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J Neurol (2005) 252 : 1155–1166 DOI 10.1007/s00415-005-0967-9

Markus Kraemer Dieter Linden Peter Berlit

REVIEW

The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa A literature review

Received: 1 March 2005 Received in revised form: 16 June 2005 Accepted: 28 June 2005 Published online: 26 August 2005

Dr. med. M. Kraemer (
) · Dr. med. D. Linden · Prof. Dr. med. P. Berlit Department of Neurology Alfried Krupp von Bohlen und Halbach Hospital Alfried Krupp Str. 21 45117 Essen, Germany Tel.: +49-201/434-2527 Fax: +49-201/434-2377 E-Mail: [email protected]

■ Abstract Livedo is a cutaneous sign of striking violaceous netlike patterned erythema of the skin. This dermatological phenomenon is of special interest in the differential diagnosis in neurological patients. In 1907 Ehrmann distinguished two different patterns of livedo: the pathological livedo racemosa and the physiological livedo reticularis. Despite important clinical differences, in the English language literature the heading livedo reticularis is still used for all types of livedo. A literature review about the spectrum of differential diagnosis in patients with livedo reticu-

Introduction

■ Key words livedo reticularis · livedo racemosa · Sneddon’s syndrome

[93]. Livedo racemosa is always associated with a pathological condition. In contrast, livedo reticularis usually is caused by functional factors such as vasoconstriction in the cold (cutis marmorata). In neurology, one of the most important differential diagnoses in patients with livedo racemosa is Sneddon’s syndrome (SS). Livedo reticularis may also be caused by amantadine. A large number of diseases accompanying livedo racemosa must be excluded by the appropriate clinical and laboratory tests. Diagnostic difficulties may occur when no other pathological signs except livedo racemosa are found. This clinical condition, known as “idiopathic livedo racemosa”, may not exist as a separate entity but may represent a very early stage of Sneddon’s syndrome (SS). JON 1967

In medical literature the term “livedo reticularis” is often used indiscriminately and clinical descriptions of livedo are often scanty. However, it is of clinical relevance to differentiate between livedo racemosa and livedo reticularis. “Livedo racemosa” was first introduced in 1907 by Ehrmann as a “tendril-like bluish pattern reminiscent of forked lightening which intensified in the cold as a sign of passive hyperaemia, somewhat cooler than the surrounding skin” [24, 55]. Livedo racemosa is characterised by a striking violaceous netlike pattering of the skin similar to the familiar livedo reticularis from which it differs by its localisation (more generalised), its shape (irregular, broken circular segments) and its skin biopsy results [106]. The livid rings in both forms are caused by reduced blood flow and lowered oxygen tension at the peripheries of the skin segments

laris (especially cutis marmorata and amantadine-induced livedo reticularis) and livedo racemosa (especially Sneddon’s syndrome, Divry-van Bogaert syndrome, systemic lupus erythematosus, antiphospholipid antibody syndrome, polyarteritis nodosa, cholesterol embolization syndrome, livedoid vasculopathy and haematological diseases) is provided.

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The spectrum of differential diagnosis in neurological patients with livedo reticularis ■ Cutis marmorata Livedo reticularis mainly affects young women and most commonly occurs on the legs [54]. An impairment of the blood flow in cutaneous vessels causes the mottling of livedo reticularis related to the vascular anatomy of normal skin. The blood supply is arranged in cones with 1–4 cm bases situated on the surface of the skin, with a central arteriole supplying each area. The regular, net-like pattern of cutis marmorata results from cyanotic discolouration occurring at the anastomoses between cones where deoxygenated blood stagnates [91]. The reduction of blood flow is usually due to functional factors such as vasoconstriction in the cold [93]. This familiar sign disappears when patients spend a significant time in a warm climate [29]. The treatment options of livedo reticularis are physical therapy with massages, sports and cold-hot-changing baths. A specific medication is not available, but the symptoms typically improve in later age [54].

■ Amantadine-induced livedo reticularis Although livedo reticularis is a known side-effect induced by amantadine, only a few scientific reports exist about this phenomenon. Amantadine-induced livedo reticularis was first described by Shealy, Welth and Mecier in 1970 [87]. The incidence of livedo reticularis in patients treated with amantadine (mostly Parkinsonism patients) is still unclear.Variable rates have been reported ranging from 2% (1 of 43) [84] to 28% (10 of 36) [87], while others have reported rates as high as 90% (36 of 41) [102]. Livedo reticularis induced by amantadine occurs more often in women [84]. Amantadine-induced livedo reticularis occurs on the legs in most cases. Skin biopsy specimens show livedo reticularis with normal epidermis and corium without signs of vasculitis [54]. Most authors have reported normal laboratory features including antiphospholipid antibody, lupus anticoagulant test, venereal disease research laboratory test and other antibodies. For a long time the “catecholamine theory” was considered as an explanation for the pathophysiology of amantadine-induced livedo reticularis. The synthetic antiviral agent amantadine, which is used to treat Parkinson’s disease and fatigue associated with multiple sclerosis, should cause depletion of dopamine, epinephrine and norepinephrine at the peripheral nerve terminals [87, 91]. Thus, some authors have suggested a depletion of catecholamines as the mechanism of the vascular effect. However, an explanation for why symptoms improve in the horizontal position or in warm at-

