Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand?
S. Ferreira,
D. P. D'Cruz1 and
G. R. V. Hughes1
Internal Medicine Department (B), S. João Hospital, Alameda Prof. Hernâni Monteiro, 4200 Porto, Portugal and 1 The Lupus Research Unit, The Rayne Institute, Lambeth Wing, St Thomas Hospital, London SE1 7EH, UK.
Correspondence to: D. David DCruz, The Lupus Research Unit, The Rayne Institute, Lambeth Wing, St Thomas Hospital, London SE1 7EH, UK. E-mail: david.d'cruz{at}kcl.ac.uk
 |
Abstract
|
---|
Multiple sclerosis (MS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are chronic, immune-mediated, relapsingremitting disorders affecting young adults, the pathogenesis of which is still largely unknown. Neurological manifestations and magnetic resonance imaging (MRI) can be indistinguishable and there are no specific diagnostic tools. Treatment and prognosis are quite different. There is controversy about the prevalence and significance of antiphospholipid antibodies (aPL) in MS. A significant number of patients with APS/SLE are misdiagnosed as MS but evidence suggests they are distinct nosological entities. However, it is essential to differentiate them since APS may be responsive to anticoagulation. When assessing MS patients, clinicians should consider APS/SLE, especially if the MS has atypical features. A trial of anticoagulation might be worthwhile in some patients with atypical MS and consistently positive aPL.
KEY WORDS: multiple sclerosis, multiple sclerosis-like illness, neuropsychiatric lupus, antiphospholid syndrome, differential diagnosis
 |
Introduction
|
---|
Multiple sclerosis (MS) is the commonest cause of neurological disability in young adults [13]. Its aetiology and pathogenesis are unknown [110]. The course and prognosis are variable and there is no definitive long-term treatment [13].
Systemic lupus erythematosus (SLE) is a multisystem disease and central nervous system (CNS) involvement occurs in about 50% of patients and carries a poor prognosis [1, 1113]. A wide spectrum of neurological and psychiatric features are recognized [1115]. Demyelinating syndromes resembling MS are a rare feature of SLE (lupoid sclerosis) and are a diagnostic challenge [1221]. The pathophysiology of CNS lupus remains poorly understood [1, 1113, 22, 23] but there is increasing evidence that it is often associated with antiphospholipid antibodies (aPL) and only rarely caused by vasculitis [1214, 2232]. This is particularly true for myelopathy [2729, 32, 34]. Combined therapy with immunosuppression and anticoagulation is often required [3234].
Antiphospholipid (Hughes) syndrome (APS) was first described in 1983 [35] and it can occur on its own (primary APS; 53%) or in association with other diseases (secondary APS), most commonly SLE (36%) [1113, 36, 37]. It is characterized by thrombosis (venous or arterial) and/or pregnancy morbidity in the presence of persistent aPL [37, 38]. Although only stroke and transient ischaemic attack (TIA) are included in the classification criteria [37, 38], more complex neurological manifestations are being recognized [12, 13, 1921, 3947] and multifocal white matter lesions on brain magnetic resonance imaging (MRI) are common [12, 13, 46]. In the Euro-Phospholipid Project cohort of 1000 European APS patients (primary and secondary), myelopathy and optic neuropathy were rare manifestations (0.4 and 1%, respectively) [36]. However, the number of patients diagnosed with MS and later shown to have APS has grown substantially [4547] and the true prevalence of aPL in unselected MS populations is controversial [20, 21, 4758]. Anticoagulation is very effective both in treatment and prevention of APS [59, 60].
The immunological nature of these diseases, the affected population, the relapsingremitting course, the neurological manifestations and the presence of multifocal white matter lesions on MRI can make them indistinguishable [1921, 4549]. Some authors even question whether they could represent the same nosological entity [21]. It is important to clarify these issues since cost-effective treatments may be useful in young patients who would otherwise be disabled. Here we review the literature with a view to improving differential diagnosis. Three clinical groups are considered: MS, primary APS (PAPS) and neuropsychiatric lupus with/without APS (NPLE/APS).
 |
Epidemiology
|
---|
MS, SLE and APS mainly affect women of childbearing age [13, 11, 37] but there is a lower female to male ratio in MS (2:1 versus 9:1 in SLE and 5:1 in PAPS) [13, 36]. Black and Japanese populations are rarely affected by MS [13] but they have one of the highest incidences of SLE [1, 11].
SLE is a relatively common autoimmune connective tissue disease [1, 11] and neurological involvement is common (2570%) [1, 1113] and frequently associated with aPL/APS (5060%) [1214, 2532, 44, 45]. The rising incidence of both diseases is possibly due to better recognition [13, 11]. At the same time, there has been a marked increase in the diagnosis of MS variants with the widespread use of MRI [48]. The potential significance of aPL and its variable prevalence in MS [20, 21, 4658] will be explored later in this review.
 |
Pathophysiology
|
---|
The pathophysiology of MS, neuropsychiatric lupus erythematosus (NPLE) and APS remains largely unknown. Immunological mechanisms in genetically predisposed individuals, triggered by environmental factors, are a reasonable explanation for both MS and SLE [2, 23]. Thrombosis is a key feature in APS and vessels of the CNS are frequently affected [13, 37, 4447]. The pathogenic role of aPL in the development of thrombosis is supported by experimental models [61, 62]. However, the possible effects of aPL are unlikely to be exclusively thrombotic and cross-reactivity with cerebral structures, inflammation, vasculopathy and accelerated atherosclerosis are all potential mechanisms [22, 23].
