[Cerebrovascular events, headache and livedoracemosa - diagnosis at a glance?] / Zerebrovaskuläre Ereignisse, Kopfschmerzen und Livedo racemosa ­ Blickdiagnose?

Sneddon's syndrome is a rare disease characterized by cerebrovascular events and livedo racemosa. There are often autoimmunological comorbidities, especially antiphospholipid antibody syndrome. The underlying pathophysiology is still not fully clarified. A causal therapy does not exist. The reported case shows a patient with a thrombophilic form of Sneddon's syndrome with the main symptoms of headache and thromboembolic events. Symptoms, laboratory parameters, histology and differential diagnoses are explained.

Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown Cause.

BACKGROUND: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon's syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). METHODS: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. RESULTS: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. CONCLUSION: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.

Sneddon's syndrome: case report and review of its relationship with antiphospholipid syndrome / Síndrome de Sneddon: relato de caso e revisão sobre a relação com a síndrome do anticorpo antifosfolipídio

The Sneddon's syndrome is a rare disorder characterized by the occurrence of cerebrovascular disease associated with livedo reticularis. The antiphospholipid syndrome is the most frequent type of acquired thrombophilia, defined by the occurrence of thrombosis or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. Approximately 80% of Sneddon's syndrome patients have an antiphospholipid antibody marker. These antibodies may play a pathogenetic role in some cases of Sneddon's syndrome, and many authors consider these two syndromes as the same entity. Although clinical features of antiphospholipid syndrome and Sneddon's syndrome may overlap, there is a distinction between clinical and laboratory evidence suggesting that these two entities are different diseases. A recent finding of coagulopathies, including elevated levels of coagulation factor VII, decreased levels of protein S, and activated protein C in Sneddon's syndrome patients suggested a possible biological link between the vasculopathy and a primary coagulopathy. Moreover, the clinical course seems to be progressive in Sneddon's syndrome patients and includes increase of disability and cognitive deterioration, more arterial involvement, and the antiphospholipid syndrome shows a more benign course. Both syndromes share clinical and laboratory features, and whether Sneddon's syndrome represents a spectrum of antiphospholipid syndrome remains unclear. Sneddon's syndrome patients have a worse prognosis and may represent a subgroup of patients who demands more rigorous follow-up. It is important to recognize the Sneddon's syndrome, particularly because stroke episodes may be prevented through appropriate treatment.

A síndrome de Sneddon é um distúrbio raro caracterizado pela ocorrência de doença cerebrovascular associada a livedo reticular. A síndrome do anticorpo antifosfolipídio é o tipo mais frequente de trombofilia, definida pela ocorrência de trombose ou morbidade gestacional na presença de anticorpos antifosfolípides persistentemente positivos. Aproximadamente 80% dos pacientes com síndrome de Sneddon apresentam um marcador de anticorpo antifosfolipídio. Esses anticorpos podem exercer um papel fisiopatológico em alguns casos de síndrome de Sneddon, e muitos autores consideram essa síndrome e a síndrome do anticorpo antifosfolipídio a mesma entidade. Apesar de os quadros clínicos das suas síndromes poderem se sobrepor, há evidência clínica e laboratorial distintiva, sugerindo que as duas entidades são doenças diferentes. Um achado recente de coagulopatia, incluindo níveis elevados do fator VII de coagulação, diminuição dos níveis da proteína S, e proteína C ativada em pacientes com síndrome de Sneddon, sugeriu uma possível ligação biológica entre a vasculopatia e coagulopatia primária. Além disso, o curso clínico pareceu ser progressivo em pacientes com síndrome de Sneddon, visto que há aumento de incapacidade e deterioração cognitiva, além de maior envolvimento arterial, enquanto a síndrome do anticorpo antifosfolipídio apresenta um curso mais benigno. Ambas as síndromes compartilham características clínicas e laboratoriais; até qual ponto a síndrome de Sneddon representa um espectro da síndrome do anticorpo antifosfolipídio permanece desconhecido. Os pacientes com a primeira síndrome apresentam pior prognóstico e podem representar um subgrupo de pacientes que requer um seguimento mais rigoroso. É importante reconhecer a síndrome de Sneddon já que os episódios de acidente vascular cerebral podem ser prevenidos com a terapia apropriada.