mosphere was lacking. Today it seems clear that amantadine inhibits the N-methyl-O-aspartic-acid-evoked release of acetylcholine in a non-competitive way. It is reported that amantadine lowers the stimulating effect of the globus pallidus and of the pars reticularis of substantia nigra to the nucleus subthalamicus in an antiglutaminergic way [21, 54]. The existence of NMDA-receptors in the skin suggests that livedo reticularis may be caused by a still unknown mechanism involving the NMDA-receptors. Livedo reticularis is a reversible sideeffect of amantadine. Löffler 1998 reported that after a two week break of amantadine-treatment the cutaneous signs were still remarkable [54], suggesting a longer discontinuation of the drug is probably necessary. Nevertheless, most patients decide to continue to take amantadine, as the drug has significantly improved their quality of life, while livedo reticularis is asymptomatic.

The spectrum of differential diagnosis in neurological patients with livedo racemosa Livedo racemosa results from irregular focal and persistent impairment of blood flow such as arterial occlusion in arteriosclerosis, vasculitides and – most important in neurology – Sneddon’s syndrome (SS). It is the typical symptom of Sneddon’s syndrome, but also occurs in other disorders. The most important differential diagnoses are livedoid vasculopathy, primary antiphospholipid antibody syndrome (in 5–10%), systematic lupus erythematodes with or without antiphospholipid antibody syndrome, essential thrombocythaemia, thromboangiitis obliterans, polycythaemia vera, polyarthritis, rheumatic disorders and pancreatitis. However, the differentiation from other similar phenomenological disorders may be difficult and has caused significant controversy. A problem of differential diagnosis in patients with livedo racemosa is that SS is defined by cerebrovascular events, but this is usually not the first manifestation of disease. Detailed differential diagnostic reflections with extensive clinical and laboratory examinations in neurological patients with livedo racemosa are therefore necessary.

■ Sneddon’s syndrome (SS) Sneddon’s syndrome is characterised by the association of cerebrovascular events with widespread livedo racemosa [96].SS was first described by Champion and Rook in 1960 [20] and was named after the British dermatologist I. B. Sneddon who reported the combination of livedo racemosa with symptoms of cerebrovascular defect in six patients in 1965 [92]. The syndrome usually occurs in young adults, and more often in women (80% of cases) [46, 55, 106]. The mean age of patients at time

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of first clinical cerebral ischaemic event is typically before the age of 45 years (mean 38.6 years with a range of 16 to 58 years) [28, 29]. A similar combination of strokelike episodes and livedo racemosa has been reported to occur in children in rare circumstances [105]. Data suggest that it is under-diagnosed [93] with the expected incidence of cases to be 4 per 1 million per annum [109]. It has been estimated that the disorder occurs in about 1:2000 stroke patients [97, 98]. It must be stressed that the prognosis in patients with SS is poor compared with young patients with cerebral infarction [10, 103].A mortality rate of 9.5% was reported in a mean observation period of 6.2 years [109]. The family history of patients with SS suggests a significant genetic predisposition.An autosomal dominant pattern of inheritance with incomplete penetrance seems to be possible [29, 61]. Reharny et al. 1998 described neuro-ophthalmological manifestations of SS in a possible autosomal recessive pattern [77]. SS has a chronic progressive course, with Livedo racemosa and symptoms of cerebrovascular defect considered as the primary symptoms [106]. Livedo racemosa may precede the onset of stroke by years and is located on limbs (100% each), trunk (84–89%), buttocks (68–74%), face (15–16%), or the hands or feet (53–59%) [29]. The trunk and/or buttocks are involved in nearly all patients. Livedo was noticed before cerebrovascular events in more than a half of patients. The cerebrovascular defect in SS is due to ischaemic strokes [95]. Most symptoms are related to infarcts of the middle cerebral artery territory [93]. The most frequent results are hemiparesis, sensory disturbances and aphasia. Dysarthria, visual field deficits and drop attacks occur less frequently [93]. Transient ischaemic attacks were reported as frequently as one attack per week to one per year [93]. Spinal strokes have also been reported [5]. Intracerebral, subarachnoid or intraventricular haemorrhage as the presenting form of SS have rarely been reported [5, 61, 64]. Some of these cases involve cerebral haemorrhage during anticoagulant treatment [64], but in very rare cases, cerebral haemorrhage was the first manifestation of SS. Various neurological problems have been associated with SS including chorea, seizures, myelopathy, migraine-like events, acute encephalopathy, internuclear ophthalmoplegia, ophthalmic arterial occlusion and myasthenia gravis [29, 52, 77, 85, 93, 103]. However, headache and vertigo are the most frequent symptoms. These symptoms may precede the onset of livedo racemosa and cerebrovascular symptoms by several years. Although these signs are non-specific, the high incidence suggests causal rather than a coincidental relation. The presence of several other organ manifestations such as cardiac and kidney lesions suggests that it is a systemic syndrome [30]. Secondary symptoms can include arterial hypertension (65%), cardiac abnormali-