SLE is a B-cell-mediated disorder in which these cells are hyperactive and spontaneously produce a range of immunoglobulins against self antigens [22, 23]. Neurological injury in lupus is multifactorial but aPL seem to play a major role [2226]. There could be a direct injury to neurones or glia (immune complex- or complement-mediated) and antibody-induced rheological disturbances leading to infarction and possible microvasculopathy [22, 23]. Toubi et al. [24] studied an unselected SLE population of 340 patients and found a significant difference in aPL positivity between patients with/without CNS involvement (55 vs 20%, respectively; P<0.001). The presence of aPL was also strongly associated with less lupus activity and with small high-density lesions on brain MRI.
This study and the pathological observations clearly favour a thrombotic hypothesis, which has major therapeutic implications. However, antineuronal antibodies have also been found both in serum and cerebrospinal fluid (CSF) of patients with NPLE [23, 63]. When injected into experimental animals, circulating immune complexes can increase permeability of the bloodbrain barrier, facilitating the entry of pathogenic autoantibodies into the brain which is normally protected from a potentially deviant host immune response [23]. Reversible glial cell injury following exposure to specific antibody has been described in vitro in SLE, with evidence for a comparable phenomenon in vivo in MS [23]. Vessel wall necrosis and thrombosis predominate in pathological studies of patients with APS/SLE [23, 49] but demyelination has been reported [53].
MS has long been recognized as an autoimmune disorder in which myelin is seen as foreign [2, 47, 9, 10]. This concept was reinforced by experimental animal models in which immunization with myelin, myelin protein or myelin protein peptides induced destruction of CNS myelin [2]. Recently, Lucchinetti et al. [6] described four patterns of disease: the first two (I and II) resembling a T-lymphocyte-mediated response, with demyelinating antibodies and complement playing a major pathogenic role and patterns III and IV resembling a primary oligodendropathy with subsequent demyelination. They also observed a different clinical course, with a more classic relapsingremitting disease in pattern II and a primary progressive form in pattern IV.
The hallmark of MS is the demyelinating plaque consisting of a hypocellular area with oligodendrocyte and myelin loss, axon degeneration, gliotic scars and perivascular inflammatory infiltrate mainly composed of lymphocytes and macrophages [2, 4, 9, 10]. However, there are few pathological studies and these usually analyse chronic lesions not necessarily reflecting the disease pathogenesis [6]. Barnett and Prineas [10] recently reported clinical and pathological findings in 12 patients with relapsingremitting MS who died during or shortly after a relapse. They suggested that oligodendrocyte apoptosis may be the first event in the type III MS pattern. Other authors observed similar findings in acute white matter stroke [8]. They speculated that a hypoxia-like metabolic injury may contribute to inflammatory white matter damage in a subset of patients with MS [8]. However, small vessel infarctions have not been reported [8, 10].
These findings suggest that MS has a multifactorial aetiology. Alternatively it may be a series of syndromes with different causes and pathogenic mechanisms [2, 6, 7, 9, 10]. The resulting clinical picture is one of a chronic demyelinating disease, but the target of injury (myelin or oligodendrocytes) and the mechanism of demyelination seem to be different in subgroups of patients [6, 7, 9, 10]. This may have major therapeutic implications [6, 7, 9, 10].
The mechanisms by which aPL may induce an MS-like illness include molecular mimicry with myelin or other CNS antigens, microvascular thrombotic events/vasculopathy and an autoimmune vasculitis similar to that seen in SLE [21]. Antiphospholipid antibodies have demonstrated cross-reactivity with myelin, myelin-related proteins and brain phospholipids (cephalin, sphingomyelin) [18, 21, 50]. Sun et al. [64] found that anticardiolipin antibodies (aCL) bound to mouse brain tissue and inhibited astrocyte proliferation in vitro.
 |
Diagnosis
|
---|
Clinically, a clear distinction between MS, NPLE and APS can be difficult since the clinical manifestations, MRI lesions and laboratory features are often indistinguishable (Fig. 1) and have a similar relapsingremitting course [20, 21, 4549]. Diagnosis is challenging because there are neither pathognomonic features nor gold standard diagnostic tools [4547] but some findings can suggest one of the diagnoses [2, 3, 12, 13, 4547, 65] (Table 1).

View larger version (93K):
[in this window]
[in a new window]
|
FIG. 1. MRI from a patient with antiphospholipid syndrome. A, B: Brain MRI showing periventricular lesions indistinguishable from those seen in MS. C, T2-high-signal widespread lesions in spinal levels C25, T13, T57.
|
|
MS can only be diagnosed when there is objective evidence of central neurological dysfunction disseminated in space and time, i.e. more than one affected area and more than one episode, and other possible explanations have been excluded [24, 65]. These points were highlighted by MacDonald et al. [65] in the revised diagnostic criteria of MS, but specific recommendations to distinguish it from PAPS and NPLE were not given. Patients can be labelled as not MS (diagnostic evaluation ruled out MS), definite MS or possible MS (at risk but diagnostic evaluation equivocal) and, in many cases, accurate diagnosis can only be made after long-term follow-up [65].
