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Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics
JNS-13378; No of Pages 7 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics De-Sheng Zhu a, Jue Fu b, Yue Zhang c, Shi-Xu Li c, Guang-Xian Zhang d, Yang-Tai Guan c,⁎, Qiang Dong a,⁎⁎ a
Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China Department of Pathology, Fuzhou Medical College of Nanchang University, Fuzhou 344000, China Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China d Department of Neurology, Thomas Jefferson University, PA 19107, USA b c
a r t i c l e
i n f o
Article history: Received 12 July 2014 Received in revised form 24 July 2014 Accepted 4 August 2014 Available online xxxx Keywords: Antiphospholipid syndrome Antiphospholipid antibodies Clinical features Neuroimaging Pathology Central nervous system
a b s t r a c t Background: Neurological antiphospholipid syndrome (NAPS) is often misdiagnosed or missed. Only limited clinical and neuroimaging information about it is available, and the pathological characteristics was rarely reported before. This study aimed to explore the clinical, neuroimaging, and pathological characteristics of NAPS. Methods: We performed a retrospective analysis of 51 patients with APS, categorized into NAPS (n = 16) and rheumatology antiphospholipid syndrome (RAPS) groups (n = 35). Demographics and clinical profile were compared between the two groups, and the neuroimaging and pathological information of NAPS was also analyzed. Results: The mean age of the NAPS patients, 81.25% of whom were female, was 37.56 ± 12.36 years, and the average duration was 1.32 ± 0.96 years (range = 18 days to 3.5 years). No significant differences in age, sex, disease duration, classification, and comorbidities at baseline were observed between NAPS and RAPS patients (p N 0.05). Chief complaint of headache and thromboembolic events was higher in NAPS patients than in RAPS patients (p b 0.05). Neuroimaging detected multiple infarcts and demyelination lesions were distributed in subcortical and cortical area asymmetrically. Skin biopsy examination showed small vessel occlusion with inflammatory cells, while brain biopsy examination showed erythrocyte accumulation with some neuron degeneration and local demyelization. Antithrombotic and immunosuppressive therapy proved to be effective. Conclusion: Headache and thromboembolic events are more common in NAPS than RAPS. Neuroimaging and biopsy examination demonstrated that NAPS is an ischemic cerebrovascular disease caused by vascular stenosis or occlusion. These characteristics might help to reduce the misdiagnosis of NAPS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Antiphospholipid syndrome (APS) is a multisystem autoimmune disease characterized by the production of antiphospholipid antibodies (aPL), which promote recurrent vascular thrombosis (venous, arterial, and microvascular) and/or pregnancy complications and failure, frequently accompanied by moderate thrombocytopenia [1]. Presence of aPL in serum, including anticardiolipin antibody (aCL), lupus anticoagulant (LA), and anti-β2 glycoprotein-I antibody (anti-β2GPI), is a characteristic indicator of APS [2]. The preliminary classification criteria for APS were formulated during a post-conference workshop held on October 10, 1998, in Sapporo, ⁎ Correspondence to: Y.-T. Guan, Department of Neurology, Changhai Hospital, Second Military Medical University, No. 168, Changhai Road, Shanghai 200433, China. Tel.: +86 13386271865; fax: +86 21 64085875. ⁎⁎ Correspondence to: Q. Dong, Department of Neurology, Huashan Hospital, Fudan University, No. 12, Mid. Wulumuqi Road, Shanghai 200040, China. Tel.: + 86 13701747065; fax: + 86 21 64085875. E-mail addresses: [email protected] (Y.-T. Guan), [email protected] (Q. Dong).
Japan [3]. In 2006, revisions to the classification and diagnostic criteria for APS were proposed in Sydney [2]. The disease is classified into primary antiphospholipid syndrome (PAPS), secondary antiphospholipid syndrome (SAPS), and catastrophic antiphospholipid syndrome (CAPS), a relatively rare subtype [4]. APS, which was first reported by Hughes in 1983 [5], had been reported by doctors specializing in rheumatology, obstetrics and gynecology, and vascular surgery. Some estimates indicate that the incidence of the APS is around five new cases per 100,000 persons per year, and the prevalence is around 40–50 cases per 100,000 persons [1]. Thrombosis is one of the prominent clinical features of APS. According to an observational study of 1000 APS patients in 13 European countries, thrombotic events appeared in 166 (16.6%) patients during the first 5-year study period and in 115 (14.4%) during the second 5-year period [6]. APS patients with aCL who suffer from hypertension and hypertriglyceridaemia are at increased risk of arterial thrombosis [7]. Currently, however, literature describing the neuroimaging characteristics of APS is limited, and few studies, both domestically and internationally, have examined the brain biopsies of APS patients. Some studies on the pathological features of APS have been conducted but
http://dx.doi.org/10.1016/j.jns.2014.08.010 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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D.-S. Zhu et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
only in experimental animals. The main finding from examination of cortical tissue from APS mice was the thrombotic occlusion of capillaries in combination with mild inflammation [8]. One distinct pathological feature of APS appears to be intravascular thrombus formation in all vessels of all levels instead of vasculitis, but this finding cannot be considered a uniform pathological diagnostic criterion. Current treatment guidelines for APS emphasize the importance of early diagnosis and recommend aggressive therapies to alleviate damage to the CNS, especially to prevent recurrence of thrombosis [9–11]. However, the intensity and duration of anticoagulation therapy in APS syndrome have been debated for long [12–14]. Treatment for recurrent thrombosis in APS patients requires further clarification, since pathological studies on APS patients are scarce. APS often affects the central nervous system (CNS) and causes cerebral infarction, epilepsy, and consciousness disorder or limb dysfunction [15]. Research on rheumatology antiphospholipid syndrome (RAPS) is common; few studies thus far have conducted a detailed investigation of neurological antiphospholipid syndrome (NAPS), and the available information, from clinical features to the imaging and pathological characteristics of NAPS, is limited. Sophisticated neuroimaging techniques, including CT, MRI, DSA, and Doppler ultrasound, would facilitate us a better understanding of NAPS. The aim of the present study is to explore the clinical features and imaging and pathological characteristics of NAPS via a retrospective analysis of clinical data. 2. Patients and methods
2.4. Statistical analysis Categorical variables were presented as counts and percentages and analyzed by Fisher's exact test or the Chi-square test. Continuous variable was reported as means and standard deviation (normal distribution) and analyzed by the independent-t-tests. Statistical analyses were performed using Statistical Package of the Social Sciences Software version 16.0 (SPSS, Chicago, IL, USA), setting the level of significance at a two-tailed p-value of b0.05. 3. Results 3.1. Demographics The demographic and clinical profiles of the patients are presented in Table 1. The mean age of the NAPS patients, 81.25% of whom were female, was 37.56 ± 12.36 years. The average disease duration of the NAPS patients was 1.32 ± 0.96 years (range = 18 days to 3.5 years). Six patients were accompanied by a history of autoimmune diseases and viral infections (37.5%). No significant differences in age, sex, disease duration, classification, and comorbidities at baseline were observed between two groups. Chief complaint of headache was higher and limb weakness was lower in NAPS patients than in RAPS patients (p b 0.05). NAPS patients showed more thromboembolic events than RAPS patients (p b 0.01). Misdiagnosis before confirm was higher in NAPS patients than in RAPS patients (p b 0.01).