ties such as valvulopathy (61%) and ischaemic heart disease, ocular (50–70%), gastrointestinal, renal involvements (50–70%) and venous occlusions [5, 30, 44]. In nearly all patients with SS, cognitive dysfunction occurs in the course of disease: Pathological results have been reported to be obtained primarily in tests which examine figural memory, visuospatial perception and calculation. SS is complicated by the development of dementia and early retirement in about a half of the patients [103]. Livine and Welsh 1987 first described a patient with SS in whom the lupus anticoagulant and anticardiolipin antibodies were documented [52]. The prevalence of antiphospholipid antibodies (aplAB) in SS has had widely differing figures reported, ranging from 0% to 85% depending upon the series [28, 29, 45]. Most authors suggest that 40–50% of SS patients are aplAB-positive [43, 46]. However, dividing SS in a aplAB-positive and an aplAB-negative subtype is a pathophysiological controversy. One line of evidence supporting the idea of subtypes is the occurrence of miscarriage, peripheral thrombosis, and thrombocytopenia. This clinical spectrum is similar to the primary antiphospholipid syndrome (APLS) in

Fig. 1 Livedo racemosa in a patient with Sneddon’s syndrome

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Fig. 2 Livedo racemosa in a patient with Sneddon’s syndrome (detail)

which antiphospholipid antibodies (aplAB) are thought to have a major pathogenic significance [79]. However, the percentage of patients with venous thrombosis is similar in aplAB-positive and aplAB-negative groups. The number of women, who had one or more miscarriages after 10-weeks of gestation has been reported to be higher in aplAB-positive than in aplAB-negative subtypes, although the difference was not significant [29]. Frances et al. reported that thrombocytopenia was present only in the aplAB-positive (45% vs. 30%) subgroup and proteinuria occurred in 11% of aplAB-negative but 26% of aplAB-positive patients. Seizures and clinically audible mitral regurgitations are more frequently observed in aplAB-positive patients [72]. Anti-β2-GP1-antibodies were more frequently detected in aplAB-positive patients while the prevalence of positive ANA was similar in both groups [29]. The fishnet of the livedo seems to be larger in aplAB-negative patients, who therefore frequently had obvious and sometimes troublesome skin involvement. This fact might explain the low prevalence of aplAB in dermatological series of SS [30, 110]. Various prothrombotic abnormalities have also been reported. A high prevalence of heterozygous factor Leiden V mutation was found in aplAB-negative patients with SS [13]. Ayoub and Frances 2004 found Protein Z-Deficiency in aplAB-negative SS. Low levels of protein Z, a down-regulator of coagulation, have been recently linked to an increased risk of arterial thrombosis [3]. Other reported abnormalities are activated protein C resistance, platelet aggregability, increased βthromboglobin levels, modifications of the ratio tissue plasmogen activator/inhibitor and familial deficiency in antithrombin III [35]. To diagnose SS extensive laboratory examinations are necessary to exclude vasculitis, toxic metabolic disturbances and other causes of livedo racemosa.The following

tests are recommended: a full blood and platelet count, sedimentation rate,coagulation tests including detection of antithrombin III,protein C,protein S,activated protein C, protein Z, serum cholesterol and fasting serum glucose, serum immunelectrophoresis, complement, cryoglobulins, cryofibrinogen, rheumatoid factor, antineutrophil cytoplasmic antibodies, lupus anticoagulant and anticardiolipin antibodies, beta-2-glycoprotein I, antinuclear antibodies,anti smooth muscle,anticentromere, Sjogren A and B, antiribonucleoprotein, Scleroderma 70 and antihistone antibodies. Additionally, it is necessary to assess renal function, including urine analysis, serum creatinin, as well as TPHA, VDRL and borrelia serology. The battery of tests in SS should also include magnetic resonance imaging of the brain, magnetic resonance angiography, doppler and duplex sonography of extra- and intracerebral arteries, electroencephalography and examinations including sonography of abdomen, radiography of the chest, echocardiography and 24-hour blood pressure monitoring. Wohlrab et al. 2001 stressed the necessity to repeat neurological examinations twice and magnetic resonance imaging of the brain once a year [106, 107]. MRI easily detects cortical, subcortical or cortical-subcortical abnormalities suggestive of arterial ischaemic infarcts which are frequently multiple. Periventricular white matter changes are also common. Diffuse corticosubcortical atrophy is observed at the late stages of the disease [72, 99]. Some authors recommend cerebral angiography [106, 107]. Angiography carries some risks because SS affects predominantly small intracranial arteries, leading Stockhammer et al. to suggest the combination of MRA and duplex sonography as a strategy for exclusion of large-vessel obstruction [93]. The reported results of cerebral angiography are inconsistent. Many authors described no abnormalities and no evidence of vasculitis in cerebral angiograms. Others have reported a variety of findings including irregular vessel calibres, medium and small vessel stenosis, occlusion or stenosis of major cerebral vessels, transdural anastomoses, large networks of fine collateral vessels and granulomatous leptomeningeal infiltration [2, 33, 93]. In 2003, Aquino Gondim et al. reported a case of lobar intracerebral haemorrhage with an angiographic pattern of “pseudoangiomatosis” as the initial manifestation of SS [2]. Angiography showed prominent leptomeningeal and transdural anastomoses as in Divry-van Bogaert syndrome. However, one problem is that all these diagnostic examinations are non-specific. The only diagnostic criterion with relatively high specificity is the histological proof of occlusion of arterioles by intimal proliferation in skin biopsy specimens. This finding may also occur prior to the development of neurological symptoms. Therefore, histological examination of skin biopsy specimens is of paramount importance. Wohlrab et al.