Clinical manifestations
An acute isolated neurological syndrome is the main diagnostic problem, since it is the most common picture in MS (90%) [2, 3, 64, 65] but can also be the only feature in APS/SLE [12, 13, 4750]. Long-term follow-up studies indicate a wide range (3080%) of progression to definite MS raising questions about the accuracy of the initial diagnosis [66].
The most common neurological manifestations of APS/SLE (stroke, TIA, seizures, headaches) [12, 13] and psychiatric disorders are not seen in MS [2, 3, 4547]. However, some uncommon reported syndromes [transverse myelitis, optic neuritis alone or associated with transverse myelitis (Devic's syndrome), brainstem/cerebellar syndromes, diplopia] [12, 13, 1521, 2732, 36] are often the first manifestation of MS [2, 3, 46, 47]. Demyelinating syndrome and myelopathy are two of the 19 recently defined syndromes in NPLE [15]. Transverse myelitis has been increasingly reported in association with APS with or without SLE [12, 13, 2732, 34, 48] and significant improvement after oral anticoagulation has been observed [20, 32, 34, 47, 49, 50]. SLE patients with transverse myelitis have a higher prevalence of aPL than SLE patients without it [29]. MS patients with aPL may present with myelopathy alone or associated with optic neuritis [21, 48, 49, 52, 53]. An ischaemic aetiology of visual symptoms is suggested by the abruptness of onset and shorter duration [13, 30, 43]. Optic neuritis associated with APS is usually unilateral but in SLE as in MS it may be bilateral [30].
Symptoms suggestive of peripheral nervous system involvement suggest SLE since MS only affects the CNS [2, 3]. Other manifestations would suggest underlying APS (thrombosis, miscarriages, pregnancy morbidity, livedo reticularis, thrombocytopenia) or connective tissue diseases (photosensitivity, rash, arthralgias or sicca syndrome) [12, 13, 32, 4249].
Diagnostic tests
There is no specific diagnostic test [2, 3, 12, 13, 4547, 65] but the most useful are brain and spinal MRI, CSF examination including immunoglobulin G (IgG) index and immunoelectrophoresis, visual evoked potentials and autoantibody serology.
MRI
MRI is an important diagnostic tool but small strokes in the white matter may produce lesions resembling demyelinating plaques in the brain and spinal cord. Similar multifocal white matter lesions can be found in MS, NPLE and APS (3070%) [12, 13, 46, 6773] and they are often clinically silent [25, 41, 46]. Gadolinium enhancement is more suggestive of inflammation but immune complexes can also induce leakage of the bloodbrain barrier [6870] and MRI is unable to ascertain the inflammatory nature of the underlying disease [48, 65, 6870].
The MRI criteria of Barkhof et al. [67] provide the best combination of sensitivity and specificity for an accurate diagnosis of MS [2, 65, 67]. MRI should be periodically repeated (ideally every 3 months) when there is no definite diagnosis and whenever new neurological symptoms appear [2, 65, 67]. The absence of multifocal lesions on brain MRI has a good negative predictive value for later development of MS [68]. Lesion distribution could be helpful, since subcortical lesions predominate in APS/SLE and periventricular and especially corpus callosum lesions are more common in MS [12, 13, 4346, 6870]. Elongated ovoid shaped lesions (Dawson's fingers) and black holes are more characteristic of MS but they are not pathognomonic [6870]. In our experience, the lesions seen in association with APS are usually static on repeat MRI compared with the dynamic nature of lesions seen in MS. Furthermore, lesions associated with APS may improve with anticoagulation [73].
CSF examination
CSF examination may be useful when clinical or imaging features are unusual [65] and it is the only method that can directly assess inflammation [2, 3, 65]. Mild lymphocytic pleocytosis, high IgG index or oligoclonal bands not present in serum (intrathecal production) are common in MS and NPLE and they are not usually found in primary APS [21, 49, 54, 55]. However, their presence does not exclude that diagnosis [20, 21, 49]. The absence of oligoclonal bands makes the diagnosis of MS unlikely [2, 3, 65].
Visual evoked potentials
Of the neurophysiological tests, only visual evoked potentials have shown sufficient discriminative diagnostic usefulness [3]. They are particularly helpful when MRI abnormalities are few (e.g. primary progressive form with progressive myelopathy) or have less specificity (e.g. older patients with risk factors for microvascular ischaemic disease) [65]. Normal visual evoked potentials are unusual in MS [2, 3, 65].
Antinuclear antibodies
The frequency of antinuclear antibodies (ANA) in MS and their significance are uncertain [48, 53, 7476]. Variable prevalences have been reported [7476] probably reflecting differences in patient selection and sensitivity of techniques [49, 54]. Barned et al. [74] retrospectively studied 150 patients with MS and found 27% to be positive for ANA. Similar findings were reported in a prospective study [54]. Other authors also found a positive correlation between titre/persistence of ANA and MS activity [75]. These data were not corroborated by others [76] and ANA can be found in healthy individuals (28%) and in infectious diseases [74]. Despite these results, when ANA titres are high and persistent and they appear in the context of other autoimmune abnormalities, a diagnosis of connective tissue disease should be considered [48, 49, 76].
Antiphospholipid antibodies
Antiphospholipid antibodies are present in 25% of the general population, usually at low titre and without symptoms [21, 37] but they are associated with increased cardiovascular risk [7779]. They also can be found in infections, neoplasms and even after administration of some drugs, where they are usually transient and not related to thrombotic events [37, 50].