2.1. Patients We performed a retrospective analysis of all patients with APS from neurology wards and rheumatology wards of Huashan Hospital and Changhai Hospital between January 2008 and December 2013. In this study, 51 patients with APS were enrolled and followed up at least six months, including 16 patients who had symptoms of CNS impairment from neurology wards and 35 patients from rheumatology wards. All patients had been diagnosed with APS on the basis of the criteria proposed in 2006 in Sydney [2]. This study only included APS patients with LA, aCL and anti-β2GPI antibody of IgG and/or IgM isotype in serum or plasma, on two or more occasions at least 12 weeks apart, measured by an inhibitor of phospholipid-dependent clotting or standardized ELISA according to the criteria. 2.2. Clinical information Retrospective analyses were performed on the following information: (1) Demographic information (gender, age, disease duration before hospitalization, and medical and pregnancy history); (2) initial symptoms (headache, limbs weakness, cognition disorder, elapse and thrombosis); (3) biochemical indicators (aCL, LA, anti-β2GPI, antinuclear antibody (ANA), and anti-double-stranded-DNA (dsDNA) and anti-ssDNA (ssDNA) antibodies; rheumatoid arthritis (RA); complete blood count (CBC); international normalized ratio (INR); prothrombin time (PT); partial prothrombin time (APTT); erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and findings of cerebrospinal fluid (CSF) examination); (4) neuroimaging (cranial computed tomography (CT); magnetic resonance imaging (MRI); digital subtraction angiography (DSA); echocardiography; and cervical vascular ultrasound); (5) pathological features (brain biopsy and skin biopsy); and (6) therapy (antiplatelet drugs, anticoagulants, glucocorticoids, and immunosuppressive agents). 2.3. Ethics This study was approved by the institutional review board of Huashan Hospital, Fudan University (Shanghai, China).
3.2. Clinical manifestations, thromboembolic events and laboratory analysis Data of NAPS patients on the initial symptoms, thromboembolic events, and results of laboratory tests are presented in Table 2. The most common initial symptoms were headache, and limb weakness. Clinical manifestations of NAPS patients during the course were complex and varied. The incidence of headache and that of cerebral infarction were ranked in the first and second respectively in this study, which was different with foreign literature. A comparison of the incidence of clinical manifestations between our study and that reported in foreign literature is presented in Table 3 [6–10]. Laboratory analysis of NAPS patients showed that one patient was rheumatoid factor positive, two patients were dsDNA and ssDNA antibody positive, and one patient was anti-smooth muscle antibody positive. CRP and ESR were higher than normal in two patients. CBC showed that the platelet count was lower than normal in five patients (31.25%). CSF examination showed that the CSF pressure was higher in three patients (37.5%), and that the erythrocyte count was higher
Table 1 Demographics and clinical profile of the study objects. Information
NAPS (n = 16)
RAPS (n = 35)
P-value
Age (years) Sex (male/female) Disease duration (years) Classification (PAPS/SAPS) Comorbidities at baseline SLE, RA, SS Miscarriages, preeclampsia Herpes zoster, viral influenza Chief complaint Headache Limb weakness Thromboembolic events Misdiagnosis before confirm
37.56 ± 12.36 3/13 1.32 ± 0.96 12/4
40.57 ± 7.28 7/28 2.04 ± 1.35 23/12
0.377 1.000 0.061 0.746
4 (25%) 3 (18.75%) 2 (12.5%)
12 (34.28%) 5 (14.28%) 5 (14.28%)
0.746 0.694 1.000
8 (50%) 6 (33.33%) 12 (75%) 14 (87.50%)
7 (20%) 25 (71.43%) 8 (22.86%) 6 (17.14%)
0.029 0.021 0.001 0.000
NAPS: neurological antiphospholipid syndrome, RAPS: rheumatology antiphospholipid syndrome.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
D.-S. Zhu et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 2 Initial symptoms, thromboembolic events and aPL antibody analysis of NAPS patients. Initial symptoms Headache Limb weakness Episodes of unconsciousness Paroxysmal convulsion Blurred vision Dizziness Cognitive disorders Thromboembolic events Arterial thrombosis Venous thrombosis Micro thrombus aPL-antibody analysis aCL positive aβ2GP-I positive LA positive aCL + aβ2GP-I positive
8 (50.00%) 6 (37.50%) 4 (25.00%) 4 (25.00%) 3 (18.75%) 2 (12.50%) 2 (12.50%) 5 (31.25%) 4 (25.00%) 3 (18.75%) 12 (75.00%) 6 (37.50%) 3 (18.75%) 4 (25.00%)
than normal in one patient (12.5%). The leukocyte number, CSF protein level, and the 24 h IgG synthesis rate were within the normal ranges, and oligoclonal bands were not found in any patient (100%).
3.3. Neuroimaging results The neuroimaging data in our study showed that the main characteristics of NAPS in the brain are ischemic changes such as multifocal cerebral infarctions, white matter demyelination, and cerebral atrophy. All NAPS patients underwent Cranial CT and MRI evaluation. Multiple new cerebral infarctions were concentrated in the periventricular white matter on CT plain (Fig. 1). Computed tomography angiography (CTA) showed stenosis or occlusion in anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) and their branches. MRI lesions, including lacunar infarctions and large area infarctions, were detected in basal ganglia and cerebral cortex (Fig. 2). Local brain tissue atrophy and widened cerebral fissures were also detected in some patients. White matter demyelination lesions, which widely distributed in the cerebral cortex, subcortex, periventricular and basal ganglia on FLAIR MRI. Different signs showed the characteristic of relapsing–remitting lesions (Fig. 3). No enhanced lesions were found with Gd-enhanced MRI in any patient. Magnetic resonance angiography (MRA) showed stenosis or occlusion in middle or anterior cerebral artery and its branches unilaterally. Magnetic resonance venography (MRV)
Table 3 Comparison of the incidence of clinical manifestations between NAPS patients in our study and foreign literature (%). Clinical manifestations
Headache Cerebral infarction Thrombocytopenia Transient ischemic attack (TIA) Cerebral venous sinus thrombosis Epilepsy Limb phlebothrombosis Cognition disorders Abortion Preeclampsia Valvular heart disease Skin ulcer Foot gangrene
In this study
Literature [6,16,19–21] incidence (%)
Number (n)
Incidence (%)
8 7 5 4
50.00 43.75 31.25 25.00
34.1 21.0 48.4 10.5
4
25.00
23.2
4 3 3 3 2 1 1 1
25.00 18.75 18.75 18.75 12.50 6.25 6.25 6.25
19.6 28.4 32.6 46.0 23.3 18.6 8.6 8.1
3
showed the thrombosis on torcular, transverse sinus, and superior sagittal sinus (Fig. 4). Nine patients underwent DSA examinations, which showed a lack of blood vessels in both parietal lobes and capillary network problems in patients. All 16 patients underwent Doppler ultrasound examinations, which showed the decreased blood flow signals in internal jugular vein in patients. Echocardiography in one patient showed the aortic valve was clover shaped, and the valve thickness was 3.5 mm and its inner diameter was 2.1 cm, which is considered the formation of vegetation. 3.4. Histopathology Skin biopsies of the lateral malleolus were examined in 10 of the 16 patients. A piece of skin tissue with a diameter of 0.5 cm was obtained. A light microscope showed that inflammatory cells appeared around the walls of the small vessels in superficial dermis, with no thrombus in the vessels (Fig. 5A). Electron microscopy showed that the structure of the epithelial cells of the skin tissue was clear, capillary walls were thickened, and some small vessels were totally occluded (Fig. 5B). In addition, three patients underwent parietal lobe brain biopsy examination. A piece of brain parenchyma with a diameter of 0.3 cm was obtained. A light microscope showed focal softening, interstitial congestion blood, and focal hemorrhage in brain tissue (Fig. 6A). Electron microscopy showed substantial accumulation of erythrocyte among the brain cells outside the blood vessels in some areas of the brain tissue, a few focal degenerations of neurons, and demyelination of myelin (Fig. 6B). 3.5. Diagnosis and treatment The misdiagnosis rate of NAPS was 87.50%. Most patients were diagnosed with cerebral infarction, cerebral vasculitis, MS, migraine, intracranial infections, motor neuron disease, optic neuromyelitis etc. Anticoagulation therapy was administered to all patients, with eight patients receiving combined immunomodulatory therapy. The main drugs included aspirin, warfarin, glucocorticoids and azathioprine. Only one patient discontinued the treatment due to complications and rapid deterioration of his condition in the short term. After treatment, the remaining 15 patients were in remission. A follow-up showed that only two patients were hospitalized with recurrent relapses of the disease, while the others remained in a stable condition. 4. Discussion In this study, we found no significant differences in age, sex, disease duration, classification, and comorbidities at baseline between NAPS patients and RAPS patients. Our research indicated that the incident ratio of NAPS patients is 1:4.3 for men and women, with a mean age at onset of 37.56 ± 12.36 years, which corresponded with the findings of the European study that showed the incidence ratio for men and women was 1:4.5, with a mean age at onset of 42 ± 14 years [16]. Patients seem to accompany viral infections and autoimmune diseases before the development of NAPS. Our study showed that NAPS has a wide spectrum of clinical presentations, including cerebrovascular diseases such as cerebral infarction, transient ischemic attack, and cerebral venous sinus thrombosis (CVST). Some studies have found that venous thrombosis is common in the deep veins of the lower limbs and/or pulmonary embolism (PE), while arterial thrombosis is common in the cerebral vasculature and upper limbs [15,17]. Other manifestations of our NAPS patients included headache, cognitive disorders, epilepsy, MS-like syndrome, and ocular symptoms. Some neurological manifestations had been reported in previous article [18,19], but in the present study, headache ranked first in terms of incidence among all clinical manifestations, and cerebral infarction was the second most frequent clinical manifestations
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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Fig. 1. Multifocal cerebral infarction in brain white matter. A 36-year-old woman presented with repeated dizziness and right upper extremity uncoordinated activities three weeks. Neuroimaging showed new multifocal cerebral infarction. A, Multiple hypodensity lesions in bilateral basal ganglia on noncontrast CT. B, Hyperintense lesions in left caudate nucleus, internal capsule and frontal knee on the DWI MR image. C, Demyelinating lesions near the bilateral corn occipitale on the FLAIR MR image. D, No enhancement lesions on the Gd-enhanced MR image. E, Absence of left anterior cerebral artery A1 segment with the right posterior communicating artery opened on the MRA. F, DSA showed normal vascular in anterior circulation area.