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stressed that it is better to take more than one deep punch biopsies (4 mm) from different areas of the livedo (from both white and red areas). This method has a sensitivity of 27% with one biopsy, 53% with two biopsies and 80% with three biopsies taken from the white areas [106, 107]. Ultrastructural and immunohistochemical investigations have shown the cells accumulating subendothelially to be migrating medial cells containing smooth muscle actin (Smooth muscle cells or myofibroblastic cells) [59, 95, 106, 107]. It should be noted that this phenomenon was also observed in livedo racemosa due to other disorders [22, 95, 106, 107]. It is important to rule out other differential diagnoses for livedo racemosa. The results of the skin biopsy can therefore only be assessed in connection with clinical symptomatology. Hilton and Footitt reported that the principal neuropathological findings are multiple small cortical infarcts associated with occlusion of medium-sized arteries and prominent focal smooth muscle hyperplasia of smaller arteriole vessels [40]. These findings are similar to those reported in the skin and previous autopsy reports of SS. Unfortunately, stereotactic brain biopsy is invasive and carries a small but definite risk of mortality. It is still unclear whether the association of dermatological and neurological phenomena is coincidental or if these phenomena are manifestations of a single generalized process [15]. Inflammatory features have been observed infrequently and the absence of vasculitis is emphasized [40, 59, 106, 107], but some brain biopsies have revealed the contrary. Boortz-Marx et al. presented a case with granulomatous leptomeningeal infiltrations, although chronic fibrotic changes were predominant [15]. Some authors have described an evolving vascular lesion in cases of SS, including an initial endotheliosis with infiltration of inflammatory cells from the lumen [15, 93, 110, 111]. In aplAB-negative cases, some authors have suggested a primary inflammatory process [93], though a number of studies have not shown inflammatory changes on skin and brain biopsy [43], and the poor efficacy of immunosuppressive therapies argues against a primary inflammatory vascular process in SS [29]. Some other authors have suggested SS to be due to a progressive occlusive, noninflammatory vasculopathy of the small and medium-sized arteries [40, 90]. Based on the existing data, it is safe to conclude that the cause of SS is still unclear and that the aetiopathology remains a source of controversy [111]. The pathogenesis seems to involve a focal thrombotic or embolic process in the arterial or arteriolar vascular system in the skin and the central nervous system [35]. Additionally, autoimmune phenomena orientated towards the endothelial cell have been observed, particularly occurring in combination with the antiphospholipid antibody syndrome. It is debated whether aplAB-positive SS represents a real overlap syndrome or is secondary to an-

tiphospholipid antibody syndrome. Schellong et al. differentiated between a primary idiopathic and an autoimmune or thrombotic form [85]. Frances et al. observed first-degree relatives with systemic lupus erythematosus (SLE) not only in aplABpositive, but also in aplAB-negative patients with SS [29]. Even today, the relationship between aplAB-positive and aplAB-negative status in SS on the one hand, and SS, antiphospholipid syndrome and systemic lupus erythematosus on the other hand is a mystery [30]. SS and primary antiphospholipid syndrome may develop with time into definite SLE. Furthermore, some patients with true primary antiphospholipid syndrome may fulfil four or more ARA criteria for SLE due to both the consequence of thrombotic events and the presence of associated biological abnormalities (lupus anticoagulant and/or anticardiolipin antibody) [29, 30]. Piette et al. stressed that it must be recalled that classification criteria are not appropriate for the diagnosis of an individual patient [71]. Frances and Piette pointed out that aplABpositive and aplAB-negative patients belong to close but different subsets of SS; however, pathological skin changes are quite similar and do not support a very different pathological mechanism [30]. So some degree of overlap may also exist between aplAB-negative SS and SLE. A functional deficit of beta-2-glycoprotein I and Willebrand-factor antigene may also be important [106, 107]. Wohlrab et al. hypothesized that an activation of factor VII and issue thromboplastin causes occlusion of small vessels followed by smooth muscle proliferation [106, 107]. Optimal management of patients with SS also remains an unsolved problem. Controlled trials have not yet been performed. The use of corticosteroids and immunosuppressives seems to be ineffective. However, categorisation of SS patients into two subsets (aplABpositive and aplAB-negative) might influence disease management. Flöel et al. stressed that aplAB-positive patients might be treated like primary antiphospholipid syndrome [28]. A retrospective analysis of patients with primary antiphospholipid syndrome suggested that long-term anticoagulation is advisable [49]. Therefore, in aplAB-positive SS patients, high dose warfarin is the most common therapy used [28]. In aplAB-positive patients, warfarin seems to be more effective than aspirin. In contrast, among aplAB-negative patients, the number of events per year observed with antiplatelet therapy or anticoagulation is quite similar and relatively low [29]. Wohlrab et al. suggested the use of a triple therapy with long-term prophylactic pharmacological therapy with pro-rheological agents (e. g. prostaglandin E1), myocyte proliferation agents (e. g. captopril) and antiplatelet therapy [106, 107]. So prevention or delay of subsequent cerebrovascular damage should be possible to achieve. ACE inhibitors are posited to reduce angiotensin II mediated proliferation and migration of subendothelial

