying condition, the major thrombotic clinical manifestations, immunological features, time of the evolution since the diagnosis of APS until the development of dementia, imaging features and treatment. Five new cases with dementia and APS from our clinics were added to the review. Those patients diagnosed as having dementia who were included in large APS series, but in whom no well-documented clinical data were recorded, were not considered for analysis in the present study.

Patients were defined as having dementia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [8]. They were classified as having systemic lupus erythematosus (SLE) if they met four or more criteria of the American College of Rheumatology [9, 10], as ‘lupus-like’ syndrome if they met only two or three criteria and as primary APS if they met criteria of the International Consensus Statement on Preliminary Classification Criteria for definite APS, and did not meet any of the above described criteria for SLE or ‘lupus-like’ syndrome [11].

Ethical approval and informed patient consent were not required because the study was an analysis of patients that were located by means of a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 25 patients with dementia associated with APS were found in the literature search [12–26]. We did not include those cases where clinical, immunological and imaging characteristics were not described in detail. Five additional patients from our clinics were also reviewed.

General characteristics
General clinical features of these 30 patients are shown in Table 1. There were 21 (70%) females and 9 (30%) males. The mean age of patients was 49 ± 15 yr (range 16–79 yr). Fourteen (47%) of the patients suffered from primary APS, 9 (30%) had SLE and 7 (23%) patients had ‘lupus-like’ syndrome. Ten (33%) patients had Sneddon's syndrome and 2 (7%) had cerebral lesions described as Binswanger's disease.


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TABLE 1. General characteristics of 30 patients with dementia and APS

 
Clinical presentation
Dementia was the presenting manifestation of the APS in 11 (37%) patients. A clinically evident past history of CVA was detected in 11 (37%) patients. Other neurological features included migraine in 7 (23%) patients, seizures in 4 (13%), TIA in 2 (7%), chorea in 2 (7%), and retinal thrombosis in 2 (7%) patients. Thrombotic glaucoma and optic neuritis were present in 1 (3%) case each. Skin involvement in the form of livedo reticularis (as a manifestation of Sneddon's syndrome) was reported in 10 (33%) patients, and skin ulcers in 3 (10%). Other APS-related manifestations were as follows: 8 (27%) patients had heart valve lesions, 7 (23%) deep-vein thrombosis (DVT), 2 (7%) pulmonary embolism, 3 (10%) myocardial infarction and 2 (7%) superficial thrombophlebitis. Previous spontaneous abortions (n = 9) were reported in 5 of the 21 (24%) female patients.

Laboratory profile
Twelve (40%) patients had thrombocytopenia and 2 (7%) had autoimmune haemolytic anaemia. LA was present in 21/29 (72%) patients, whilst aCL was present in 24/29 (83%) patients.

Neuroimaging features
Most patients exhibited several types of lesions on cerebral computed tomography (CT) scan or magnetic resonance imaging (MRI). Cortical infarcts were detected in 19 (63%) patients, subcortical infarcts in 9 (30%), basal ganglia infarcts in 7 (23%) and cerebral atrophy in 11 (37%). Silent brain infarcts (cerebral ischaemic lesions without any focal neurological features) were found in 14 (47%) patients.

Treatment and evolution towards dementia
Anticoagulation was used in 14/25 (56%) patients, steroids in 12/25 (48%), aspirin in 6/25 (24%) and dypiridamole in 5/25 (20%). Treatment was not reported for five cases.

In the 19 (63%) patients who presented APS manifestations previous to the diagnosis of dementia, anticoagulation had been used in 7 (37%) patients, steroids in 6 (32%), aspirin in 5 (26%) and dypiridamole in 4 (21%). The mean time of evolution from the initial APS manifestations to the diagnosis of dementia in these 19 patients was 3.5 yr (range, 1–10 yr).


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The relationship between dementia and APS has been proposed in several studies. Mosek et al. [6] studied 87 patients diagnosed as having dementia and compared them with 69 elderly healthy controls. They found higher levels of aPL in patients with dementia than in controls. Juby et al. [27] analysed the prevalence of aCL in 218 elderly patients. They disclosed that 34 patients suffered from dementia and a significant association between aCL and both vascular dementia and Alzheimer's disease was noted. Recently, Chapman et al. [4] studied 23 patients with primary APS and found that 13 (56%) fulfilled criteria for dementia using the Hachinski Ischemia Score (HIS). Patients with dementia were older, had more CT scan abnormalities and more electroencephalography changes than those without dementia. However, the ‘Euro-Phospholipid’ consortium, in their cohort of 1000 APS patients, described the presence of vascular dementia in only 25 (2.5%) cases [2]. It is possible that the higher prevalence of dementia in the Chapman et al. series [4] could be merely due to the small and probably highly selected group of patients studied, but it could also be due to the exclusion of SLE patients as it is know that in APS associated with SLE the incidence of neurological manifestations is higher than in primary APS [28].