observed in our NAPS patients, which was different with RAPS patients and literatures [16,20,21]. This may be caused by the study objects in NAPS group who were enrolled from neurology wards and usually had initial symptoms of CNS impairment, which increased the incidences of headache and cerebral infarction. These differences demonstrated that headache and cerebral infarction may be the predominant symptom and event in NAPS patients. Therefore, patients, especially those young female individuals, presented with headache and thromboembolic events without any other risk factors for stroke, should be considered to possibly have the disease of NAPS. Previous studies indicated that patients with thrombosis showed a higher amount of aPL than normal, and the positive correlation between
thrombosis risk and antibody titers strengthened this causal connection [22,23]. Several clinical studies have consistently reported that LA is a stronger risk factor than aCL and anti-β2GPI for both arterial and venous thrombosis [17]. On the contrary, the current laboratory analysis found that aCL and anti-β2GPI are relatively sensitive indicators for NAPS patients. Our study also found that NAPS patients may show a lower than normal platelet count in the CBC test. In addition, the NAPS patients showed ANA, anti-DNA antibody, and RF positivity. These patients should be followed up closely in order to discriminate between NAPS and other autoimmune disorders. Intracranial hypertension was usually observed during lumbar puncture examination, while tests for proteins, cytological examination, and biochemical, oligoclonal band,
Fig. 2. Multifocal cerebral infarction in brain cortex. A 21-year-old woman presented with occipital pain and blurred vision three days. Neuroimaging showed cerebral infarction in bilateral occipital cortex. A, Hypointense lesions on the T1WI MR image. B, Hyperintense lesions on the T2WI MR image. C, No enhancement lesions on the Gd-enhanced MR image. D, Hyperintense lesions on the DWI MR image. E, DSA showed the formation of microvascular network in posterior circulation area.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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Fig. 3. Repeated demyelization of white matter in subcortex. A 28-year-old woman presented with headache associated with memory descent three years. Neuroimaging showed repeated demyelinating lesions in white matter. Part of the lesions disappeared with new lesions appeared between 2010 (A, B, C, D, E) and 2013 (F, G, H, I, J) on the Flair MR image. K, MRA showed normal vascular. L, DSA indicated deficient vascular area in bilateral frontal and parietal lobes.
and immunologic tests all yielded normal results in this study. We found that all laboratory features of NAPS help in its differentiation from MS, central nervous system vasculitis, encephalitis, and meningeal carcinomatosis. In the present study, multiple subcortical and cortical infarcts and demyelination, which commonly involved both lobes of the brain and asymmetrically, were the imaging characteristics of NAPS patients.
Previous studies found that some APS patients had frequent asymptomatic white matter lesions and cerebral ischemic lesions (silent brain infarcts) on routine MRI, and that routine cognitive function testing revealed asymptomatic dysfunction; it also showed that white matter hyperintensity on MRI may be related to underlying attentional and executive cognitive impairment in APS [24–26]. No enhanced lesions were found on Gd-enhanced MRI in our patient, possibly because the
Fig. 4. Thrombosis of venous sinus. A 45-year-old man presented with headache associated with conscious dysfunction three days. Neuroimaging showed the superior sagittal sinus thrombosis. A, Hopyintense lesions in frontal and parietal lobes on the T1WI MR image. B, Hyperintense lesions on the T2WI MR image. C, No enhancement lesions on Gd-enhanced MR image. D: MRV showed low blood flow signal in the anterior superior sagittal sinus. E: DSA indicated deficient vascular area in bilateral parietal lobes.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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Fig. 5. Skin biopsy. Skin biopsies of lateral malleolus. A, A light microscope indicated inflammatory cells around the walls of small vessels in superficial dermis; no thrombus was observed (hematoxylin–eosin, original manification ×40). B, Electron microscopy indicated the structure of the epithelial cells was clear; capillary walls were thickened and some small vessels were totally occluded (uranium–lead, original manification ×2500).
pathological changes caused by aPL mostly affect blood circulation and result in a hypercoagulable state, while injury to vascular endothelial cells is not serious, so the blood–brain barrier (BBB) remains intact. The medium and large intracranial arteries could easily be involved in stenosis, especially in the middle cerebral artery; further, small vascular stenosis and occlusions were found on DSA in the NAPS patients. The lesions in our NAPS patients distributed multiply and asymmetrically and they could not be explained by any single-vessel mechanism; therefore, DSA may be effective in detecting the responsible vessels in patients with multifocal vascular stenosis. Echocardiography can frequently detect heart valve lesions (vegetations, valve thickening, and dysfunction) in APS, but the association of these lesions with aPL remains unclear [15]. There is evidence that aPL is a risk factor for stroke, and the mechanisms of ischemic stroke are considered to be thrombotic and embolic [27]. Additionally, multifocal lesions may be related to microvascular thrombosis or immune pathogenesis [28–30]. In our study, skin and brain biopsies suggested that APS-related cerebral infarction or ischemia was mainly presented as microangiopathy, with inflammatory cell infiltration, erythrocyte accumulation, neuron degeneration and local demyelization. Our study indicated that the damage to different target organs in different period may differ in some degree. Skin biopsy showed the primary pathological change in small vessel, and brain biopsy indicated the secondly pathological change in neuron and myelin. Both of them revealed the pathological characters of NAPS. These pathological characteristics may play a role in differentiation from cerebral vasculitis. Previous study showed that microvascular involvement may be the most common pathological finding in patients affected by the catastrophic variant of the syndrome [31]. Because brain biopsy examination is an invasive method, APS patients rarely agree to have it done. In contrast, skin biopsy examination is minimally invasive and therefore convenient to perform on patients.