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vascular myocytes. Prostaglandin E1 might improve microcirculation by altering the rheological properties of the blood. It has been reported that five patients treated with this triple combination showed no further deterioration over the course of 3–5 years [28, 106, 107]. Additionally, it is necessary to avoid smoking and oestrogencontaining oral contraceptives [106, 107].

them as a single group [25]. It has been argued that the Divry-van Bogaert syndrome merely represents an infanto-juvenile version of SS [25]. Other authors still differentiate between these two entities because of the presence of anticardiolipin antibodies in SS and the difference in incidence between the sexes [2, 94], although this distinction seems to be implausible.

■ Divry-van Bogaert syndrome

■ Thromboangiitis obliterans

In 1946 Divry and van Bogaert described three brothers with livedo racemosa,seizures,pseudobulbar syndrome, extrapyramidal and pyramidal signs and dementia [96]. Since then more cases have been reported. Divry-van Bogaert syndrome is a very serious disease leading to a bedridden state and dementia [36]. The prognosis of the patients seems to be very poor [36]. Most patients reported to have this very rare syndrome were young males. Bussone et al. reported that death occurs at an average of about 20 years after onset of the first clinical symptoms [18]. Autopsy of patients with Divry-van Bogaert syndrome demonstrated multiple cerebral infarcts, white-matter changes and diffuse non-calcifying cerebromeningeal angiomatosis [94].Imaging studies,in addition to a complete neurological examination, therefore have an important role in the assessment of cerebral lesions due to this corticomeningeal angiomatosis [36]. Angiography shows prominent leptomeningeal and transdural anastomoses. This large network of collateral vessels has been called “angiomatosis”.However,it can be argued that this is a misnomer because there is no evidence of a true neoplastic vascular proliferation [2]. Some groups have referred to it as a “pseudoangiomatosis”, because it is a vascular dilatation with transdural anastomoses [2, 76]. These abnormalities are similar to those in moyamoya disease. Historically the distinguishing features between Divry-van Bogaert syndrome and SS have been the presence of cerebromeningeal angiomatosis and the familiar presentation of Divry-van Bogaert syndrome [94, 96], although there have also been several reports of vascular dilatation with leptomeningeal and transdural anastomoses in SS [2].Adding to the confusion, an autosomal dominant and recessive inheritance in SS has been reported [94]. Aquino Gondim believes that haemorrhage might be due to rupture of an abnormal vessel, similar to the mechanism described in moyamoya [2], particularly in cases with intracerebral haemorrhages. It can be hypothesized that this “pseudoangiomatosis” is a marker of high risk for haemorrhage in SS and thus proposed that cerebral angiography should be performed in all patients with SS. As early as 1987, Ellie et al. could not find distinctive characteristics between Divry-van Bogaert syndrome and SS and so suggested considering

In the neurological literature, we found a disease, published as “cerebral thromboangiitis obliterans” (CTAO), which has a clinical picture similar to SS and Divry-van Bogaert syndrome which is difficult to differentiate from both diseases. Rai et al. described cerebrovascular complications occurring in 2% of patients with Buerger’s disease [74]. CTAO has two types: Type 1 is associated with large artery changes, while type 2 is associated with medium and small artery changes. Rai et al. reported the patients with type 2 CTAO usually have multiple infarcts in the cerebral arterial border zone and may develop progressive cognitive decline. Isolated cerebral thromboangiitis (Spatz-Lindenberg disease) was also described [51]. The patients described in the paper were typically young males who became progressively demented and died young, sometimes from cerebromeningeal haemorrhage. Neuroimaging usually revealed multiple areas of white matter changes. Cerebral angiography usually showed diffuse distal obliteration of the cerebral arteries with deep networks of the moyamoya type [69]. Brain biopsy demonstrated intimal thickening of the walls of leptomeningeal and intraparenchymal arteries, almost to complete occlusion, with an intact internal elastic lamina and media and without inflammation or infiltration. Livedo racemosa was described as lesions similar to those in SS, but without the inflammatory changes characteristic of Buerger’s disease [76]. As these cases do not fulfil the minimal criteria for diagnosing Buerger’s disease without which CTAO is excluded Rebollo and colleagues suggested that CTAO with diffuse livedo racemosa and SS are probably one and the same process [76].

