The diagnostic value of skin biopsies in Sneddon syndrome.

BACKGROUND: Sneddon syndrome (SS) is defined by widespread livedo reticularis (LR) and stroke. There is no single diagnostic test for SS and diagnosis can be solely based on clinical features. This cross-sectional case-control study aimed to determine the diagnostic value of skin biopsies in SS patients. MATERIALS AND METHODS: We studied skin biopsies from patients with a clinical diagnosis of SS or isolated LR. We also studied controls with vitiligo or normal skin. Biopsies were considered standardized if 3 biopsies were taken from the white centre of the livedo and reached until the dermis-subcutis border. Biopsies were scored for features of an occlusive microangiopathy without knowledge of the clinical features. Sensitivity and specificity of the biopsy findings were calculated with the clinical criteria as the reference standard. RESULTS: We included 34 SS patients, 14 isolated LR patients and 41 control patients. Biopsies of 17 patients with SS (50%), 4 with isolated LR (31%) and 10 control patients (24%) showed at least one artery in the deep dermis with a thickened vessel wall combined with recanalization or neovascularization (sensitivity 50% and specificity 69% with LR as reference). Standardized biopsies increased the sensitivity to 70%. In a post hoc analysis the combination of an occlusive microangiopathy and the presence of a livedo pattern in the superficial dermis increased the specificity to 92%. CONCLUSIONS: Standardized skin biopsies can support the clinical diagnosis of SS. An occlusive microangiopathy as the only positive criterion for the diagnosis of SS had insufficient specificity for a definite diagnosis.

Sneddon syndrome: a comprehensive clinical review of 53 patients.

BACKGROUND: The presence of livedo reticularis in patients with ischaemic stroke is associated with Sneddon syndrome (SS). Our objective was to present the clinical features of SS patients and to assess the role of antiphospholipid antibodies (APL). METHODS: Consecutive patients, diagnosed with SS between 1996 and 2017, were retrospectively reviewed for their demographic, neurological, dermatological, cardiac and extracerebral vascular features. Diagnosis of SS was made only if other causes of stroke were excluded. Patients with and without APL were included and compared for their clinical features. RESULTS: Fifty-three patients (79% female) were included, of whom 14 patients were APL-positive. Median age at diagnosis was 40 years. Approximately 60% of the patients had ≥ 3 cardiovascular risk factors. There were 129 previous vascular events (66 ischaemic strokes, 62 TIAs and 1 amaurosis fugax) during a median period of 2 years between the first event and diagnosis of SS. Skin biopsy was positive for SS in 29 patients (67%), mostly showing a thickened vessel wall with neovascularization in the deep dermis. After a median follow-up of 28 months, 4 patients, either on antiplatelet or oral anticoagulation therapy, had a recurrent stroke. There were few statistically significant differences between APL-negative and APL-positive patients, including the number of vascular events before diagnosis. CONCLUSIONS: SS predominantly affects young women with a relatively large number of cardiovascular risk factors. Clinical features of SS are comparable across different studies. We found no differences in the main clinical features between APL-positive and APL-negative patients.

[Cerebral vasculitis, a diagnostic labyrinth]. / Cerebrale vasculitis, een diagnostisch doolhof.

- A diagnosis of cerebral vasculitis is frequently considered in patients with new or progressive neurological symptoms for which there is no other explanation.- A clinician considering a diagnosis of cerebral vasculitis should be well aware of alternative diagnoses, since these are generally more common.- Several consecutive examinations are required for diagnosing cerebral vasculitis, because there is no diagnostic procedure that is highly sensitive as well as highly specific.- The added value of the different procedures may depend on the type of blood vessels involved.- Standard MRI examinations are sensitive but not specific.- Special MRI techniques now make it also possible to make images of the vessel wall itself.- Catheter angiography remains important, especially when non-invasive angiographic techniques do not reveal any abnormalities.- Brain biopsy can provide proof of cerebral vasculitis and also serves to exclude mimicking conditions.

Changes in cerebral perfusion around the time of delayed cerebral ischemia in subarachnoid hemorrhage patients.

BACKGROUND: Because the pathogenesis of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is unclear, we studied cerebral perfusion at different time points around the occurrence of DCI. METHODS: We prospectively enrolled 53 patients admitted to the University Medical Center Utrecht who underwent CT perfusion (CTP) scans on admission, and within 2 weeks after hemorrhage on 2 scheduled time points or during clinical deterioration. The occurrence of DCI was assessed according to predefined criteria by 2 neurological observers blinded to perfusion results. Clinically stable patients (no-DCI) served as reference, and patients with other causes of deterioration (n = 11) were excluded. In DCI patients, the day of DCI onset and in no-DCI patients the median day of DCI onset was taken as t = 0. Scans made before and after DCI were clustered into 5 additional time points. At each time point, cerebral blood volume (CBV) and flow (CBF), and mean transit time (MTT) were measured, and absolute and relative (interhemispheric asymmetry) values were compared between DCI and no-DCI patients. RESULTS: Absolute CBF was lower and MTT was higher in the 18 DCI patients than in the 24 no-DCI patients before, during and after DCI. MTT asymmetry increased during DCI and partially recovered afterwards in DCI patients while it remained constant in no-DCI patients. Absolute and relative CBV remained constant in both groups. CONCLUSIONS: Our findings suggest that DCI patients already have diffusely worse perfusion (absolute values) than no-DCI patients before focal worsening (increased asymmetry) occurs and becomes symptomatic. The partial recovery in the measured areas suggests that DCI can be partly reversible.