Skin biopsy examination has played an important role in the diagnosis of small vessel diseases and in differentiating them from other connective tissue diseases. Further, peripheral neuropathy is a common asymptomatic abnormality in patients with PAPS [32]. Microvascular thrombosis in APS may be a potential cause of multiorgan failure including, but not limited to, the lungs, brain, and kidneys [15]. Some studies reported the hemorrhagic complication of APS, for instance of the bleeding in adrenal gland or lung, which are somewhat mysterious and in need of explanation [33]. Whether the brain lesion in our study reflects the same pathology of hemorrhagic in other organ needs further research. We suggest that skin biopsy examination should be routinely performed while evaluating patients in whom NAPS is suspected. Treatment with antithrombotic therapy and immunotherapy was effective in NAPS patients. We suggest that NAPS patients with thrombosis should receive aggressive antithrombotic therapy, although the optimal time and duration of treatment remain unclear. Studies have shown that some patients may benefit from treatment with statins and hydroxychloroquine [34–36]. In addition to conventional therapy, long-term treatment with intravenous immunoglobulin has been found to be effective in preventing recurrent thrombosis [37,38]. This study had some limitations. First, the small sample size limits to draw a solid conclusion. Second, brain biopsy was examined only in three patients in this study, and, examination of many more biopsy specimens is necessary to accurately understand the pathological features of NAPS. Third, this study was a retrospective analysis. Further follow-up study is needed to confirm the results. 5. Conclusion In sum, NAPS mostly affects young female individuals, with initial symptom of headache and thromboembolic events which are more
Fig. 6. Brain biopsy. Brain biopsy of parietal lobe. A, A light microscope indicated focal softening, interstitial stagnant blood and focal hemorrhage (hematoxylin–eosin, original manification ×40). B, Electron microscopy indicated erythrocyte overriding among brain cells, neuron degeneration and demyelization (uranium–lead, original manification ×2500).
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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common in NAPS than RAPS during the disease course. Neuroimaging and biopsy examination demonstrated that NAPS is an ischemic cerebrovascular disease caused by vascular stenosis or occlusion. However, the mechanisms underlying NAPS occurrence are not yet clear, and the definitive pathological criteria have not been established. Basic and clinical research is still urgently needed to reduce the misdiagnosis of NAPS. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgment This study was supported by grants from the State Key Program of National Natural Science Foundation of China (No. 81230027), the National Natural Science Foundation of China (No. 81070959), the Science and Technology Key Project of Shanghai (No. 11411950300), and the Technology Support Project of Shanghai (No. 14140903300). References [1] Gomez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 2014;48–49:20–5. [2] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (aps). J Thromb Haemost 2006;4:295–306. [3] Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309–11. [4] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic Antiphospholipid Syndrome Registry Project G. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [5] Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GR. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287:1021–3. [6] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al. On behalf of the Euro-Phospholipid Project G. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2014 Jan 24. http://dx.doi.org/10.1136/ annrheumdis-2013-204838 [Epub ahead of print]. [7] Matyja-Bednarczyk A, Swadzba J, Iwaniec T, Sanak M, Dziedzina S, Cmiel A, et al. Risk factors for arterial thrombosis in antiphospholipid syndrome. Thromb Res 2014; 133:173–6. [8] Ziporen L, Polak-Charcon S, Korczyn DA, Goldberg I, Afek A, Kopolovic J, et al. Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model. Clin Dev Immunol 2004; 11:67–75. [9] Nalli C, Andreoli L, Casu C, Tincani A. Management of recurrent thrombosis in antiphospholipid syndrome. Curr Rheumatol Rep 2014;16:405. [10] Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th international congress on antiphospholipid antibodies task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014;13:685–96. [11] Muscal E, Brey RL. Neurological manifestations of the antiphospholipid syndrome: risk assessments and evidence-based medicine. Int J Clin Pract 2007;61:1561–8. [12] Erkan D, Lockshin MD. Aps action–antiphospholipid syndrome alliance for clinical trials and international networking. Lupus 2012;21:695–8. [13] Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration of anticoagulation therapy in antiphospholipid syndrome. Semin Thromb Hemost 2012;38:339–47. [14] Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Antiprothrombin (apt) and anti-phosphatidylserine/prothrombin (aps/pt) antibodies
[15]
[16]
[17] [18] [19]
[20]
[21]
[22] [23]
[24] [25]
[26]
[27] [28]
[29] [30] [31]
[32] [33] [34]
[35]
[36]
[37]
[38]
7
and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost 2014;111:354–64. Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. British Committee for Standards in H. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012;157:47–58. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. EuroPhospholipid Project G: antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019–27. Favaloro EJ, Wong RC. The antiphospholipid syndrome: diagnosis, pathogenesis, laboratory testing, and management. Semin Thromb Hemost 2012;38:299–304. Suarez AL, Hughes GR, Khamashta MA. Neurological manifestations of the antiphospholipid syndrome. Med Clin (Barc) 2005;124:630–3. Bertero MT, Bazzan M, Carignola R, Montaruli B, Silvestro E, Sciascia S, et al. Antiphospholipid syndrome in northwest Italy (aps piedmont cohort): demographic features, risk factors, clinical and laboratory profile. Lupus 2012;21:806–9. Etemadifar M, Dehghani L, Tahani S, Toghianifar N, Rahaimi M, Eskandari N. Neurological manifestations in patients with antiphospholipid syndrome. Iran J Neurol 2013;12:172–5. Marchetti T, Cohen M, Gris JC, de Moerloose P. Diagnosis and management of obstetrical antiphospholipid syndrome: where do we stand? Pol Arch Med Wewn 2013; 123:713–20. De Groot PG, Meijers JC, Urbanus RT. Recent developments in our understanding of the antiphospholipid syndrome. Int J Lab Hematol 2012;34:223–31. Du VX, Kelchtermans H, de Groot PG, de Laat B. From antibody to clinical phenotype, the black box of the antiphospholipid syndrome: pathogenic mechanisms of the antiphospholipid syndrome. Thromb Res 2013;132:319–26. Erkan D, Kozora E, Lockshin MD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology 2011;18:93–102. Gomez-Puerta JA, Cervera R, Calvo LM, Gomez-Anson B, Espinosa G, Claver G, et al. Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients. Rheumatology (Oxford) 2005;44:95–9. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006;166: 2278–84. Panichpisal K, Rozner E, Levine SR. The management of stroke in antiphospholipid syndrome. Curr Rheumatol Rep 2012;14:99–106. Nishimura M, Nii T, Trimova G, Miura S, Umezawa K, Ushiyama A, et al. The NFkappaB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathol 2013;2:114–21. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis in antiphospholipid antibody syndrome. J Autoimmun 2010;35:248–55. Oku K, Amengual O, Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. Eur J Clin Invest 2012;42:1126–35. Taraborelli M, Andreoli L, Tincani A. Much more than thrombosis and pregnancy loss: the antiphospholipid syndrome as a 'systemic disease'. Best Pract Res Clin Rheumatol 2012;26:79–90. Santos MS, de Carvalho JF, Brotto M, Bonfa E, Rocha FA. Peripheral neuropathy in patients with primary antiphospholipid (Hughes') syndrome. Lupus 2010;19:583–90. Forastiero R. Bleeding in the antiphospholipid syndrome. Hematology 2012; 17(Suppl. 1):S153–5. Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, Barbarroja N, Perez-Sanchez C, Buendia P, et al. Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis 2011;70:675–82. Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, Rodriguez-Ariza A, Cuadrado MJ. Potential use of statins in the treatment of antiphospholipid syndrome. Curr Rheumatol Rep 2012;14:87–94. Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost 2013;11:1927–9. Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol 2012;30:409–13. Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82.