■ Antiphospholipid syndrome (APS) Antiphospholipid syndrome (APS) is characterised by detection of antiphospholipid antibodies (aplAB) (lupus anticoagulant and/or anticardiolipin antibody), associated with arterial or venous thrombosis and/or miscarriage by patients with no associated condition such as autoimmume SLE, malignant, or infectious diseases [19]. The clinical manifestations of antiphospholipid syndrome affect almost every organ or system. The most common manifestations are probably cutaneous ones

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such as leg ulcers, lower limb thrombophlebitis, cutaneous necrosis, peripheral ischaemia and gangrene, acrocyanosis, Raynaud’s phenomenon, purpura, cyanotic macules, haemorrhages, cutaneous nodules and livedo racemosa [23, 50, 66]. Antiphospholipid antibodies have been associated with a variety of neurological manifestations, including cerebrovascular ischaemia, transient ischaemic attacks, cerebral venous sinus thrombosis, dementia, migrainous-like events, seizures, and chorea [17]. The only neurological manifestation that satisfies the diagnostic criteria for the antiphospholipid antibody syndrome is cerebral ischaemia due to thrombosis or embolism of cerebral arteries or veins [17]. The prevalence of aplAB in SS has been reported to range from 0% to 85% [28, 30,72].In the experience of Piette and Frances,it is about 40% [30]. These data are consistent with the hypothesis of direct (i. e. non-ischemia-mediated) interaction between aplAB and cerebral parenchyma [89]. In patients with antiphospholipid syndrome, livedo racemosa and neurological symptoms (aplAB-positive SS) high-dose Warfarin is currently used since it has been shown as the most effective treatment in APS [47, 49].

■ Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease characterised by circulating autoantibodies. Features that define the disease are a particular pattern of autoantibodies (dsDNA or ribosomal proteins) and evidence of organ system damage, usually through immune complex deposition (e. g., in the skin or kidneys) or direct autoantibody effects (e. g., anaemia, thrombocytopenia) [63]. The pooled incidence of SLE seems to be 7.3 per 100,000 [81]. Therapeutic options include chloroquine, methotrexate, ciclosporin, thalidomide, human intravenous immunglobulin, mycophenolate mofetil and immunoablative therapy with and without autologous marrow stem cell transplantation [81]. The most prevalent non-specific mucocutaneous lesions in patients with SLE are alopecia (59.7%), photosensitivity (57%), Raynaud’s syndrome (46.7%), oral ulcerations (15.6%), but also livedo racemosa in 11.7% [83]. Livedo racemosa is more frequent among patients with active disease and with the presence of anti-Ro [67, 83]. In SLE possible neurological symptoms are encephalopathies which manifest by memory loss, confusion, changes in cognition and level of arousal, but also seizures either focal or generalised and behavioural changes including depression. Strokes occur in SLE although the actual frequency remains undefined. Microvascular disease is a frequent histological finding occurring in excess of documented clinical episodes of ischaemia [63].

The relation of SS with SLE probably needs to be reconsidered since the recognition of aplAB. Indeed in SLE both ischaemic cerebral events and livedo racemosa are associated with the presence of aplAB [67, 72]. Piette and Frances, in 2000, pointed out that SLE and aplAB-related SS are indistinguishable [30]. True cerebral vasculitis is very uncommon in SLE. In SLE, nervous system involvement has been attributed to autoantibodies which interact directly with neurons (antineuronal antibodies) or indirectly lead to thrombotic vasculopathy by influencing the coagulation system (antiphospholipid antibodies) [11, 12, 70]. Arteriolar changes in the skin and brain of patients with SS are very similar to those that have been described in SLE patients [40,72,109].Some authors have reported that both SS and primary APS may transform with time into definite SLE [30]. Indeed, Piette and Frances also stress that it is important to consider that SLE should probably not be excluded from the spectrum of SS.

■ Polyarteritis nodosa (PAN) Polyarteritis nodosa (PAN) is a segmentary leucocytoclastic vasculitis that affects small and medium-sized arteries. It is the classic systemic necrotising vasculitis defined by both the widespread vasculitis organ involvement and the necrosis prominent in the wall of affected vessels [63].Although any organ may be involved, those principally affected are the kidney, liver, heart or the gastrointestinal tract. Hepatitis B associated polyarteritis nodosa was separated from other forms to emphasise that the addition of antiviral agents in association with immunosuppressive and anti-inflammatory therapy improves the outcome [63]. In classification there is a distinction between polyarteritis nodosa and microscopic polyarteritis nodosa, which is based on clinically restricted disease and an association with ANCAs in the latter. In polyarteritis nodosa both central and peripheral nervous system abnormalities occur. Peripheral neuropathies, which are both frequent (typically 50–75% of patients) and early (i. e., they are often the presenting features of disease) are considered one of the defining features of the disease. Except for seizures and subarachnoid haemorrhage that may occur early, CNS abnormalities, such as stroke, usually occur later in the course of disease (in ~40% of patients) [63]. The typical cutaneous lesions in the systemic PAN are usually palpable purpura and the presence of nodules. Ulcers, necrosis, gangrene or livedo racemosa being rare [63]. Laboratory studies usually find some evidence of systemic inflammation. Characteristic findings are leucocytosis and eosinophilia, persistent proteinuria and high blood pressure [32]. In 1931, Lindberg described the existence of a cutaneous variant of PAN without vis-

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ceral involvement and a more favourable prognosis. The clinical manifestations are characterised by the presence of cutaneous nodules and livedo racemosa, mainly localised at the lower extremities. The erythrocyte sedimentation rate is usually the only laboratory finding altered in most of the patients with cutaneous PAN. For the accurate diagnosis of this disease histopathological studies are necessary. A deep incisional biopsy usually shows a leucocytoclastic vasculitis with or without associated fibrinoid necrosis [57]. Cutaneous PAN does not require the intensive treatment to bring about remission that is necessary for systemic PAN, but it is very important to pay attention to cutaneous symptoms like livedo racemosa in the spectrum of differential diagnosis.