Sneddon syndrome associated with Protein S deficiency.

Sneddon syndrome (SS) is rare, arterio-occlusive disorder characterized by generalized livedo racemosa of the skin and various central nervous symptoms due to occlusion of medium-sized arteries of unknown. Seizure, cognitive impairment, hypertension, and history of repetitive miscarriages are the other symptoms seen in this disease. Livedo racemosa involves persisting irreversible skin lesions red or blue in color with irregular margins. Usually, SS occurs in women of childbearing age. Protein S deficiency is an inherited or acquired disorder associated with an increased risk of thrombosis. We present a 33-year-old woman with SS with diffuse livedo racemosa, recurrent cerebrovascular diseases, migraine-type headache, sinus vein thrombosis, and protein S deficiency. Protein S deficiency and with Sneddon syndrome rarely encountered in the literature.

Primary antiphospholipid syndrome with and without Sneddon's syndrome.

The main objective of this study was to compare clinical and laboratory data obtained from patients with primary antiphospholipid syndrome (PAPS) with and without Sneddon's syndrome (SS). A transverse study with 54 (85.2% female) PAPS patients (Sapporo criteria) was performed. Demographic, drug use, and antiphospholipid antibodies data were evaluated, as well as clinical and laboratory findings of SS. Patients were subdivided into one of two groups: PAPS with SS and PAPS without SS. Both groups were similar with respect to age (p = 0.05), gender (p = 0.34), race (p = 0.31), weight (p = 0.93), height (p = 0.27), and body mass index (p = 0.75); however, the SS group exhibited higher disease duration (96.0 ± 54.9 vs. 55.2 ± 52.0 months, p = 0.01). By definition, all PAPS with SS patients suffer from stroke, an arterial event; the frequency of stroke events (28.5 vs. 7.5%, p = 0.04), as well as of limb ischemia (100 vs. 30.0%, p < 0.0001) was higher in this group than in the PAPS without SS group. On the other hand, patients in the PAPS without SS group had more venous events, such as deep venous thrombosis, than those in the PAPS with SS group (80.0 vs. 50.0%, p = 0.03). In conclusion, an understanding of the relationship between APS and SS is important in order to identify a subgroup for which more rigorous accompaniment and therapy may be necessary.

A rarely seen syndrome in rehabilitation of hemiplegia: antiphospholipid antibody-negative Sneddon's syndrome.

Sneddon's syndrome is a rarely seen disorder and it is characterized by livedo reticularis (LR) and neurologic findings. Some systematic findings may also be seen with neurologic and cutaneous findings. In this case, we aimed to present a 28-year-old female patient with diffuse LR, cardiac valve disease and migraine-type headache who had a right hemiplegic attack.

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.

Antibodies to glutamate receptor subtype 3 (GluR3) are found in some patients suffering from epilepsy as the main disease, but not in patients whose epilepsy accompanies antiphospholipid syndrome or Sneddon's syndrome.

Autoantibodies (Ab's) to the "B" peptide (amino acids 372-395) of glutamate/AMPA receptor subtype 3 (GluR3) are found in serum and cerebrospinal fluid of some patients with different types of epilepsy. Since such anti-GluR3B Ab's can activate and/or kill neurons in vitro and in vivo, they may contribute to epilepsy. To investigate whether anti-GluR3B Ab's may also be relevant to epilepsy when it accompanies some autoimmune-diseases, we tested for these Ab's in patients suffering from epilepsy that accompanies anti-phospholipid syndrome (APS) or Sneddon's syndrome (SNS), both being autoimmune-diseases with frequent neurological complications. We tested 77 pediatric patients whose epilepsy is their main disease; 31 adult patients whose epilepsy accompanies APS (primary or SLE-associated) or SNS; 45 epilepsy-free APS and SNS patients; and 90 healthy controls. Compared to the controls, significantly elevated anti-GluR3B Ab's were found in 22/77 (29%) patients whose epilepsy is their main disease, but in none of the patients whose seizures accompany APS or SNS. Yet, all the APS and SNS patients harbored the characteristic anti-phospholipid Ab's (aPL), directed against cardiolipin and beta2-glycoprotein I, and had lupus anti-coagulant. Thus, anti-GluR3B Ab's are not crossreactive with aPL, and not produced as a non-specific consequence of seizures on the one hand, or autoimmune-diseases on the other. Taken together with new findings accumulated recently in our lab, we suggest that anti-GluR3B Ab's are produced primarily in the periphery due to specific/non-specific "irritation" of the immune system, and that once they reach the brain via a leaky blood-brain barrier they may cause neuronal/glial damage and facilitate the outburst of epilepsy and additional neurological abnormalities. In contrast, the presence of anti-GluR3B Ab's does not seem to increase the probability of developing APS, SNS or the seizures that often accompany these autoimmune-diseases. These findings may have important diagnostic and therapeutic implications.