Higher prevalences are reported in autoimmune diseases, mainly in SLE (36%) [1113, 36, 37] where they are associated with CNS involvement (5060%) [1214, 2532]. aPL have been described in neurological conditions such as myasthenia gravis, LambertEaton syndrome and migraine [50]. They also have been reported with variable frequency in patients with MS [20, 21, 4558], especially of the neuromyelitic type [21, 49, 50]. Whether this is an incidental finding, an epiphenomenon reflecting underlying immune activation, the result of nervous system damage or is in fact pathogenic is a matter of discussion. Specific characteristics of the selected populations and study protocols, utilization of different techniques and interlaboratory variation, type of aPL measured (lupus anticoagulant (LA) not determined in most cases) and no uniform cut-off value for positive results are possible explanations for the wide variability of the results. aPL titres can fluctuate and they are sometimes negative in the acute phase [48] but most studies have not measured aPL sequentially. There is also no consensus about routinely measuring aPL in patients with MS but some authors have suggested it would be important to add aPL testing to diagnostic criteria [54]. The most relevant published studies are summarized in Table 2.
In the United States, Scott et al. [20] reported four patients diagnosed as MS. aCL of the IgG isotype were positive at medium to high titre in all patients, LA were also found in three and all but one patient had previous clinical manifestations suggestive of APS. In Japan, SLE is very common [1, 11] while MS is rare [13] and characterized by a high incidence of neuromyelitis optica and transverse myelitis [80]. Fukazawa et al. [51] studied a Japanese MS population and found a significant prevalence of aPL (5.3%, two of 38 patients) when compared with controls. Both patients presented with recurrent optic neuritis and transverse myelitis. Both had normal brain MRI, swelling of the spinal cord, no oligoclonal bands on CSF examination, abnormal visual evoked potentials and no evidence of connective tissue disorders. Similar results were reported by others in a similar population but with a predominance of the aCL IgM isotype [52]. Karussis et al. [21] found an aPL prevalence of 5.7% in patients with classic MS but much higher (20%, mainly of IgG isotype) in patients with atypical features (myelitis alone or associated with optic neuritis/cerebellar signs, migraine, absence of oligoclonal bands in CSF). MRI findings typical of MS were found in the majority of these patients. This group had a slower progression and the authors suggested it may represent a specific subset of patients with MS or a different nosological entity. All patients were treated with acetylsalicylic acid (100 mg o.d.) and most remained stable.
In a study involving 322 patients referred to a rheumatology clinic, 59% (n = 189) had positive aPL and 8% (n = 26) had a previous diagnosis of MS [48]. In these patients transverse myelitis and optic neuritis were common. Most of them were aPL positive [23/26 (88%), most commonly of IgM isotype]. Almost all MRI studies were abnormal, but only 50% were labelled as diagnostic or compatible with MS by a radiologist blind to the diagnosis. Also, 50% of patients had previous manifestations suggesting APS/SLE. Cuadrado et al. [49] corroborated these data when evaluating 27 female patients with atypical MS (symptoms suggesting underlying connective tissue disease, uncommon findings for MS on MRI, atypical evolution, aPL positivity). All were aPL positive and fulfilled the classification criteria for APS (16 PAPS, 11 secondary to SLE). Transverse myelitis was the commonest presenting feature and most of them had MRI abnormalities indistinguishable from the patients with definite MS. These findings suggest that a significant number of patients with aPL are initially diagnosed as MS and the authors advised screening for aPL in MS population, at least when atypical features are present.
Some negative studies have also been published and the authors argued that occasionally higher prevalences of aPL in MS populations are merely an epiphenomenon [50, 5358]. They do not recommend screening for aPL in MS patients but they agree that APS should be considered in the differential diagnosis.
Tourbah et al. [53] found that about 50% of an unselected MS population of 161 patients had atypical features (e.g. isolated clinical abnormalities, ANA and/or aCL positivity). No significant difference was found between them and patients with classic MS. However, after 5 yr of follow-up, a diagnosis of MS was not established in about 20% of patients in the atypical group. These were characterized by a combination of clinical, biological and MRI abnormalities suggesting APS/SLE as an alternative diagnosis (positive ANA in combination with positive aPL in about 40%; anti-DNA antibodies in about 30%; punctiform or diffuse T2 hyperintense lesions in about 40%).
Roussel et al. [54] studied a population of 89 MS patients and about 30% had aPL, either aCL (21%) or ß2-glycoprotein (GPI) (16%) but, contradicting other studies, they did not observe a different clinical presentation or evolution in these patients. Nevertheless, they actually found one of the highest prevalences of aPL in an unselected MS population, even higher than in patients with stroke. Heinzlef et al. [55] reported similar results in a larger unselected MS population, but only patients with definite MS were included. Sastre-Garriga et al. [56] studied the largest unselected MS population to date and they did not find either a higher prevalence of aPL than in general population (2%) or specific characteristics in the positive patients. Similar findings have been reported by other authors in smaller populations [50, 57, 58].
Despite discordance in these results, because APS is a treatable disease and aPL screening is a non-invasive, widely available and inexpensive diagnostic test, it seems reasonable to consider it in patients with MS, especially in those with atypical features. Repeated negative results make a diagnosis of APS unlikely. Consistently positive aPL might suggest a different treatment approach.