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Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics De-Sheng Zhu a, Jue Fu b, Yue Zhang c, Shi-Xu Li c, Guang-Xian Zhang d, Yang-Tai Guan c,⁎, Qiang Dong a,⁎⁎ a
Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China Department of Pathology, Fuzhou Medical College of Nanchang University, Fuzhou 344000, China Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China d Department of Neurology, Thomas Jefferson University, PA 19107, USA b c
a r t i c l e
i n f o
Article history: Received 12 July 2014 Received in revised form 24 July 2014 Accepted 4 August 2014 Available online xxxx Keywords: Antiphospholipid syndrome Antiphospholipid antibodies Clinical features Neuroimaging Pathology Central nervous system
a b s t r a c t Background: Neurological antiphospholipid syndrome (NAPS) is often misdiagnosed or missed. Only limited clinical and neuroimaging information about it is available, and the pathological characteristics was rarely reported before. This study aimed to explore the clinical, neuroimaging, and pathological characteristics of NAPS. Methods: We performed a retrospective analysis of 51 patients with APS, categorized into NAPS (n = 16) and rheumatology antiphospholipid syndrome (RAPS) groups (n = 35). Demographics and clinical profile were compared between the two groups, and the neuroimaging and pathological information of NAPS was also analyzed. Results: The mean age of the NAPS patients, 81.25% of whom were female, was 37.56 ± 12.36 years, and the average duration was 1.32 ± 0.96 years (range = 18 days to 3.5 years). No significant differences in age, sex, disease duration, classification, and comorbidities at baseline were observed between NAPS and RAPS patients (p N 0.05). Chief complaint of headache and thromboembolic events was higher in NAPS patients than in RAPS patients (p b 0.05). Neuroimaging detected multiple infarcts and demyelination lesions were distributed in subcortical and cortical area asymmetrically. Skin biopsy examination showed small vessel occlusion with inflammatory cells, while brain biopsy examination showed erythrocyte accumulation with some neuron degeneration and local demyelization. Antithrombotic and immunosuppressive therapy proved to be effective. Conclusion: Headache and thromboembolic events are more common in NAPS than RAPS. Neuroimaging and biopsy examination demonstrated that NAPS is an ischemic cerebrovascular disease caused by vascular stenosis or occlusion. These characteristics might help to reduce the misdiagnosis of NAPS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Antiphospholipid syndrome (APS) is a multisystem autoimmune disease characterized by the production of antiphospholipid antibodies (aPL), which promote recurrent vascular thrombosis (venous, arterial, and microvascular) and/or pregnancy complications and failure, frequently accompanied by moderate thrombocytopenia [1]. Presence of aPL in serum, including anticardiolipin antibody (aCL), lupus anticoagulant (LA), and anti-β2 glycoprotein-I antibody (anti-β2GPI), is a characteristic indicator of APS [2]. The preliminary classification criteria for APS were formulated during a post-conference workshop held on October 10, 1998, in Sapporo, ⁎ Correspondence to: Y.-T. Guan, Department of Neurology, Changhai Hospital, Second Military Medical University, No. 168, Changhai Road, Shanghai 200433, China. Tel.: +86 13386271865; fax: +86 21 64085875. ⁎⁎ Correspondence to: Q. Dong, Department of Neurology, Huashan Hospital, Fudan University, No. 12, Mid. Wulumuqi Road, Shanghai 200040, China. Tel.: + 86 13701747065; fax: + 86 21 64085875. E-mail addresses: [email protected] (Y.-T. Guan), [email protected] (Q. Dong).
Japan [3]. In 2006, revisions to the classification and diagnostic criteria for APS were proposed in Sydney [2]. The disease is classified into primary antiphospholipid syndrome (PAPS), secondary antiphospholipid syndrome (SAPS), and catastrophic antiphospholipid syndrome (CAPS), a relatively rare subtype [4]. APS, which was first reported by Hughes in 1983 [5], had been reported by doctors specializing in rheumatology, obstetrics and gynecology, and vascular surgery. Some estimates indicate that the incidence of the APS is around five new cases per 100,000 persons per year, and the prevalence is around 40–50 cases per 100,000 persons [1]. Thrombosis is one of the prominent clinical features of APS. According to an observational study of 1000 APS patients in 13 European countries, thrombotic events appeared in 166 (16.6%) patients during the first 5-year study period and in 115 (14.4%) during the second 5-year period [6]. APS patients with aCL who suffer from hypertension and hypertriglyceridaemia are at increased risk of arterial thrombosis [7]. Currently, however, literature describing the neuroimaging characteristics of APS is limited, and few studies, both domestically and internationally, have examined the brain biopsies of APS patients. Some studies on the pathological features of APS have been conducted but
http://dx.doi.org/10.1016/j.jns.2014.08.010 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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D.-S. Zhu et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
only in experimental animals. The main finding from examination of cortical tissue from APS mice was the thrombotic occlusion of capillaries in combination with mild inflammation [8]. One distinct pathological feature of APS appears to be intravascular thrombus formation in all vessels of all levels instead of vasculitis, but this finding cannot be considered a uniform pathological diagnostic criterion. Current treatment guidelines for APS emphasize the importance of early diagnosis and recommend aggressive therapies to alleviate damage to the CNS, especially to prevent recurrence of thrombosis [9–11]. However, the intensity and duration of anticoagulation therapy in APS syndrome have been debated for long [12–14]. Treatment for recurrent thrombosis in APS patients requires further clarification, since pathological studies on APS patients are scarce. APS often affects the central nervous system (CNS) and causes cerebral infarction, epilepsy, and consciousness disorder or limb dysfunction [15]. Research on rheumatology antiphospholipid syndrome (RAPS) is common; few studies thus far have conducted a detailed investigation of neurological antiphospholipid syndrome (NAPS), and the available information, from clinical features to the imaging and pathological characteristics of NAPS, is limited. Sophisticated neuroimaging techniques, including CT, MRI, DSA, and Doppler ultrasound, would facilitate us a better understanding of NAPS. The aim of the present study is to explore the clinical features and imaging and pathological characteristics of NAPS via a retrospective analysis of clinical data. 2. Patients and methods
2.4. Statistical analysis Categorical variables were presented as counts and percentages and analyzed by Fisher's exact test or the Chi-square test. Continuous variable was reported as means and standard deviation (normal distribution) and analyzed by the independent-t-tests. Statistical analyses were performed using Statistical Package of the Social Sciences Software version 16.0 (SPSS, Chicago, IL, USA), setting the level of significance at a two-tailed p-value of b0.05. 3. Results 3.1. Demographics The demographic and clinical profiles of the patients are presented in Table 1. The mean age of the NAPS patients, 81.25% of whom were female, was 37.56 ± 12.36 years. The average disease duration of the NAPS patients was 1.32 ± 0.96 years (range = 18 days to 3.5 years). Six patients were accompanied by a history of autoimmune diseases and viral infections (37.5%). No significant differences in age, sex, disease duration, classification, and comorbidities at baseline were observed between two groups. Chief complaint of headache was higher and limb weakness was lower in NAPS patients than in RAPS patients (p b 0.05). NAPS patients showed more thromboembolic events than RAPS patients (p b 0.01). Misdiagnosis before confirm was higher in NAPS patients than in RAPS patients (p b 0.01).
2.1. Patients We performed a retrospective analysis of all patients with APS from neurology wards and rheumatology wards of Huashan Hospital and Changhai Hospital between January 2008 and December 2013. In this study, 51 patients with APS were enrolled and followed up at least six months, including 16 patients who had symptoms of CNS impairment from neurology wards and 35 patients from rheumatology wards. All patients had been diagnosed with APS on the basis of the criteria proposed in 2006 in Sydney [2]. This study only included APS patients with LA, aCL and anti-β2GPI antibody of IgG and/or IgM isotype in serum or plasma, on two or more occasions at least 12 weeks apart, measured by an inhibitor of phospholipid-dependent clotting or standardized ELISA according to the criteria. 2.2. Clinical information Retrospective analyses were performed on the following information: (1) Demographic information (gender, age, disease duration before hospitalization, and medical and pregnancy history); (2) initial symptoms (headache, limbs weakness, cognition disorder, elapse and thrombosis); (3) biochemical indicators (aCL, LA, anti-β2GPI, antinuclear antibody (ANA), and anti-double-stranded-DNA (dsDNA) and anti-ssDNA (ssDNA) antibodies; rheumatoid arthritis (RA); complete blood count (CBC); international normalized ratio (INR); prothrombin time (PT); partial prothrombin time (APTT); erythrocyte sedimentation rate (ESR); C-reactive protein (CRP); and findings of cerebrospinal fluid (CSF) examination); (4) neuroimaging (cranial computed tomography (CT); magnetic resonance imaging (MRI); digital subtraction angiography (DSA); echocardiography; and cervical vascular ultrasound); (5) pathological features (brain biopsy and skin biopsy); and (6) therapy (antiplatelet drugs, anticoagulants, glucocorticoids, and immunosuppressive agents). 2.3. Ethics This study was approved by the institutional review board of Huashan Hospital, Fudan University (Shanghai, China).