[Sneddon's syndrome and systemic lupus erythematosus with cerebrovascular disturbances and widespread livedo].

A comparative clinical and instrumental analysis of 97 patients with Sneddon's syndrome (SS), a combination of cerebrovascular ischemic disturbances with widespread livedo, and 12 patients with systemic lupus erythematosus (SLE) with the same combination, has been conducted. Despite the presence of similar features related to antiphospholipid syndrome (APS)--cerebrovascular disturbances, livedo, fetal loss, peripheral venous thrombosis, thrombocytopenia, antibodies to phospholipids, etc--there were distinct differences between SS and SLE. In SS, no skin lesions ("butterfly", discoid lupus, photosensibilization) typical for SLE as well as sores of mucous oral cavity, polyarthritis, serosity, diagnostically significant titers of antinuclear factor and antibodies to DNA were observed. SS emerged with livedo (44%), cerebrovascular disturbances (24%) and systemic APS appearances (32%). SLE in 75% cases began with its classical symptoms and in 25% with systemic APS signs and never with livedo or cerebrovascular disturbances. For 10.5 +/- 8.0 years, no cases of SS were featured by typical SLE symptoms. Pathomorphological study indicated that SS and SLE were independent diseases. Their similarity was due to development of secondary APS, including cerebrovascular disturbances and livedo, in some patients with SLE.

[Anti-phosphatidylethanolamine antibodies in patients with Sneddon's syndrome].

Anti-phosphatidylethanolamine antibodies (aPE) belong to the group of anti-phospholipid antibodies (aPL) and are directed against neutral phospholipid, connected with co-factor protein, while cardiolipin antibodies (aKL) are directed against negative phospholipid. The paper presents a study of prevalence and clinical significance of IgG aPE in 28 patients (22 women and 6 men, mean age 47.6 +/- 11.6 years) with Sneddon's syndrome (SS), which consists in cerebrovascular disturbances and extensive livedo reticularis. IgG aPE were detected by immune-enzyme assay. The upper normal limit, calculated as mean + 3SD after studying 19 healthy donors, was 0.303 optic density units. aPE were found in 15 (54%), aKL and/or lupus anticoagulant (LA)--in 6 (21%) patients with SS. aPE were found in 10 (46%) out of 22 aKL- and LA-negative patients. Among the aPE-positive patients there was a higher incidence of cortic dementia (53% vs. 8%, p = 0.02), the widening of cortical sulci, detected by means of computed tomography and magnetic resonance imaging (73% vs. 31%, p = 0.05), and mild renal syndrome (73% vs. 16%, p = 0.03). Besides, they displayed a higher rate of headaches (87% vs. 62%), chorea (33% vs. 8%), epilepsy (27% vs. 8%), non-carrying of pregnancy (91% vs. 50%), peripheral venous thrombosis (27% vs. 15%), coronary heart disease (47% vs. 31%), cardiac valvular thickening, detected by means of EchoCG (93% vs. 69%), arterial hypertension (87% vs. 54%), thrombocytopenia (20% vs. 0), anemia (40% vs. 15%); however, the difference was not significant. The results show that aPE detection, performed in addition to detection of classic immunological antiphospholipid syndrome markers (aKL and LA), increases the portion of aPE-positive patients with SS by 33%. aPE are often (in 46% of cases) found in aKL- and LA-negative patients with SS. aPE is likely to be the most significant factor of thrombosis in small arteries of the brain cortex and kidneys, which could explain their association with dementia and renal syndrome.

Sneddon's syndrome: clinical and laboratory analysis of 10 cases.