Other diagnostic tests
More specific neuroimaging techniques are being developed. The application of single photon emission computed tomography has been studied in patients with APS where it can show focal low-perfusion areas that improve with anticoagulation [49, 81]. Rovaris et al. [72] suggested that magnetization transfer imaging combined with standard MRI could discriminate MS from APS, but images were indistinguishable from SLE.
Some neurophysiological studies in MS found an increase of slow frequencies (
and
) in the left frontotemporal-region and decrease of the
band, the significance of which is not well understood [8284]. Similar studies in SLE reported
and
slowing and sharp wave activity suggesting selective damage to the left temporolimbic region [85]. Seizures were reported in SLE associated with APS [86] soon after the first description of the syndrome [35]. Recently, Lampropoulos et al. (unpublished data) observed a significantly higher prevalence of abnormal electroencephalograms (EEGs) in APS patients when compared with those who were only aPL positive and with patients with SLE without aPL (100, 71 and 39.1%, respectively). Two patients (2/81) who were also diagnosed as MS had focal slow activity and small periventricular lesions which are unlikely to explain those abnormalities on EEG. The authors suggested that EEG may be useful since a normal recording is less compatible with APS.
 |
Treatment
|
---|
The classic treatment for MS is interferon-ß which reduces relapses by 30%, but delay in disability progression or long-term benefit is not proven [1, 2]. It is an expensive parenteral therapy [1, 2] and it may potentially induce or aggravate lupus activity [87].
Choice of the most appropriate treatment for NPLE is always challenging because it is difficult to be certain of the underlying mechanism [12, 13, 33] and combined therapy is often required (immunosuppressive drugs and anticoagulation) [3234, 46]. Cyclophosphamide is the recommended agent in severe cases, with good results [33]. Azathioprine, mycophenolate mofetil or methotrexate can be used to maintain remission [33]. Corticosteroids are used in both SLE [33] and MS [1, 2], mainly to control symptoms during the acute phase.
High-intensity anticoagulation with warfarin (international normalized ratio (INR) 34) is the most effective treatment for APS, with a low haemorrhagic risk [37, 59, 60]. Primary prevention with anti-aggregation or even low-dose oral anticoagulation is probably suboptimal [39, 59]. Some patients with MS-like illnesses and aPL with or without SLE had a significant improvement after anticoagulation, both clinically and radiologically [20, 32, 34, 4549]. This suggests that in patients with MS and persistently positive aPL and/or atypical features, a trial of anticoagulation with a target INR of 34 for 6 months might be cost-effective. Clearly the patients should be carefully counselled about the risks of anticoagulation.
 |
Prognosis
|
---|
The course of MS is largely unpredictable but about 50% will need help with walking 15 yr after diagnosis and 70% will have secondary progression despite treatment [14].
Recent studies have shown a reduction in mortality in SLE [88, 89] probably because of earlier recognition and treatment. NPLE [12, 13] and secondary APS [12, 50] carry a worse prognosis, suggesting potential benefit from combined therapy.
Primary APS is being increasingly recognized and treated, and even healthy individuals with aPL are now regarded as a population at risk [37, 59]. Treatment definitely improves prognosis [37, 59].
 |
Conclusion
|
---|
Evidence suggests that MS, APS and NPLE are distinct entities. Epidemiological data differ and some APS/SLE clinical features are unusual in MS. The striking response to anticoagulant therapy in some patients with MS and aPL is probably the strongest argument for distinguishing the two diagnoses.
However, as seems evident from the literature and from the everyday practice of those working with APS/SLE, a significant number of these patients are probably mislabelled as MS. Transverse myelitis and multifocal white matter lesions seem to be the most common confounding factors.
APS primary or secondary to SLE is an essential differential diagnosis of MS because treatment in this young population may improve both quality of life and mortality. When dealing with patients with MS or MS-like illnesses, some points should be emphasized:
- APS/SLE should be considered in the differential diagnosis.
- A careful medical history looking for manifestations of APS or connective tissue diseases should always be carried out (e.g. previous thrombosis, recurrent miscarriages, livedo reticularis, thrombocytopenia, Raynaud's phenomenon, photosensitivity, rash, arthralgias, sicca syndrome).
- Antiphospholipid antibodies (aCL IgM and IgG and LA) should be considered, especially in patients with atypical MS (transverse myelitis, optic neuritis, isolated neurological syndrome, headaches, epilepsy, dementia, unusual progression, absence of oligoclonal bands in CSF, normal brain MRI or abnormal localization of lesions). Sequential determinations could be useful.
- In some patients, an accurate diagnosis may only emerge after long-term follow-up.
- A trial of oral anticoagulation with a target INR of 34 for 6 months with careful patient counselling of the risks should be considered if there is persistent aPL positivity and/or there are features suggesting APS (primary or secondary).
 |
Acknowledgments
|
---|
We thank Dr M. Sharief (consultant Neurologist, Guy's and St Thomas Hospital) for his helpful advice and criticism of this review.
The authors have declared no conflicts of interest.
 |
References
|
---|
- Braunwald E, Fauce AS, Kasper DL, Hauser SL, Longo DL, Jameson JL. Multiple sclerosis and other demyelinating diseases. In: Harrison's principles of internal medicine, 15th edn. New York: McGraw Hill, 2001;245261.
- Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Eng J Med 2000;343:93852.[Free Full Text]
- Lublin F. The diagnosis of multiple sclerosis. Curr Opin Neurol 2002;15:2536.[CrossRef][ISI][Medline]
- Hafler D. Multiple sclerosis. J Clin Invest 2004;113:78894.[Abstract/Free Full Text]
- Ludwin SK. Understanding multiple sclerosis: lessons from pathology. Ann Neurol 2000;46:6912.
- Lucchinetti C, Bruck W, Parisi J, Schethauer B, Rodriguez M, Lassman H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:70717.[CrossRef][ISI][Medline]
- Archelos JJ, Storch MK, Hartung HP. The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol 2000;47:694706.[CrossRef][ISI][Medline]
- Aboul-Enein F, Rauschka H, Kornek B et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol 2003;62:2533.[ISI][Medline]
- Trapp BD. Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend. Ann Neurol 2004;55:4557.[CrossRef][ISI][Medline]
- Barnett MH, Prineas J. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004; 55:45868.[CrossRef][ISI][Medline]
- Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GRV. Systemic lupus erythematosus. Lancet 2001;357:102732.[CrossRef][ISI][Medline]
- Sanna G, Bertolaccini ML, Cuadrado MJ et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003;30:98592.[ISI][Medline]
- Sanna G, Bertolaccini ML, Cuadrado MJ, Khamashta MA, Hughes GRV. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology 2003;42:20013.[Abstract/Free Full Text]
- Bruyn GA. Controversies in lupus: nervous system involvement. Ann Rheum Dis 1995;54:15967.[Abstract]
- The American College Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599608.[CrossRef][ISI][Medline]
- Harris EN, Gharavi AE, Mackworth-Young CG, Patel BM, Derue G, Hughes GRV. Lupoid sclerosis: a possible pathogenetic role for antiphospholipid antibodies. Ann Rheum Dis 1985;44:2813.[Abstract]
- Lorcerie B, Marchal G, Borsotti JP et al. Multiple sclerosis associated with biological symptoms of systemic lupus erythematosus. A case with anatomical study. Rev Med Interne 1989; 10:4714.[ISI][Medline]
- Marullo S, Clauvel JP, Intrator L, Danon F, Brouet JC, Oksenhendler E. Lupoid sclerosis with antiphospholipid and antimyelin antibodies. J Rheumatol 1993;20:7479.[ISI][Medline]
- Siam AM, Hammoudeh M, Khanjar I. Multiple sclerosis-like picture in association with Hughes syndrome. Lupus 1998;7:3679.[CrossRef][ISI][Medline]
- Scott TF, Hess D, Brillman J. Antiphospholipid antibody syndrome mimicking multiple sclerosis both clinically and by magnetic resonance imaging. Arch Intern Med 1994;154:91720.[CrossRef][ISI][Medline]
- Karussis D, Leker RR, Ashkenazi A, Abramsky O. A subgroup of multiple sclerosis patients with anticardiolipin antibodies and unusual clinical manifestations: do they represent a new nosological entity? Ann Neurol 1998;44:62934.[ISI][Medline]
- Jennekens F, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Pathogenetic mechanisms of clinical syndromes: a literature investigation. Rheumatology 2002; 41:61930.[Abstract/Free Full Text]
- Scolding NJ, Joseph FG. The neuropathology and pathogenesis of systemic lupus erythematosus. Neuropathol Appl Neurobiol 2002;28:1739.[CrossRef][ISI][Medline]
- Toubi E, Khamashta MA, Panarra A, Hughes GRV. Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus. Am J Med 1995;9:397401.[CrossRef]
- Karassa FB, Ioannidis JP, Touloumi G, Boki KA, Moutsopoulos HM. Risk factors for central nervous system involvement in systemic lupus erythematosus. Q J Med 2000;93:16974.[ISI]
- Alarcon-Segovia D, Delize M, Oria CV et al. Antiphospholipid antibodies and antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients. Medicine 1989;68:35365.[ISI][Medline]
- Lavalle C, Pizarro S, Drenkard C, Sánchez-Guerrero J, Alarcón-Segovia D. Transverse myelitis: a manifestation of systemic lupus erythematosus strongly associated with antiphospholipid antibodies. J Rheumatol 1990;17:347.[ISI][Medline]
- Campi A, Filippi M, Comi G, Scotti G. Recurrent acute transverse myelopathy associated with anticardiolipin antibodies. Am J Neuroradiol 1998;19:7816.[Abstract]
- Kovacs B, Lafferty TL, Lawrence H, DeHoratius RJ. Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis 2000;59:1204.[Abstract/Free Full Text]
- Giorgi D, Gabrieli CB. Optic neuropathy in systemic lupus erythematosus and antiphospholipid syndrome: clinical features, pathogenesis, review of the literature and proposed ophthalmological criteria for APS diagnosis. Clin Rheumatol 1999;18:12431.[CrossRef][ISI][Medline]
- Seze J. Neuromyelitis optica. Arch Neurol 2003;60:13368.[Free Full Text]
- DCruz D, Mellor-Pita S, Joven B et al. Transverse myelitis as the first manifestation of systemic lupus erythematosus or lupus-like disease: good functional outcome and relevance of antiphospholipid antibodies. J Rheumatol 2004;31:2805.[ISI][Medline]
- Sanna G, Bertolaccini ML, Mathieu A. Central nervous system lupus: a clinical approach to therapy. Lupus 2003;12:93542.[CrossRef][ISI][Medline]
- Aziz A, Conway MD, Robertson HJ, Espinosa LR, Wilson WA. Acute optic neuropathy and transverse myelitis in patients with antiphospholipid syndrome: favorable outcome after treatment with anticoagulants and glucocorticoids. Lupus 2000;9:30710.[CrossRef][ISI][Medline]