■ Herman’s syndrome In the Polish neurological literature it is possible to find rare case reports about a syndrome similar to SS [39, 56, 78]. Herman’s syndrome is reported to be a post-traumatic vasomotor syndrome after brain-injuries with livedo racemosa, pyramidal and extrapyramidal symptoms, speech disorders, epileptic seizures and progressive dementia. However, Rebollo et al. concluded that in reality Herman’s syndrome does not exist and is instead a manifestation of SS because of the lack of adequate clinical and pathological evidence of it being a separate phenomenon [76].

■ Migraine In the literature we found numerous reports about the association of livedo racemosa and migraine. Most of patients with SS have suffered from migraine for a long time. The working group of Tietjen et al. pointed out that livedo racemosa is significantly linked with migraine and this association seems to be a marker for stroke risk [97, 98].

■ Cholesterol embolisation syndrome Cholesterol embolisation syndrome is a systemic disease caused by distal showering of cholesterol crystals from atherosclerotic plaques of the aorta or large feeder arteries as a significant complication of vascular procedures including angiography, major vessel surgery or thrombolysis. It causes multi-organ dysfunction including acute renal insufficiency in 50–75% of patients and cutaneous lesions in 32–34% of cases [16, 37]. Cutaneous lesions are livedo racemosa of the lower limbs and/or “blue-toe syndrome” (cyanosis of the toes) mostly presenting as acute, painful, persisting pampini-

form and asymmetrical skin discolorations [108]. The dermatological signs usually occur before renal impairment and reflect embolic disturbances of peripheral circulation [37]. Nodules appear occasionally as a result of the inflammatory reaction surrounding cholesterol crystals [37]. Cutaneous manifestations seem to be important indicators of cholesterol crystal embolisation. Other clinical observations include new-onset or accelerated hypertension resulting from extensive renine release from damaged kidneys, ischaemic events in the central nervous system such as strokes in 14% of cases, in the gastrointestinal system events such as ischaemia of mesenteric artery in 31% of patients, in the muscles in 9% and in the retina in 10% [16]. Eosinophilia is present in over 80% of patients with CCE. It reflects an allergic reaction and generally lasts for only a few days [37]. Livedo racemosa is a common but often under-diagnosed finding in CCE that may not be evident during routine examination performed in the supine posture.A detailed skin examination performed in both supine and upright posture often demonstrates the persistence of previously unrecognised livedo racemosa. The diagnosis of CCE can be determined by histological examination and from clinical symptoms including livedo racemosa and eosinophilia. Deep cutaneous biopsy of areas of livedo racemosa can be safely used to confirm the presence of CCE. Proof lies in the histological picture of slit-like spaces in the arteriolar vessels at the coriumsubcutis junctions, previously occupied by cholesterol crystals dissolved during fixation, and surrounding inflammatory changes with vessel wall thickening. Cholesterol crystal embolism results in a high oneyear mortality rate ranging from 64% to 84% [37]. Because patients with cerebrovascular diseases often have ulcerated plaque in the aorta, vascular procedures for such patients may risk cholesterol embolism. The incidence of CCE increases in patients with atherosclerotic disease, hypertension, a history of smoking and the elevation of baseline plasma C-reactive protein (CRP). The frequency of CCE following left-heart catheterization was 1.4% in Fukomoto’s prospective study with 1,786 consecutive patients [31]. Cerebral catheterization often needs a guiding catheter of smaller gauge than cardiac catheterization and is very unlikely to invade the ascending aorta, and accordingly does not induce CCE as often as cardiac catheterization. Neurologists and neuroradiologists tend to under-diagnose CCE. They are aware of the occurrence of ischaemic stroke due to CCE, but often seem to overlook more common systemic events (i. e., renal failures and cutaneous lesions) [31]. It is important to avoid anticoagulant or thrombolytic therapies because these may actually lead to CCE. Some authors have reported that corticosteroids seem to be useful for reducing the inflammatory response [9, 26]. However, a compromised state accompa-

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nied with CCE often presents after using a therapeutic dose of steroids [37]. Statin is a potential agent for stabilisation of cholesterol-rich plaques and preventing the recurrence of an embolisation [9].

