Life history of cutaneous vascular lesions in Sneddon's syndrome.

Sneddon's syndrome is a potentially fatal arterio-occlusive disorder characterized by generalized livedo racemosa and cerebrovascular lesions. Skin biopsies often fail to yield diagnostic arterial lesions. In the present series, affected vessels were found in skin biopsies from 12 of 15 patients with Sneddon's syndrome. Selection of the correct biopsy site (seemingly uninvolved skin at the center of a livedo racemosa area), adequate biopsy size (1 to 2 cm), and serial sections are essential for the detection of relevant vascular pathology. Only small to medium-sized arteries of the dermis-subcutis boundary were found to be involved. Lesions follow a distinct course. The initial stage displays partial detachment of endothelial cells, adhesion of mononuclear cells interspersed with fibrin ("endothelitis"), a marked edema of the surrounding connective tissue with numerous dilated capillaries, and a predominantly lymphohistiocytic infiltrate with polymorphonuclear leukocytes. In the early phase a sponge-like plug is formed from mononuclear cells, fibrin, and red blood cells, leading to partial to complete obstruction. A perivascular inflammatory infiltrate, devoid of polymorphonuclear leukocytes, is located around affected arteries; in the adventitia of the occluded vessel, a very regular corona of dilated capillaries appears that is continuous with more peripheral dilated and branching vessels. Organization of the occluding plug ensues in the intermediate stage by "subendothelial cell proliferation," most likely due to immigrating smooth muscle cells. In the final stage, the occluding artery undergoes fibrosis, shrinkage, and atrophy.     

A patient with idiopathic cholesterol crystal embolization: effectiveness of early detection and treatment

A 72-year-old man was admitted to our hospital because of progressive renal dysfunction persisting for 1.5 months. Physical examination showed livedo reticularis of the toes of both feet, peripheral edema, and gait disturbance due to the toe pain. The levels of blood urea nitrogen (50.0 mg/dL) and creatinine (2.81 mg/dL) were elevated, and eosinophilia (10%, 870/μL) was noted. A biopsy of the area of livedo reticularis revealed cholesterin crystals. The patient had not undergone angiography, anticoagulation therapy, or antithrombotic treatment. Idiopathic cholesterol crystal embolization was diagnosed. Transesophageal echocardiography revealed intimal thickening of the aorta and plaque. Oral steroid therapy was started because of the progressive renal dysfunction. After steroid therapy, the symptoms improved. Early diagnosis and treatment are important. Renal dysfunction is a common symptom in elderly patients. Cholesterol crystal embolization should also be considered as a cause of unexplained renal dysfunction, especially in such patients.     

Yq- in a child with livedo reticularis, snub nose, microcephaly, and profound mental retardation.

A child with terminal deletion of the long arm of the Y chromosome (Yq--) presented with marked livedo reticularis, snub nose, microcephaly, short stature, and other dysmorphic features. He was profoundly mentally retarded. Most of the patients with Yq- have been reported as having varying dysmorphic features, mental retardation, and short stature. This child, in addition to the above, has livedo reticularis and microcephaly. He was of normal birthweight and, therefore, does not come into the syndrome of microcephaly, snub nose, livedo reticularis, and low birthweight dwarfism. Further information on Yq- should be obtained to ascertain if consistent patterns of abnormalities exist.     

Livedo Reticularis as a Criterion for Antiphospholipid Syndrome

Many consensus meetings were organized in an attempt to improve the present criteria for antiphospholipid syndrome (APS) classification. In this regard, a high prevalence of antiphospholipid antibodies in systemic lupus erythematosus patients was reported in association with the presence of livedo reticularis (LR). In these studies, the association between LR, migraine, and the development of thrombosis (strokes, valvular dysfunctions) was evident. During the last decade, it was strongly suggested that many clinical symptoms (LR, valvular dysfunctions) or laboratory features (thrombocytopenia) should be considered as "minor criteria" for APS. The inclusion of these clinical symptoms in the criteria for APS classification could become of additive value especially when they exist together in one patient. This review summarizes the data that question or support this idea.     