- Hughes GRV. Thrombosis, abortion, cerebral disease and lupus anticoagulant. Br Med J 1983;287:10889.[ISI][Medline]
- Cervera R, Piette JC, Font J et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:101927.[CrossRef][ISI][Medline]
- Levine J, Branch W, Rauch J. The antiphospholipid syndrome. N Eng J Med 2002;346:75263.[Free Full Text]
- Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthitis Rheum 1999;42:130911.[CrossRef][ISI][Medline]
- Levine SR, Dugan MJ, Futrell N, Welch KM. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology 1990;40:11819.[Abstract]
- Hughes GRV. The antiphospholipid syndrome: 10 years on. Lancet 1993;342:3414.[ISI][Medline]
- Brey R, Gharavi AE, Locksin MD. Neurologic complications of antiphospholipid syndrome. Rheum Dis North Am 1993;19:83350.[ISI][Medline]
- Brey R. Differential diagnosis of central nervous system manifestations of the antiphospholipid syndrome. J Autoimmun 2000; 15:1338.[CrossRef][ISI][Medline]
- Cuadrado MJ, Hughes GRV. Hughes (antiphospholipid) syndromeclinical features. Rheum Dis Clin 2001;27:50724.[ISI]
- Sastre-Garriga J, Montalban X. APS and the brain. Lupus 2003;12:87782.[CrossRef][ISI][Medline]
- Hughes GRV. Migraine, memory loss and multiple sclerosis. Neurological features of the antiphospholipid (Hughes) syndrome. Postgrad Med J 2003;79:813.[Abstract/Free Full Text]
- Ruiz-Irastorza G, Khamashta MA. Warfarin for multiple sclerosis? Q J Med 2000;93:4979.
- Hughes GRV. The antiphospholipid syndrome and multiple sclerosis. Lupus 1999;8:89.[CrossRef][ISI][Medline]
- Ijdo JW, Conti-Kelly AM, Greco P et al. Anti-phospholipid antibodies in patients with multiple sclerosis and MS-like illnesses: MS or APS? Lupus 1999;8:10915.[ISI][Medline]
- Cuadrado MJ, Khamashta MA, Ballesteros A, Godfrey T, Simon MJ, Hughes GRV. Can neurologic manifestations of Hughes syndrome (antiphospholipid) syndrome be distinguished from multiple sclerosis? Medicine 2000;79:5768.[CrossRef][ISI][Medline]
- Rombos A, Evangelopoulou-Katsiri, Leventakou A, Voumvourakis K, Triantafyllou N, Papageorgiou C. Serum IgG and IgM anticardiolipin antibodies in neurological diseases. Acta Neurol Scand 1990;81: 435.[ISI][Medline]
- Fukazawa T, Moriwaka F, Mukai M, Hamada T, Koike T, Tashiro K. Anticardiolipin antibodies in Japanese patients with multiple sclerosis. Acta Neurol Scand 1993;88:1849.[ISI][Medline]
- Sugyama Y, Yamamoto T. Characterization of serum antiphospholipid antibodies in patients with multiple sclerosis. Tokohu J Exp Med 1996;178:20315.[ISI][Medline]
- Tourbah A, Clapin A, Gout O et al. Systemic autoimmune features and multiple sclerosisa 5-year follow-up study. Arch Neurol 1998;55:51721.[Abstract/Free Full Text]
- Roussel V, Jaubertau MO, Couderq C et al. Prevalence and clinical significance of anti-phospholipid antibodies in multiple sclerosis: a study of 89 patients. J Autoimmun 2000;14:25965.[CrossRef][ISI][Medline]
- Heinzlef O, Weill B, Johanet C et al. Anticardiolipin antibodies in patients with multiple sclerosis do not represent a subgroup of patients according to clinical, familial and biological characteristics. J Neurol Neurosurg Psychiatry 2002;72:6479.[Abstract/Free Full Text]
- Sastre-Garriga J, Reverter JC, Font J, Tintoré M, Espinosa G, Montalban X. Anticardiolipin antibodies are not a useful screening tool in a nonselected large group of patients with multiple sclerosis. Ann Neurol 2001;49:40811.[CrossRef][ISI][Medline]
- Cordoliani MA, Michon-Pasturel U, Perat K et al. Scléroses en plaques et anticorps antiphospholipides: étude consécutive de 62 patients. Rev Med Interne 1998;19:6359.[ISI][Medline]
- Baraczka K, Lakos G, Sipka S. Immunoserological changes in the cerebro-spinal fluid and serum in systemic lupus erythematosus patients with demyelinating syndrome and multiple sclerosis. Acta Neurol Scand 2002;105:37883.[CrossRef][ISI][Medline]
- Khamashta MA, Cuadrado MJ, Mujic F, Taub NP, Hunt BJ, Hughes GRV. The management of thrombosis in the antiphospholipid syndrome. N Engl J Med 1995;332:9937.[Abstract/Free Full Text]
- Ruiz-Irastoza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GRV. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Int Med 2002;162:11649.[CrossRef][ISI]
- Pierangeli SS, Harris EN. In vivo models of thrombosis for the antiphospholipid syndrome. Lupus 1996;5:4515.[ISI][Medline]
- Radway-Bright EL, Inanc M, Isenberg DA. Animal models of the antiphospholipid syndrome. Rheumatology 1999;38:591601.[Abstract]
- Scolding NJ, Housten WA, Morgan BP et al. Reversible injury of cultured rat oligodendrocytes by complement. Immunology 1989; 67:4416.[ISI][Medline]
- Sun KH, Liu WT, Tsai CY, Liao TJ, Lin WM, Yu CL. Inhibition of astrocyte proliferation and binding to brain tissue of anticardiolipin antibodies purified from lupus serum. Ann Rheum Dis 1992;51:70712.[Abstract]
- McDonald WI, Compston A, Edan G et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:1217.[CrossRef][ISI][Medline]
- Dalton CM, Brex PA, Miszkiel KA et al. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 2002;52:4753.[CrossRef][ISI][Medline]
- Barkhof F, Filippi M, Miller DH et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:205969.[Abstract]
- Arnold DL, Matthews PM. MRI in the diagnosis and management of multiple sclerosis. Neurology 2002;58(Suppl 4):S23S31.