■ Livedoid vasculopathy Livedoid vasculopathy is a rare dermatosis otherwise known as livedoid vasculitis, segmental hyalinizing vasculitis, livedo reticularis with summer/winter ulcerations, atrophie blanche or hypersensitivity vasculitis. It affects young women. The acronym PURPLE [68] describes the clinical symptoms: painful purpuric ulcers with reticular pattern of the lower extremities. The aetiology of the disorder is unknown. Skin biopsy argues against a real vasculitis and shows fibrin deposition within affected walls of vessels and thrombus formation within the lumen [1]. Livedoid vasculopathy seems to be thrombo-occlusive vasculopathy. It can be associated with systemic disorders like SLE or present in an “ideopathic” form [60]. A number of studies report about different coagulation abnormalities: elevated fibrinopeptid A [62], defective release of vascular plasminogen activator [73], decreased thrombomodulin expression [100] and protein C deficiency [4].Acland et al. have suggested that livedoid vasculopathy may be a manifestation of antiphospholipid syndrome [1]. Regarding treatment options of livedoid vasculopathy, we found inconsistent advice in the literature. Various antithrombotic agents have been used [1], including tissue activator [48], prostacyclin and antiplatelet therapy. There are also reports about successful use of corticosteroids and dapson [1]. However, steroids and immunosuppressive drugs have not been shown to have a long-term benefit [1, 41]. Acland et al. concluded that if thromboses have occurred, prophylactic treatment should be similar to that in antiphospholipid syndrome (Warfarin) [1].

■ Other diseases Livedo racemosa has also been recognised in association with a number of other diseases and conditions which are characterised by vasculopathy or coagulopathy. Clinical, pathological and laboratory examinations are important to exclude this secondary livedo racemosa. Livedo racemosa may be a rare cutaneous manifestation in haematological diseases such as essential thrombocythemia [6, 42], polycythemia vera [27], pernicious anaemia [86] and disseminated intravascular coagulation [97, 98]. More often, livedo racemosa is associated with essential and secondary cryofibrogenemia [8, 34, 65, 101]. The diagnosis of cryofibrinogenemia has to be

considered in patients with livedo racemosa, oedema, painful purpura and slow healing ulcera after cold exposure. Other associations of livedo racemosa with diseases may also be caused by coagulopathy, for example relapsing livedo racemosa in the setting of chronic pancreatitis [34]. Liel reported livedo racemosa as a rare manifestation of Grave’s hyperthyroidism associated with anticardiolipin antibodies [53]. In different studies anticardiolipin antibodies were detected in 0–38% of Grave’s disease patients and in up to 14% of patients with Hashimoto’s thyreoiditis. Some authors have reported the rare cutaneous manifestation of livedo racemosa in rheumatoid arthritis, Sjogren syndrome, dermatomyositis, scleroderma and arteriitis temporalis [88, 97, 98, 107]. In these associations an overlap syndrome has to be suspected. Sherer et al. described dermatomyositis and polymyositis associated with the antiphospholipid syndrome. Sherer et al. 2000 concluded that antiphospholipid syndrome can be associated with a wide range of diseases [88]. The rare association of livedo racemosa with calciphylaxis has also been described in chronic dialysis patients [38]. X-ray examinations revealed calcinosis of peripheral arteries, especially of the pelvis, thigh and hands, while histological examinations showed a fibrosis and calcinosis of small subcutaneous arteries. Another rare disease presenting with livedo racemosa is hyperoxaluria [58, 80]. Symptoms are recurrent calcium oxalate nephrolithiasis and nephrocalcinosis, leading to chronic renal failure and death from uraemia. Skin biopsy demonstrates numerous characteristic elongate to diamond-shaped, radially oriented, pale yellow translucent oxalate crystals within the vessels, and vessel walls of the subcutaneous fat that were strongly birefringent under polarised light [58, 80]. Also caused by arterial occlusion by embolising material is livedo racemosa in arterial myxoma [104]. Arterial myxoma may mimic Sneddon’s syndrome: Typical symptoms are livedo racemosa, Raynaud’s phenomenon, multifocal recurring transitory and complete ischemic attacks, muscle pain and feelings of coldness on the forearms [75]. Special staining of skin biopsies with alcain-blue showed arterial occlusion caused by myxomatous material [75]. Livedo racemosa may also be a rare clinical manifestation of post-streptococcal syndromes with arthritis [14] and of fulminate pneumococcal septicaemia [82], infectious diseases including tuberculosis and syphilis. Finally, there are case reports about livedo racemosa as an unusual late manifestation of borreliosis associated with histologically confirmed acrodermatitis chronica atrophicans [7].

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Conclusion In conclusion, it is important to differentiate between physiological livedo reticularis (often named cutis marmorata) and livedo racemosa. Livedo reticularis is evanescent in nature, often becoming more prominent on exposure to cold [97, 98]. In neurological patients it is important to consider amantadine-induced livedo reticularis. Livedo racemosa is always associated with pathological features. It differs from livedo reticularis by its localisation, its persistence on warming, its shape and most important by its histology. Livedo racemosa has been recognised in association with a number of diseases and conditions, so extensive clinical and labora-

tory examinations are necessary. In neurology it is important to consider the possibility of Sneddon’s syndrome. Any case of livedo racemosa requires the search for cerebral neurological lesions. Many affected patients give little attention to the livedo and often are not able to accurately report when they first noticed it [97, 98]. It is important for neurologists to recognise this dermatological symptom by examining neurological patients in the undressed and upright state and by asking patients about dermatological symptoms. ■ Acknowledgements The authors are grateful to M. U. Goebel, PhD, M. Harnish, PhD and H. Meyn, MD for important help and fruitful discussions.

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