Secondary infarction in single or in multiple vascular territories: two different entities following subarachnoid hemorrhage?

The pathogenesis of secondary infarctions (SI) after aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. To assess whether SI in single (SSI) or multiple (MSI) vascular territories represent different disease entities, we compared clinical profiles of patients with these patterns of SI. CT/MRI-examinations of 448 patients were reviewed for new infarctions within 28 days after SAH, and categorized into SSI or MSI. Only patients with adequate follow-up imaging excluding any new infarctions were included for analysis (269 patients). Procedure-related infarctions were excluded. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for patients with SSI or MSI versus patients without SI to analyze differences in demographic characteristics, vascular risk factors, disease-related characteristics and treatment modalities. Thirty-six patients had SSI, 53 MSI and 180 no SI. ORs in MSI-patients were >1.5 times higher compared with ORs in SSI-patients for multiple vascular risk factors [MSI:5.4 (2.3-13) versus SSI:1.2 (0.5-2.8)], poor clinical condition on admission [MSI:4.6 (2.4-8.9) versus SSI:2.4 (1.1-5.2)], initial loss of consciousness [MSI:2.6 (1.3-5.3) versus SSI:1.1 (0.5-2.3)] and large amounts of intraventricular blood [MSI:2.9 (1.4-5.8) versus SSI:1.5 (0.7-3.2)]. In multivariate analysis ORs remained higher in MSI for presence of multiple vascular risk factors [MSI:1.9 (1.2-2.9) versus SSI:1.1 (0.8-1.7)] and initial loss of consciousness [MSI:3.0 (1.0-8.9) versus SSI:1.6 (0.6-4.0)]. Our findings suggest that SSI and MSI after SAH are not distinct disease entities. MSI was related to the same characteristics as SSI but to a larger extent, specifically to the presence of multiple vascular risk factors, initial loss of consciousness, larger amounts of intraventricular blood, and poor clinical status on admission.

Association of platelet and leukocyte counts with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: A proinflammatory prothrombotic state may increase the risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). We studied the relationship of levels of leukocytes, platelets, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) with the development of DCI and with clinical outcome in patients with aneurysmal SAH. METHODS: In 125 patients admitted within 72 h after aneurysmal SAH, we dichotomized initial blood levels at their median values and investigated the prediction of DCI with Cox proportional hazard analysis and of poor clinical outcome with logistic regression analysis. We also analyzed concentrations before and after onset of DCI with the paired-samples t test and compared changes with those in patients without DCI. RESULTS: During the development of DCI (unrelated to treatment), patients had a larger increase in counts of platelets (difference 49 x 10(9)/l; 95% CI: 2-98) and leukocytes (difference 2.6 x 10(9)/l; 95% CI: 0.4-5.0) than patients without DCI during the same period. CRP increased during DCI and decreased in patients without DCI (difference 14 mg/l; 95% CI: -29 to 58). ESR increased slightly in both groups (difference 3 mm/h; 95% CI: -15 to 20). None of the determinants at baseline predicted the development of DCI. An increased risk of poor outcome predicted by a high initial leukocyte count (OR 2.5; 95% CI: 1.1-5.7) decreased after adjustment for clinical variables (OR 2.1; 95% CI: 0.8-5.5). CONCLUSION: Counts of platelets and leukocytes disproportionally increase during the occurrence of DCI after aneurysmal SAH. Drugs with anti-thrombotic or anti-inflammatory properties should be studied for prevention and treatment of DCI.

Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin.

BACKGROUND: Several genetic variants involved in hemostasis have been associated with ischemic stroke or myocardial infarction (MI). Stroke patients who carry a prothrombotic genotype may also be at increased risk for subsequent vascular events. PATIENTS AND METHODS: We included 887 patients with non-disabling cerebral ischemia of arterial origin, who were referred to the University Medical Center Utrecht in the Netherlands between 1995 and 2005 and followed them for the occurrence of ischemic stroke, MI or death. The primary outcome was a composite of death from all vascular causes, non-fatal ischemic stroke, non-fatal MI, whichever happened first. We selected 22 prothrombotic variants in 14 genes that were previously associated with ischemic stroke or MI or had evidence of functionality. RESULTS: During a 4.6-year mean follow-up period new vascular events occurred in 135 patients (annual event rate 3.3%). None of the 22 variants was associated with the occurrence of new vascular events. Eight additional analyses with secondary outcomes or among subgroups revealed four associations that were likely to be false positive after accounting for multiple testing. CONCLUSIONS: In this cohort, prothrombotic genetic variants do not affect the risk of new vascular events after cerebral ischemia of arterial origin. This study does not support the use of prothrombotic genetic variants to identify stroke patients at increased risk for new vascular events or to guide antithrombotic treatment.