Unusual manifestations of the antiphospholipid syndrome

The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous and arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or antibodies to the protein "cofactor" b2 glycoprotein I. Single vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Any combination of vascular occlusive events may occur in the same individual and the time interval between them also varies considerably from weeks to months or even years. Deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation in this syndrome. Cerebrovascular accidents-either stroke or transient ischemic attacks-are the most common arterial thrombotic manifestations. Early and late fetal losses, premature births and pre-eclampsia are the most frequent fetal and obstetric manifestations. Additionally, several other clinical features are relatively common in these patients, i.e., thrombocytopenia, livedo reticularis, heart valve lesions, hemolytic anemia, epilepsy, myocardial infarction, leg ulcers, and amaurosis fugax. However, a large variety of other clinical manifestations have been less frequently described in patients with the APS, with prevalences lower than 5%. These include, among others, large peripheral or aortic artery occlusions, Sneddon's syndrome, chorea, transverse myelopathy, intracardiac thrombus, adult respiratory distress syndrome, renal thrombotic microangiopathy, Addison's syndrome, Budd-Chiari syndrome, nodular regenerative hyperplasia of the liver, avascular necrosis of the bone, cutaneous necrosis or subungual splinter hemorrhages. In this article, some of these "unusual" manifestations are reviewed.     

The 'primary' antiphospholipid syndrome: antiphospholipid antibody pattern and clinical features of a series of 23 patients.

Twenty-three patients with the 'primary' antiphospholipid syndrome were studied over 2-6 years. Twenty-two (96%) had antiphospholipid antibodies detected by ELISA (87% had antibodies to thromboplastin and 70% to cardiolipin), and 18 out of the 21 tested patients (86%) had lupus anticoagulant activity by coagulative assays. Mean age of the cohort was 29.9 years and the sex ratio (female:male) 4.75:1. Eleven patients presented 18 venous and/or arterial thrombosis and 13 had 25 foetal losses (84% occurred during the second and third trimester). Other clinical features were migraine, livedo reticularis, and epilepsy. Three patients had relatives with systemic lupus erythematosus. Thrombocytopaenia was seen in 33%, antinuclear antibodies in low or moderate titre in 30%, and haemolytic anaemia in 13%. During the follow-up, two patients presented recurrent thrombosis despite anticoagulant therapy, one of them dying because of recurrent pulmonary thromboembolism. Four patients achieved successful term pregnancies after treatment with aspirin and a further patient after treatment with aspirin and low dose prednisolone. No patient developed systemic lupus erythematosus or any other definable connective tissue disease. The 'primary' antiphospholipid syndrome may exist as a distinct clinical entity and all younger patients presenting with thrombotic events, foetal losses and/or thrombocytopaenia, without any evidence of a well defined disease, should be tested for antiphospholipid antibodies in order to rule out this syndrome.     

New subsets of the antiphospholipid syndrome in 2006: "PRE-APS" (probable APS) and microangiopathic antiphospholipid syndromes ("MAPS")

The concept of "probable" antiphospholipid syndrome (APS) is almost identical with several conditions which may presage the development of the APS with its major complications of large vessel thromboses resulting in deep vein occlusions in the lower limbs (DVT) particularly and strokes. These conditions comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions. These conditions, comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions may be followed, often years later by diagnosable APS. The issue whether these patients should be more aggressively treated on presentation in order to prevent the thrombotic complications. A new subset of the APS is proposed viz. microangiopathic antiphospholipid syndrome ("MAPS") comprising those patients presenting with thrombotic microangiopathy and demonstrable antiphospholipid antibodies who may share common although not identical provoking factors (e.g. infections, drugs), clinical manifestations and haematological manifestations (severe thrombocytopenia, hemolytic anaemia) and treatments viz. plasma exchange. Patients without large vessel occlusions may be included in the MAPS subset. These conditions include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and the HELLP syndrome. Patients with catastrophic antiphospholipid syndrome (CAPS) who do not demonstrate large vessel occlusions also fall into this group. Disseminated intravascular coagulation (DIC) has also been reported with demonstrable antiphospholipid antibodies and also manifests severe thrombocytopenia and small vessel occlusions. It may cause problems in differential diagnosis.     