- Graham JW, Jan W. MRI and the brain in systemic lupus erythematosus. Lupus 2003;12:8916.[CrossRef][ISI][Medline]
- Miller DH, Buchanan N, Barker G et al. Gadolinium-enhanced magnetic resonance imaging of the central nervous system in systemic lupus erythematosus. J Neurol 1992;239:4604.[CrossRef][ISI][Medline]
- Molad Y, Sidi Y, Gornish M, Lerner M, Pinkhas J, Weinberger A. Lupus anticoagulant: correlation with magnetic resonance imaging of brain lesions. J Rheumatol 1992;19:55661.[ISI][Medline]
- Rovaris M, Viti B, Ciboddo G et al. Brain involvement in systemic immune mediated diseases: magnetic resonance and magnetisation transfer imaging study. J Neurol Neurosurg Psychiatry 2000; 68:1707.[Abstract/Free Full Text]
- Hachulla E, Michon-Pasturel U, Leys D et al. Cerebral MRI in patients with or without antiphospholipid antibodies. Lupus 1998; 7:12431.[ISI][Medline]
- Barned S, Goodman A, Mattson D. Frequency of antinuclear antibodies in multiple sclerosis. Neurology 1995;45:3845.[Abstract]
- Collard R, Koehler R, Mattson D. Frequency and significance of antinuclear antibodies in multiple sclerosis. Neurology 1997;49:85761.[Abstract]
- Michielsens B, Walravens M, Vermylen J, Carton H. Diagnostic significance of antinuclear antibodies in neurologic patients. Acta Neurol Scand 1991;84:1026.[ISI][Medline]
- Tuhrim S, Rand JH, Wu XX et al. Elevated anticardiolipin antibodies titer is a stroke risk factor in a multiethnic population, independent of isotype or degree of positivity. Stroke 1999;30:15615.[Abstract/Free Full Text]
- Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992;117:3038.[ISI][Medline]
- Shah NM, Khamashta MA, Atsumi T, Hughes GRV. Outcome of patients with anticardiolipin antibodies: a 10 year follow-up of 52 patients. Lupus 1998;7:36.[CrossRef][ISI][Medline]
- Fukazawa T, Tashiro K, Hamada T et al. Multiple sclerosis in Hokkaido, the northern most island of Japan: prospective analysis of clinical features. Intern Med 1992;31:34952.[ISI][Medline]
- Kato T, Morita A, Matsumoto Y. Hypoperfusion of brain single photon emission computed tomography in patients with antiphospholipid syndrome. J Dermatol Sci 1997;14:208.[CrossRef][ISI][Medline]
- Facchetti D, Mai R, Colombo A et al. Limited clinical significance of traditional and quantitative EEG in multiple sclerosis. Acta Neurol Belg 1994;94:24550.[ISI][Medline]
- Leocani L, Comi G. Neurophysiological investigations in MS. Curr Opin Neurol 2000;13:25561.[CrossRef][ISI][Medline]
- Leocani L, Locatelli T, Martinelli V et al. Electroencephalographic coherence analysis in multiple sclerosis: correlation with clinical, neuropsychological and MRI findings. J Neurol Neurosurg Psychiatry 2000;69:1928.[Abstract/Free Full Text]
- Glanz BI, Schur PH, Khoshbin S. EEG abnormalities in systemic lupus erythematosus. Clin Electroencephalogr 1998;29:12831.[ISI][Medline]
- Mackworth-Young C, Hughes GRV. Epilepsy: an early symptom of SLE. J Neurol Neurosurg Psychiatry 1985;48:185.[ISI][Medline]
- Crow MK. Interferon-
: a new target for therapy in systemic lupus erythematosus? Arthritis Rheum 2003;48:2396401.[CrossRef][ISI][Medline]
- Uramoto KM, Michet CJ, Thumboo J, Sunku J, OFallon WM, Gabriel SE. Trends in the incidence and mortality of systemic lupus erythematosus, 195092. Arthritis Rheum 1999;42:4650.[CrossRef][ISI][Medline]
- Urowitz MB, Gladman DD, Abu-Shakra M, Farewell VT. Mortality studies in SLE: results from a single center, III improved survival in SLE. J Rheumatol 1997;24:10615.[ISI][Medline]
Submitted 15 June 2004;
revised version accepted 26 November 2004.