3.2. Clinical manifestations, thromboembolic events and laboratory analysis Data of NAPS patients on the initial symptoms, thromboembolic events, and results of laboratory tests are presented in Table 2. The most common initial symptoms were headache, and limb weakness. Clinical manifestations of NAPS patients during the course were complex and varied. The incidence of headache and that of cerebral infarction were ranked in the first and second respectively in this study, which was different with foreign literature. A comparison of the incidence of clinical manifestations between our study and that reported in foreign literature is presented in Table 3 [6–10]. Laboratory analysis of NAPS patients showed that one patient was rheumatoid factor positive, two patients were dsDNA and ssDNA antibody positive, and one patient was anti-smooth muscle antibody positive. CRP and ESR were higher than normal in two patients. CBC showed that the platelet count was lower than normal in five patients (31.25%). CSF examination showed that the CSF pressure was higher in three patients (37.5%), and that the erythrocyte count was higher
Table 1 Demographics and clinical profile of the study objects. Information
NAPS (n = 16)
RAPS (n = 35)
P-value
Age (years) Sex (male/female) Disease duration (years) Classification (PAPS/SAPS) Comorbidities at baseline SLE, RA, SS Miscarriages, preeclampsia Herpes zoster, viral influenza Chief complaint Headache Limb weakness Thromboembolic events Misdiagnosis before confirm
37.56 ± 12.36 3/13 1.32 ± 0.96 12/4
40.57 ± 7.28 7/28 2.04 ± 1.35 23/12
0.377 1.000 0.061 0.746
4 (25%) 3 (18.75%) 2 (12.5%)
12 (34.28%) 5 (14.28%) 5 (14.28%)
0.746 0.694 1.000
8 (50%) 6 (33.33%) 12 (75%) 14 (87.50%)
7 (20%) 25 (71.43%) 8 (22.86%) 6 (17.14%)
0.029 0.021 0.001 0.000
NAPS: neurological antiphospholipid syndrome, RAPS: rheumatology antiphospholipid syndrome.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
D.-S. Zhu et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx Table 2 Initial symptoms, thromboembolic events and aPL antibody analysis of NAPS patients. Initial symptoms Headache Limb weakness Episodes of unconsciousness Paroxysmal convulsion Blurred vision Dizziness Cognitive disorders Thromboembolic events Arterial thrombosis Venous thrombosis Micro thrombus aPL-antibody analysis aCL positive aβ2GP-I positive LA positive aCL + aβ2GP-I positive
8 (50.00%) 6 (37.50%) 4 (25.00%) 4 (25.00%) 3 (18.75%) 2 (12.50%) 2 (12.50%) 5 (31.25%) 4 (25.00%) 3 (18.75%) 12 (75.00%) 6 (37.50%) 3 (18.75%) 4 (25.00%)
than normal in one patient (12.5%). The leukocyte number, CSF protein level, and the 24 h IgG synthesis rate were within the normal ranges, and oligoclonal bands were not found in any patient (100%).
3.3. Neuroimaging results The neuroimaging data in our study showed that the main characteristics of NAPS in the brain are ischemic changes such as multifocal cerebral infarctions, white matter demyelination, and cerebral atrophy. All NAPS patients underwent Cranial CT and MRI evaluation. Multiple new cerebral infarctions were concentrated in the periventricular white matter on CT plain (Fig. 1). Computed tomography angiography (CTA) showed stenosis or occlusion in anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) and their branches. MRI lesions, including lacunar infarctions and large area infarctions, were detected in basal ganglia and cerebral cortex (Fig. 2). Local brain tissue atrophy and widened cerebral fissures were also detected in some patients. White matter demyelination lesions, which widely distributed in the cerebral cortex, subcortex, periventricular and basal ganglia on FLAIR MRI. Different signs showed the characteristic of relapsing–remitting lesions (Fig. 3). No enhanced lesions were found with Gd-enhanced MRI in any patient. Magnetic resonance angiography (MRA) showed stenosis or occlusion in middle or anterior cerebral artery and its branches unilaterally. Magnetic resonance venography (MRV)
Table 3 Comparison of the incidence of clinical manifestations between NAPS patients in our study and foreign literature (%). Clinical manifestations
Headache Cerebral infarction Thrombocytopenia Transient ischemic attack (TIA) Cerebral venous sinus thrombosis Epilepsy Limb phlebothrombosis Cognition disorders Abortion Preeclampsia Valvular heart disease Skin ulcer Foot gangrene
In this study
Literature [6,16,19–21] incidence (%)
Number (n)
Incidence (%)
8 7 5 4
50.00 43.75 31.25 25.00
34.1 21.0 48.4 10.5
4
25.00
23.2
4 3 3 3 2 1 1 1
25.00 18.75 18.75 18.75 12.50 6.25 6.25 6.25
19.6 28.4 32.6 46.0 23.3 18.6 8.6 8.1
3
showed the thrombosis on torcular, transverse sinus, and superior sagittal sinus (Fig. 4). Nine patients underwent DSA examinations, which showed a lack of blood vessels in both parietal lobes and capillary network problems in patients. All 16 patients underwent Doppler ultrasound examinations, which showed the decreased blood flow signals in internal jugular vein in patients. Echocardiography in one patient showed the aortic valve was clover shaped, and the valve thickness was 3.5 mm and its inner diameter was 2.1 cm, which is considered the formation of vegetation. 3.4. Histopathology Skin biopsies of the lateral malleolus were examined in 10 of the 16 patients. A piece of skin tissue with a diameter of 0.5 cm was obtained. A light microscope showed that inflammatory cells appeared around the walls of the small vessels in superficial dermis, with no thrombus in the vessels (Fig. 5A). Electron microscopy showed that the structure of the epithelial cells of the skin tissue was clear, capillary walls were thickened, and some small vessels were totally occluded (Fig. 5B). In addition, three patients underwent parietal lobe brain biopsy examination. A piece of brain parenchyma with a diameter of 0.3 cm was obtained. A light microscope showed focal softening, interstitial congestion blood, and focal hemorrhage in brain tissue (Fig. 6A). Electron microscopy showed substantial accumulation of erythrocyte among the brain cells outside the blood vessels in some areas of the brain tissue, a few focal degenerations of neurons, and demyelination of myelin (Fig. 6B). 3.5. Diagnosis and treatment The misdiagnosis rate of NAPS was 87.50%. Most patients were diagnosed with cerebral infarction, cerebral vasculitis, MS, migraine, intracranial infections, motor neuron disease, optic neuromyelitis etc. Anticoagulation therapy was administered to all patients, with eight patients receiving combined immunomodulatory therapy. The main drugs included aspirin, warfarin, glucocorticoids and azathioprine. Only one patient discontinued the treatment due to complications and rapid deterioration of his condition in the short term. After treatment, the remaining 15 patients were in remission. A follow-up showed that only two patients were hospitalized with recurrent relapses of the disease, while the others remained in a stable condition. 4. Discussion In this study, we found no significant differences in age, sex, disease duration, classification, and comorbidities at baseline between NAPS patients and RAPS patients. Our research indicated that the incident ratio of NAPS patients is 1:4.3 for men and women, with a mean age at onset of 37.56 ± 12.36 years, which corresponded with the findings of the European study that showed the incidence ratio for men and women was 1:4.5, with a mean age at onset of 42 ± 14 years [16]. Patients seem to accompany viral infections and autoimmune diseases before the development of NAPS. Our study showed that NAPS has a wide spectrum of clinical presentations, including cerebrovascular diseases such as cerebral infarction, transient ischemic attack, and cerebral venous sinus thrombosis (CVST). Some studies have found that venous thrombosis is common in the deep veins of the lower limbs and/or pulmonary embolism (PE), while arterial thrombosis is common in the cerebral vasculature and upper limbs [15,17]. Other manifestations of our NAPS patients included headache, cognitive disorders, epilepsy, MS-like syndrome, and ocular symptoms. Some neurological manifestations had been reported in previous article [18,19], but in the present study, headache ranked first in terms of incidence among all clinical manifestations, and cerebral infarction was the second most frequent clinical manifestations
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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Fig. 1. Multifocal cerebral infarction in brain white matter. A 36-year-old woman presented with repeated dizziness and right upper extremity uncoordinated activities three weeks. Neuroimaging showed new multifocal cerebral infarction. A, Multiple hypodensity lesions in bilateral basal ganglia on noncontrast CT. B, Hyperintense lesions in left caudate nucleus, internal capsule and frontal knee on the DWI MR image. C, Demyelinating lesions near the bilateral corn occipitale on the FLAIR MR image. D, No enhancement lesions on the Gd-enhanced MR image. E, Absence of left anterior cerebral artery A1 segment with the right posterior communicating artery opened on the MRA. F, DSA showed normal vascular in anterior circulation area.