Sneddon's syndrome is characterized by livedo reticularis and cerebrovascular lesions. We report the cases of women (mean age, 36.2 +/- 8.1 years) diagnosed with Sneddon's syndrome based on the presence of livedo reticularis and characteristic cerebrovascular findings. Seven of these patients had cerebral infarcts on cranial computed tomography scan. Antiphospholipid antibodies were positive in 6 of these cases. Three cases had abnormal levels of antithrombin III. Analyses of chromosome 6 revealed no abnormalities. In 3 of the cases, investigation of the pedigrees revealed autosomal dominant traits. Two cases had epilepsy, and 3 had migraine. One case with migraine also had myasthenia gravis. In addition, we detected inferior altudinal hemianopia in 2 cases, cognitive functional disorder in 3 and depression in 2. Based on these findings, the entire vascular, haematologic, neurologic, and dermatologic systems should be evaluated in patients diagnosed with Sneddon's syndrome.

Factor V Leiden mutation in Sneddon syndrome.

Sneddon syndrome (SNS) is characterized by the association of ischaemic cerebrovascular events and widespread livedo racemosa. Its pathophysiology is still controversial. The aim of this study was to evaluate the prevalence of factor V Leiden mutation in consecutive patients referred for SNS according to antiphospholipid antibodies (aPL) status. Fifty-three Caucasian patients were enrolled from 1996 to 2001. Diagnosis of SNS was based on the presence of a widespread livedo racemosa and at least one clinical neurologic ischaemic event. The following investigations were performed: detection of antithrombin III, protein C and protein S deficiency, lupus anticoagulant, anticardiolipin and anti-beta2 glycoprotein I antibodies, biologic false-positive test for syphilis, and factor V Leiden mutation by direct genomic analysis. Fisher's test and t-test were used for statistics. Detection of aPL on multiple determinations was negative in 31 patients (group 1) and positive in 22 patients (group 2). Factor V Leiden mutation was detected in six patients (11.3%), heterozygous in all. The frequency of this mutation was statistically higher in group 1 (6/31, 19.3%) than in group 2 (0/22; P = 0.035). Within aPL-negative SNS, the comparison of patients with versus without factor V Leiden mutation showed no difference for clinical data or familial history of thrombosis. A high prevalence of heterozygous factor V mutation was found in aPL-negative patients with SNS. This finding adds further arguments to consider SNS as a heterogeneous entity.

The mystery of Sneddon syndrome: relationship with antiphospholipid syndrome and systemic lupus erythematosus.

Since its description in 1965, Sneddon syndrome (SNS) is usually characterized by the association of an ischemic cerebrovascular disease and a widespread livedo reticularis. The presence of many other manifestations suggests that it is a systemic syndrome. The prevalence of anti-phospholipid antibodies (aPL) is highly variable, 41% in our experience. Comparison of patients with or without aPL showed that the fishnet of the livedo was clearly larger in aPL-negative patients who nevertheless, did not develop thrombocytopenia. Seizures and clinically audible mitral regurgitation were more frequently observed in aPL-positive patients. These data lead to consider that SNS is not a unique entity. As patients with primary anti-phospholipid syndrome (APS) and SNS did not differ from those with livedo reticularis, ischemic cerebral events and APS within systemic lupus erythematosus (SLE), there is no reason today to exclude patients with SLE. On one hand, SNS might cover a continuum spectrum joining diverse clinico-biological entities ranging from aPL-negative to SLE-related cases, with primary APS-SNS standing amidst. On the other hand, one might speculate that SNS should be regarded as a nearly similar clinical expression of two distinct disorders, i.e. a peculiar form of APS characterized by preferential arteriolar involvement or on the opposite a primary non-aPL related small artery disease mainly involving brain and skin vessels.

Antibodies to prothrombin in patients with Sneddon's syndrome.

Antiprothrombin antibodies (aPT), a new serologic marker of antiphospholipid syndrome, were studied in 46 patients randomly selected from 73 with Sneddon's syndrome and 20 matched normal controls. aPT were elevated in 26 patients (57%) and were not found in any of the controls. The addition of aPT data increased the proportion of Sneddon's syndrome patients with at least one type of antiphospholipid syndrome marker from 65 to 78%. The finding that aPT are common in Sneddon's syndrome supports the hypothesis that Sneddon's syndrome is a form of antiphospholipid syndrome.