The presence of aPL in patients with cognitive problems seems to be more than an epiphenomenon, as it has been demonstrated in experimental studies. Shrot et al. [29] performed an elegant study with BALB/c mice using a staircase test and a T maze alternation test as cognitive assessment tools. Mice immunized with anti-ß2-glycoprotein I antibodies developed a higher degree of behavioural and cognitive abnormalities than those that had not been immunized.

One-third of the patients from our series had Sneddon's syndrome. Francès et al. [30] described a specific subset of patients with this syndrome having aPL who presented more thrombocytopenia, mitral regurgitation and irregular livedo reticularis than patients without aPL. There is controversy concerning whether patients with Sneddon's syndrome without aPL could be a special group of transient ‘seronegative’ APS patients.

In the present study, almost one-third of patients had valve disease. It is well known that a high proportion of cerebral infarcts have a cardiac embolic origin and that patients with aPL have higher prevalence of valvular abnormalities [31]. Thickening of the valve leaflets is the most common lesion detected by echocardiography in both SLE and primary APS patients. The mitral valve is involved most commonly, followed by the aortic valve [32].

Epilepsy is a common neurological manifestation in APS [2]. Recent studies by Shoenfeld et al. [33] have confirmed a link between this manifestation and cerebrovascular involvement, heart valve lesions and livedo reticularis. In the present series, 13% of the patients with dementia presented seizures, thus reinforcing the role of focal brain ischaemic lesions in the pathogenesis of APS-related epilepsy.

Patients with dementia exhibit a wide variety of cerebral lesions on CT or MRI studies. Cortical and subcortical infarcts are the more frequent findings. Other ischaemic lesions such as lacunar and periventricular infarcts are not uncommon. Cerebral atrophy and white matter lesions (leukoaraiosis), similar to the lesions found in Binswanger's disease, are often seen, specially in elderly APS patients [15]. In SLE, these findings have been shown to be in close association with the presence of APS, but other factors, e.g. hypertension, could also contribute to their presence [34]. The continuous improvement and development of new CNS imaging techniques [i.e. positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] will allow to us differentiate the distinct perfusion patterns on these cerebral disorders. Kao et al. [35] studied 22 patients with primary APS with only mild neuropsychiatric manifestations (headache, depression, personality disorders, memory loss and cognitive function deficits) and normal brain MRI. They found that 16 (73%) of the patients had abnormal SPECT findings, mainly diffuse hypoperfusion lesions in cerebral cortex.

It is not only those patients with evident cerebral lesions and cognitive impairment who deserve special attention, but also those patients with an asymptomatic course or subtle decline in cerebral functions having cerebral ischaemic lesions on MRI (silent brain infarcts). Vermeer et al. [36] followed 1077 elderly patients without dementia over 5 yr, with periodical MRI evaluation. Two hundred and seventeen (21%) patients had silent brain infarcts at baseline, with a global cognitive function significantly worse than in those patients without brain infarcts. During the follow-up, 30 (3%) of these patients developed dementia. Erkan et al. [5], in a 10-yr follow-up study of 66 patients with primary APS, found that 3 patients (<30 yr old) developed dementia, independently of the presence of CVA. In the present series, previous history of CVA and/or TIA was present in only 11 and 2 patients, respectively; however, silent brain infarcts were present in 14 (47%) patients.

Several strategies have been suggested for the treatment of dementia. The management of atherogenic risk factors (i.e. diabetes, hypertension, hyperlipidaemia) is crucial. However, there is still no evidence that aspirin alone is effective in treating patients with a diagnosis of dementia. In dementia associated with APS, anticoagulant treatment is required, with special care in possible everyday situations with the risk of bleeding. Furthermore, the compliance of demented patients is usually poor, which requires special thought and attention. On the other hand, prevention of dementia should be of paramount importance in those patients with a diagnosis of APS. Unfortunately, it is difficult from the present study to recommend any therapeutic strategy because patients were previously treated with a variety of medications. However, it is worth noting that the majority of patients were not on anticoagulants when the first manifestations of dementia appeared. Therefore, this reinforces the need for active antithrombotic prophylaxis once the diagnosis of APS is made.

In conclusion, dementia can be present in patients with APS in multiple scenarios, such as primary APS, Sneddon's syndrome or with white matter lesions similar to Binswanger's disease. Due to the high disability impact and prognostic consequences, we consider that an echocardiographic and cerebral CT or MRI evaluation should be recommended in all patients with APS. Also, it is important to rule out an APS in young subjects with no explicable cause of dementia, and therefore aPL should be tested in these patients in order to prevent disease progression and enable adequate treatment to begin.

The authors have declared no conflicts of interest.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 8 July 2004; revised version accepted 10 August 2004.