observed in our NAPS patients, which was different with RAPS patients and literatures [16,20,21]. This may be caused by the study objects in NAPS group who were enrolled from neurology wards and usually had initial symptoms of CNS impairment, which increased the incidences of headache and cerebral infarction. These differences demonstrated that headache and cerebral infarction may be the predominant symptom and event in NAPS patients. Therefore, patients, especially those young female individuals, presented with headache and thromboembolic events without any other risk factors for stroke, should be considered to possibly have the disease of NAPS. Previous studies indicated that patients with thrombosis showed a higher amount of aPL than normal, and the positive correlation between
thrombosis risk and antibody titers strengthened this causal connection [22,23]. Several clinical studies have consistently reported that LA is a stronger risk factor than aCL and anti-β2GPI for both arterial and venous thrombosis [17]. On the contrary, the current laboratory analysis found that aCL and anti-β2GPI are relatively sensitive indicators for NAPS patients. Our study also found that NAPS patients may show a lower than normal platelet count in the CBC test. In addition, the NAPS patients showed ANA, anti-DNA antibody, and RF positivity. These patients should be followed up closely in order to discriminate between NAPS and other autoimmune disorders. Intracranial hypertension was usually observed during lumbar puncture examination, while tests for proteins, cytological examination, and biochemical, oligoclonal band,
Fig. 2. Multifocal cerebral infarction in brain cortex. A 21-year-old woman presented with occipital pain and blurred vision three days. Neuroimaging showed cerebral infarction in bilateral occipital cortex. A, Hypointense lesions on the T1WI MR image. B, Hyperintense lesions on the T2WI MR image. C, No enhancement lesions on the Gd-enhanced MR image. D, Hyperintense lesions on the DWI MR image. E, DSA showed the formation of microvascular network in posterior circulation area.
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Fig. 3. Repeated demyelization of white matter in subcortex. A 28-year-old woman presented with headache associated with memory descent three years. Neuroimaging showed repeated demyelinating lesions in white matter. Part of the lesions disappeared with new lesions appeared between 2010 (A, B, C, D, E) and 2013 (F, G, H, I, J) on the Flair MR image. K, MRA showed normal vascular. L, DSA indicated deficient vascular area in bilateral frontal and parietal lobes.
and immunologic tests all yielded normal results in this study. We found that all laboratory features of NAPS help in its differentiation from MS, central nervous system vasculitis, encephalitis, and meningeal carcinomatosis. In the present study, multiple subcortical and cortical infarcts and demyelination, which commonly involved both lobes of the brain and asymmetrically, were the imaging characteristics of NAPS patients.
Previous studies found that some APS patients had frequent asymptomatic white matter lesions and cerebral ischemic lesions (silent brain infarcts) on routine MRI, and that routine cognitive function testing revealed asymptomatic dysfunction; it also showed that white matter hyperintensity on MRI may be related to underlying attentional and executive cognitive impairment in APS [24–26]. No enhanced lesions were found on Gd-enhanced MRI in our patient, possibly because the
Fig. 4. Thrombosis of venous sinus. A 45-year-old man presented with headache associated with conscious dysfunction three days. Neuroimaging showed the superior sagittal sinus thrombosis. A, Hopyintense lesions in frontal and parietal lobes on the T1WI MR image. B, Hyperintense lesions on the T2WI MR image. C, No enhancement lesions on Gd-enhanced MR image. D: MRV showed low blood flow signal in the anterior superior sagittal sinus. E: DSA indicated deficient vascular area in bilateral parietal lobes.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
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Fig. 5. Skin biopsy. Skin biopsies of lateral malleolus. A, A light microscope indicated inflammatory cells around the walls of small vessels in superficial dermis; no thrombus was observed (hematoxylin–eosin, original manification ×40). B, Electron microscopy indicated the structure of the epithelial cells was clear; capillary walls were thickened and some small vessels were totally occluded (uranium–lead, original manification ×2500).
pathological changes caused by aPL mostly affect blood circulation and result in a hypercoagulable state, while injury to vascular endothelial cells is not serious, so the blood–brain barrier (BBB) remains intact. The medium and large intracranial arteries could easily be involved in stenosis, especially in the middle cerebral artery; further, small vascular stenosis and occlusions were found on DSA in the NAPS patients. The lesions in our NAPS patients distributed multiply and asymmetrically and they could not be explained by any single-vessel mechanism; therefore, DSA may be effective in detecting the responsible vessels in patients with multifocal vascular stenosis. Echocardiography can frequently detect heart valve lesions (vegetations, valve thickening, and dysfunction) in APS, but the association of these lesions with aPL remains unclear [15]. There is evidence that aPL is a risk factor for stroke, and the mechanisms of ischemic stroke are considered to be thrombotic and embolic [27]. Additionally, multifocal lesions may be related to microvascular thrombosis or immune pathogenesis [28–30]. In our study, skin and brain biopsies suggested that APS-related cerebral infarction or ischemia was mainly presented as microangiopathy, with inflammatory cell infiltration, erythrocyte accumulation, neuron degeneration and local demyelization. Our study indicated that the damage to different target organs in different period may differ in some degree. Skin biopsy showed the primary pathological change in small vessel, and brain biopsy indicated the secondly pathological change in neuron and myelin. Both of them revealed the pathological characters of NAPS. These pathological characteristics may play a role in differentiation from cerebral vasculitis. Previous study showed that microvascular involvement may be the most common pathological finding in patients affected by the catastrophic variant of the syndrome [31]. Because brain biopsy examination is an invasive method, APS patients rarely agree to have it done. In contrast, skin biopsy examination is minimally invasive and therefore convenient to perform on patients.