Histocompatibility class I and II antigens in extensive kindred with Sneddon's syndrome and related hypercoagulation disorders

We have studied the relationship between the histocompatibility class I and II antigens and Sneddon's syndrome (SS) in a Spanish patient with SS and her relatives (13 available members of an extensive 3-generation pedigree with diverse autoimmune hypercoagulation abnormalities). The patient and her father were diagnosed with a primary antiphospholipid antibody syndrome and were HLA-A30-B13-Bw6. In addition, a HLA-Bw6-DQ1 association was present in all the members of this kindred. These data suggest that the combination of the histocompatibility class I and II antigens in this family may be a marker for predisposition to SS.     

Vasculitis from the dermatological point of view]

In vasculitis, dermatologists generally examine two kinds of patient who present with small-vessel vasculitis as defined by the Chapel Hill Consensus Conference nomenclature, and idiopathic cutaneous polyarteritis nodosa (CPN). CPN is a vasculitis of small and medium-sized arteries within the skin that does not involve internal organs. When these patients visit my clinic, I characterize the cutaneous manifestations at initial presentation and assess the histopathological findings. In systemic antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, the characteristic cutaneous clinical pattern of microscopic polyangiitis is livedo reticularis, whereas Churg-Strauss syndrome presents as purpura and petechiae with paresthesias on the lower extremities. When a patient presents with nodules on the elbows with histological palisading granuloma, diagnosis of three ANCA-associated vasculitis including Wegener's granulomatosis should be considered. In immune-complex-mediated vasculitis, Henoch-Sch?nlein purpura (HSP) is characterized by palpable non-thrombocytopenic purpura on initial clinical presentation. These clinical cutaneous investigations in vasculitis patients may allow us to refine our earlier diagnostic strategies. On the other hand, histological examination in a cryoglobulinaemic vasculitis patient revealed microvascular thrombus and leucocytoclastic vasculitis in the dermis. From these findings, I speculated that the presence of thrombosis may be somehow related to the pathogenesis of the vasculitis process and investigated the association between vasculitis, especially immune-complex-mediated vasculitis, and antiphospholipid antibodies (Abs). Serum levels of IgA anticardiolipin antibody (aCL) are elevated in the initial active stage of adult HSP, suggesting that the IgA aCL may play some role in the onset of adult HSP. We also suggest that CPN could be dependently associated with the presence of anti-phosphatidylserine-prothrombin complex Abs.     

Evaluation of novel assays for the detection of autoantibodies in antiphospholipid syndrome

Patients with antiphospholipid syndrome (APS) present with clinical features of recurrent thrombosis and pregnancy morbidity and persistently test positive for the presence of antiphospholipid antibodies (aPL). At least one clinical (vascular thrombosis or pregnancy morbidity) and one lab-based (positive test result for lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein 1 antibodies) criterion have to be met for a patient to be classified as having APS. Nevertheless, the clinical variety of APS encompasses additional signs and symptoms, potentially affecting any organ, that cannot be explained exclusively by a prothrombotic state. Those manifestations, also known as extra-criteria manifestations, include haematologic (thrombocytopenia and haemolytic anaemia), neurologic (chorea, myelitis and migraine) manifestations as well as the presence of livedo reticularis, nephropathy and valvular heart disease. The growing body of evidence describing the clinical aspect of the syndrome has been paralleled over the years by emerging research interest focusing on the development of novel biomarkers that might improve the diagnostic accuracy for APS when compared to the current aPL tests. This review will focus on the clinical utility of extra-criteria aPL specificities. Besides, the promising role of a new technology using particle based multi-analyte testing that supports aPL panel algorithm testing will be discussed. Diagnostic approaches to difficult cases, including real-world case studies investigating the diagnostic added value of extra criteria aPL, particularly anti-phosphatidylserine/prothrombin, will also be examined.     

Sex and gonadotropic hormones in arteriopathy with lesions of the brain and skin (Sneddon's syndrome)

Changed levels of sex and gonadotropic hormones in the follicular and lutein phases of the menstrual cycle have been revealed in 12 women with Sneddon's syndrome. The detected disorders contribute to the genesis of obstetrical and gynecological abnormalities and of arteriopathy, which are characteristic of this syndrome. Reduced testosterone levels in 3 female and 4 male patients correlate with disordered sexual function.     

Relapsing polychondritis presenting as cutaneous polyarteritis nodosa

Summary Relapsing polychondritis is an infrequently diagnosed, though not neccessarily uncommon, systemic disorder characterized by recurrent and potentially destructive inflammation of cartilaginous structures, the eye, and the audiovestibular and cardiovascular systems. Although dermal involvement occurs in approximately 25% of patients with relapsing polychondritis, in only few cases has a skin biopsy been obtained revealing lesions such as leukocytoclastic vasculitis, livedo reticularis, erythema nodosum or keratodermia blenorrhagicum. We describe a patient with relapsing polychondritis in whom a cutaneous polyarteritis nodosa preceded cartilage inflammation by 6 months. Cutaneous polyarteritis nodosa is a rare form of vasculitis that appears to be limited primarily to the skin, muscles, and joints. In contrast to the systemic form of the disease it is characterized by the absence of visceral lesions and a relapsing but benign course. The present case and the fact that vasculitis is a concomitant feature in approximately 30% of patients with relapsing polychondritis [21] demonstrates that this condition may not represent a distinct clinical entity.Abbreviations CPN cutaneous polyarteritis nodosa - RP relapsing polychondritis Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Childhood-onset systemic lupus erythematosus-related antiphospholipid syndrome: A multicenter study with 1519 patients

ObjectiveTo assess childhood-onset systemic lupus erythematosus-related antiphospholipid syndrome(cSLE-APS) in a large Brazilian population.MethodsA retrospective observational cohort study was carried-out in 27 Pediatric Rheumatology university centers, including 1519 cSLE patients.ResultscSLE-APS was observed in 67/1519 (4%) and was diagnosed at disease onset in 39/67 (58%). The median disease duration was 4.9 (0–17) years. Thrombosis recurrences were evidenced in 18/67 (27%) cSLE-APS patients. The most frequent thrombosis sites in cSLE-APS patients were: venous thrombosis in 40/67 (60%), especially deep vein thrombosis in 29/40 (72%); arterial thrombosis in 35/67 (52%), particularly stroke; small vessels thrombosis in 9/67 (13%) and mixed thrombosis in 3/67 (4%). Pregnancy morbidity was observed in 1/67 (1%). Non-thrombotic manifestation associated to cSLE-APS occurred in 21/67 (31%), mainly livedo reticularis in 14/67 (21%), valvar thickening in 4/67 (6%) and valvar vegetations not related to infections in 2/67 (3%). None of them had catastrophic APS. Further analysis demonstrated that the median of SLICC/ACR-DI [1(0–5) vs. 0(0–7),p < 0.0001] was significantly higher in cSLE-APS patients compared to cSLE without APS. The frequencies of cerebrovascular disease (40% vs. 1%,p < 0.0001), polyneuropathy (9% vs. 1%,p < 0.0001), SLICC/ACR-DI ≥1 (57% vs. 27%, p < 0.0001) and intravenous cyclophosphamide use (59% vs. 37%, p < 0.0001) were significantly higher in the former group.ConclusionsOur large multicenter study demonstrated that cSLE-APS was a rare condition, occurring during disease course with a high accrual damage. Central and peripheral neuropsychiatric involvements were distinctive features of this autoimmune thrombosis.     

Role of viral-bacterial associations in meningitis in children]

A total of 50 section cases of meningitis in children were investigated. All patients revealed acute viral respiratory infections with generalization, including lesions of the central nervous system (CNS). In 14 children moreover meningococcal infection was diagnosed. In 30 children lesions of the CNS were due to mixed bacterial microflora. In 6 children along with acute viral respiratory infections (AVRI) mycoplasmosis was also revealed. Etiology of the process was determined on the basis of characteristic structural changes in the CNS and other organs, findings of virological and bacteriological investigations. In the majority of children the intravascular blood coagulation was observed. Waterhouse-Friderichsen's syndrome was revealed mainly in meningococcal infection. In order to ascertain the data obtained case records of 120 children, who had undergone treatment in connection with meningococcal infection, were analysed. It turned out that all 42 children, who had developed this disease independently, recovered. Combination of the disease with AVRI led to fatal outcomes in 12 cases out of 72.     