Skin biopsy examination has played an important role in the diagnosis of small vessel diseases and in differentiating them from other connective tissue diseases. Further, peripheral neuropathy is a common asymptomatic abnormality in patients with PAPS [32]. Microvascular thrombosis in APS may be a potential cause of multiorgan failure including, but not limited to, the lungs, brain, and kidneys [15]. Some studies reported the hemorrhagic complication of APS, for instance of the bleeding in adrenal gland or lung, which are somewhat mysterious and in need of explanation [33]. Whether the brain lesion in our study reflects the same pathology of hemorrhagic in other organ needs further research. We suggest that skin biopsy examination should be routinely performed while evaluating patients in whom NAPS is suspected. Treatment with antithrombotic therapy and immunotherapy was effective in NAPS patients. We suggest that NAPS patients with thrombosis should receive aggressive antithrombotic therapy, although the optimal time and duration of treatment remain unclear. Studies have shown that some patients may benefit from treatment with statins and hydroxychloroquine [34–36]. In addition to conventional therapy, long-term treatment with intravenous immunoglobulin has been found to be effective in preventing recurrent thrombosis [37,38]. This study had some limitations. First, the small sample size limits to draw a solid conclusion. Second, brain biopsy was examined only in three patients in this study, and, examination of many more biopsy specimens is necessary to accurately understand the pathological features of NAPS. Third, this study was a retrospective analysis. Further follow-up study is needed to confirm the results. 5. Conclusion In sum, NAPS mostly affects young female individuals, with initial symptom of headache and thromboembolic events which are more
Fig. 6. Brain biopsy. Brain biopsy of parietal lobe. A, A light microscope indicated focal softening, interstitial stagnant blood and focal hemorrhage (hematoxylin–eosin, original manification ×40). B, Electron microscopy indicated erythrocyte overriding among brain cells, neuron degeneration and demyelization (uranium–lead, original manification ×2500).
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010
D.-S. Zhu et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
common in NAPS than RAPS during the disease course. Neuroimaging and biopsy examination demonstrated that NAPS is an ischemic cerebrovascular disease caused by vascular stenosis or occlusion. However, the mechanisms underlying NAPS occurrence are not yet clear, and the definitive pathological criteria have not been established. Basic and clinical research is still urgently needed to reduce the misdiagnosis of NAPS. Conflict of interest The authors declare that they have no conflict of interest. Acknowledgment This study was supported by grants from the State Key Program of National Natural Science Foundation of China (No. 81230027), the National Natural Science Foundation of China (No. 81070959), the Science and Technology Key Project of Shanghai (No. 11411950300), and the Technology Support Project of Shanghai (No. 14140903300). References [1] Gomez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 2014;48–49:20–5. [2] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (aps). J Thromb Haemost 2006;4:295–306. [3] Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309–11. [4] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic Antiphospholipid Syndrome Registry Project G. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [5] Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GR. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287:1021–3. [6] Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al. On behalf of the Euro-Phospholipid Project G. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2014 Jan 24. http://dx.doi.org/10.1136/ annrheumdis-2013-204838 [Epub ahead of print]. [7] Matyja-Bednarczyk A, Swadzba J, Iwaniec T, Sanak M, Dziedzina S, Cmiel A, et al. Risk factors for arterial thrombosis in antiphospholipid syndrome. Thromb Res 2014; 133:173–6. [8] Ziporen L, Polak-Charcon S, Korczyn DA, Goldberg I, Afek A, Kopolovic J, et al. Neurological dysfunction associated with antiphospholipid syndrome: histopathological brain findings of thrombotic changes in a mouse model. Clin Dev Immunol 2004; 11:67–75. [9] Nalli C, Andreoli L, Casu C, Tincani A. Management of recurrent thrombosis in antiphospholipid syndrome. Curr Rheumatol Rep 2014;16:405. [10] Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th international congress on antiphospholipid antibodies task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014;13:685–96. [11] Muscal E, Brey RL. Neurological manifestations of the antiphospholipid syndrome: risk assessments and evidence-based medicine. Int J Clin Pract 2007;61:1561–8. [12] Erkan D, Lockshin MD. Aps action–antiphospholipid syndrome alliance for clinical trials and international networking. Lupus 2012;21:695–8. [13] Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration of anticoagulation therapy in antiphospholipid syndrome. Semin Thromb Hemost 2012;38:339–47. [14] Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Antiprothrombin (apt) and anti-phosphatidylserine/prothrombin (aps/pt) antibodies
[15]
[16]
[17] [18] [19]
[20]
[21]
[22] [23]
[24] [25]
[26]
[27] [28]
[29] [30] [31]
[32] [33] [34]
[35]
[36]
[37]
[38]
7
and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost 2014;111:354–64. Keeling D, Mackie I, Moore GW, Greer IA, Greaves M. British Committee for Standards in H. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol 2012;157:47–58. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. EuroPhospholipid Project G: antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019–27. Favaloro EJ, Wong RC. The antiphospholipid syndrome: diagnosis, pathogenesis, laboratory testing, and management. Semin Thromb Hemost 2012;38:299–304. Suarez AL, Hughes GR, Khamashta MA. Neurological manifestations of the antiphospholipid syndrome. Med Clin (Barc) 2005;124:630–3. Bertero MT, Bazzan M, Carignola R, Montaruli B, Silvestro E, Sciascia S, et al. Antiphospholipid syndrome in northwest Italy (aps piedmont cohort): demographic features, risk factors, clinical and laboratory profile. Lupus 2012;21:806–9. Etemadifar M, Dehghani L, Tahani S, Toghianifar N, Rahaimi M, Eskandari N. Neurological manifestations in patients with antiphospholipid syndrome. Iran J Neurol 2013;12:172–5. Marchetti T, Cohen M, Gris JC, de Moerloose P. Diagnosis and management of obstetrical antiphospholipid syndrome: where do we stand? Pol Arch Med Wewn 2013; 123:713–20. De Groot PG, Meijers JC, Urbanus RT. Recent developments in our understanding of the antiphospholipid syndrome. Int J Lab Hematol 2012;34:223–31. Du VX, Kelchtermans H, de Groot PG, de Laat B. From antibody to clinical phenotype, the black box of the antiphospholipid syndrome: pathogenic mechanisms of the antiphospholipid syndrome. Thromb Res 2013;132:319–26. Erkan D, Kozora E, Lockshin MD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology 2011;18:93–102. Gomez-Puerta JA, Cervera R, Calvo LM, Gomez-Anson B, Espinosa G, Claver G, et al. Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients. Rheumatology (Oxford) 2005;44:95–9. Tektonidou MG, Varsou N, Kotoulas G, Antoniou A, Moutsopoulos HM. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings. Arch Intern Med 2006;166: 2278–84. Panichpisal K, Rozner E, Levine SR. The management of stroke in antiphospholipid syndrome. Curr Rheumatol Rep 2012;14:99–106. Nishimura M, Nii T, Trimova G, Miura S, Umezawa K, Ushiyama A, et al. The NFkappaB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. J Nephropathol 2013;2:114–21. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis in antiphospholipid antibody syndrome. J Autoimmun 2010;35:248–55. Oku K, Amengual O, Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. Eur J Clin Invest 2012;42:1126–35. Taraborelli M, Andreoli L, Tincani A. Much more than thrombosis and pregnancy loss: the antiphospholipid syndrome as a 'systemic disease'. Best Pract Res Clin Rheumatol 2012;26:79–90. Santos MS, de Carvalho JF, Brotto M, Bonfa E, Rocha FA. Peripheral neuropathy in patients with primary antiphospholipid (Hughes') syndrome. Lupus 2010;19:583–90. Forastiero R. Bleeding in the antiphospholipid syndrome. Hematology 2012; 17(Suppl. 1):S153–5. Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, Barbarroja N, Perez-Sanchez C, Buendia P, et al. Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome. Ann Rheum Dis 2011;70:675–82. Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, Rodriguez-Ariza A, Cuadrado MJ. Potential use of statins in the treatment of antiphospholipid syndrome. Curr Rheumatol Rep 2012;14:87–94. Schmidt-Tanguy A, Voswinkel J, Henrion D, Subra JF, Loufrani L, Rohmer V, et al. Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost 2013;11:1927–9. Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol 2012;30:409–13. Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82.
Please cite this article as: Zhu D-S, et al, Neurological antiphospholipid syndrome: Clinical, neuroimaging, and pathological characteristics, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.08.010