Noonan syndrome and cavernous hemangioma of the brain

We present two patients with multiple characteristics that occur in Noonan phenotype and cavernous hemangioma of the brain. The first patient, who had been diagnosed radiographically as having a cavernous hemangioma in the left basal ganglia at age 15 years, developed massive intracerebral hemorrhage, resulting in sudden death at home at 19 years. The second patient, who was diagnosed radiographically as having a cavernous hemangioma in the left parietal lobe at age 17 years, is being followed carefully (the patient is currently 18 years old). A review disclosed four cases of structural cerebrovascular abnormalities with or without subsequent hemorrhage. Neither these four patients nor our two patients had any severe anomalies in the heart or large vessels, which are frequently seen in patients with Noonan syndrome. Cerebrovascular abnormalities might have a significant influence on the prognosis of patients with Noonan syndrome, especially those having no severe abnormalities in the heart or large vessels.     

Thin Glomerular Basement Membranes in Patients with Hematuria and Minimal Change Disease

A detailed morphometric analysis of glomerular basement membrane (GBM) thickness was carried out on biopsies from 16 patients exhibiting normal histology and unremarkable immunofluorescence. Eleven of these patients presented with proteinuria, 8 in the nephrotic syndrome range, while 5 had hematuria as well. The remaining 5 patients presented with hematuria only. Eight patients had an initial diagnosis of minimal change disease, 4 were diagnosed as thin-membrane nephropathy, 2 had Alport syndrome, and the remaining 2 had hypertensive nephropathy. Quantitative morphometric analysis of GBM identified 3 subsets of patients. The first subset consisted of 6 patients: 5 adults, with an average GBM width of 361+/- 34 nm, and 1 child. The second subset included 8 patients with thin GBMs and a mean thickness of 253+/- 15 nm. The last subset comprised 2 patients with Alport syndrome showing marked variability in GBM thickness. This study has confirmed the presence of thin GBMs in hematurics, but has also revealed GBM thinning in 50% of patients with a diagnosis of minimal change disease.     

Vitamin B12 deficiency neurological syndromes: a clinical,MRI and electrodiagnostic study

BACKGROUND: Vegetarianism is an important cause of vitamin B12 deficiency, especially in countries like India. We managed 17 patients with neurological syndrome due to vitamin B12 deficiency in a tertiary care referral teaching hospital which caters to relatively affluent population. AIM: To evaluate neurophysiological and MRI changes in patients presenting with vitamin B12 deficiency neurological syndrome and interpret these is the light of reported autopsy findings. SETTING: Tertiary care referral teaching hospital. METHODS: Patients with vitamin B12 deficiency neurological syndrome diagnosed by low serum vitamin B12 and/or megaloblastic bone marrow were subjected to clinical evaluation and spinal MRI. The neurophysiological tests included nerve conduction studies, tibial somatosensory evoked potential (SEP), motor evoked potential (MEP) and visual evoked potential (VEP) studies. The recovery was defined on the basis of 6 months Barthel Index score into complete, partial or poor. RESULTS: There were 17 patients with vitamin B12 deficiency neurological syndrome, 3 were females and 12 lactovegetarian. The clinical syndrome was that of myelopathy in 8, myeloneuropathy in 5, dementia myelopathy in 3 and neuropathy in 1 patient. All the patients had impaired joint position and vibration sensation in the lower limbs and 4 had in upper limbs as well. Lower limbs were spastic in 13 and upper limbs in 2 patients. Spinal MRI revealed T2 hyperintensity in cervicodorsal region in 6 and cord atrophy in 3 patients. Sural nerve conduction was abnormal in 8 and peroneal conduction in 5 patients. In one patient all sensory nerve conductions were unrecordable but motor conductions were normal. Tibial SEP was abnormal in 12 out of 15 and lower limb MEP in 8 out of 12 patients. P100 latency of VEP was prolonged in 7 out of 13 patients. Right to left asymmetry was present in tibial SEP in 4 and VEP in 2 patients. At 6 months followup 2 patients improved completely, 7 partially and 3 had poor recovery. Clinical recovery correlated with MEP but not with SEP or MRI changes. CONCLUSION: The evoked potential and MRI changes in vitamin B12 deficiency neurological syndrome are consistent with focal demyelination of white matter in spinal cord and optic nerve. Myelopathic presentation is commoner and SEP is more frequently abnormal. The outcome at 6 months correlated with MEP changes.