Spontaneous recovery of dermatomyositis and unspecified myositis in three adult patients.

Dermatomyositis (DM), polymyositis and unspecified myositis are idiopathic inflammatory myopathies in which prednisone is usually started as soon as the diagnosis has been established. Therefore, little is known about the natural history of these diseases and spontaneous recovery may escape attention. Here, we present three patients who achieved remission without administration of immunosuppressants. In these three patients, treatment was not started because of spontaneously improving symptoms and signs during the diagnostic process. After 3-5 years, all patients are still free of muscle weakness. These case reports demonstrate that spontaneous long lasting remission can occur in a small proportion of patients with subacute onset idiopathic inflammatory myopathies. In some patients, immunosuppressive treatment with the risk of serious side effects can perhaps be omitted. However, close and frequent monitoring is required in these instances.

[Diagnostic image (309). An Indonesian woman with headache, confusion and fever]. / Diagnose in beeld (309). Een Indonesische vrouw met hoofdpijn, verwardheid en koorts.

A 30-year-old Indonesian woman presented with headache, confusion, vomiting, diplopia and fever, due to multiple intracranial tuberculomata.

The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.

Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

[Spontaneous bilateral rupture of the Achilles tendon in an elderly woman undergoing prednisone pulse therapy with a history of polymyalgia rheumatica]. / Spontane bilaterale achillespeesruptuur bij een oudere vrouw met prednisonstootkuren en in de voorgeschiedenis polymyalgia rheumatica.

An 83-year-old woman presented at the neurology out-patient clinic with acute bilateral weakness of the calf muscles that had lasted for a few weeks. Ultrasound and MRI evaluation of the Achilles tendons revealed bilateral ruptures. Possible predisposing factors included treatment with prednisone pulse therapy for obstructive pulmonary disease and prior polymyalgia rheumatica. Surgical reconstruction of the tendons resulted in a major clinical improvement. Rupture of the Achilles tendons can occur spontaneously, and sometimes bilaterally. A predisposing factor is present in nearly every case of spontaneous bilateral rupture of the Achilles tendons. As in spontaneous unilateral ruptures, the most frequently described predisposing factor is the use of corticosteroids or quinolones.

Endothelial cell activation markers and delayed cerebral ischaemia in patients with subarachnoid haemorrhage.

BACKGROUND: Endothelial cell activation may be connected with the pathogenesis of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH). AIM: To assess the relationship between serial concentrations of circulating markers of endothelial cell activation (soluble intercellular adhesion molecule-1, soluble platelet selectin (sP-selectin), soluble endothelial selectin, ED1-fibronectin, Von Willebrand Factor (VWF) and VWF propeptide) and development of DCI. METHODS: 687 blood samples were collected from 106 consecutive patients admitted within 72 h after onset of SAH. Changes in levels were analysed in the last sample before and in the first sample after the onset of DCI (n = 30), and in subgroups with DCI occurring within 24 h after treatment of the aneurysm (n = 12) or unrelated to treatment of the aneurysm (n = 18). Patients without DCI (n = 56) served as controls. RESULTS: Concentrations of sP-selectin, but not of the other markers, were found to increase considerably after DCI unrelated to treatment of the aneurysm (increase 25 ng/ml, 95% CI 8 to 43), whereas they tended to decrease in the control patients without DCI (decrease 13 ng/ml, 95% CI -28 to 2.4). Surgery was found to profoundly influence the levels of the markers irrespective of the occurrence of DCI. CONCLUSION: The rise in sP-selectin level during DCI is suggested to be the result of platelet activation, as levels of the other markers of endothelial cell activation were not increased after DCI unrelated to treatment. Whether a causal role of platelet activation is implicated in the development of DCI should be determined in further studies in which the relationship between concentrations of markers and treatment is taken into account.

Early circulating levels of endothelial cell activation markers in aneurysmal subarachnoid haemorrhage: associations with cerebral ischaemic events and outcome.

OBJECTIVE: To investigate the relation of endothelial cell activation with delayed cerebral ischaemia (DCI) and outcome after subarachnoid haemorrhage (SAH). METHODS: Concentrations of soluble (s) intercellular adhesion molecule-1, sE-selectin, sP-selectin, ED1-fibronectin, von Willebrand Factor (vWf), and vWf propeptide were measured within three days of SAH onset. The associations with poor outcome were investigated at three months in 106 patients. In 90 patients in whom the occurrence of cerebral ischaemia could be dated accurately, two analyses were undertaken: one for all ischaemic events (n = 32), including those related to treatment, and another for spontaneous DCI (n = 11). Concentrations of markers were dichotomised at their medians. The associations of endothelial cell activation markers with outcome were expressed as odds ratios (OR) from logistic regression and those with ischaemic events as hazard ratios (HR) derived from Cox regression. RESULTS: Early vWf concentrations were associated with poor outcome (crude OR = 4.6 (95% CI, 2.0 to 10.9; adjusted OR = 3.3 (1.1 to 9.8). Early levels of vWf were also positively related to occurrence of all ischaemic events (crude HR = 2.3 (1.1 to 4.9); adjusted HR = 1.8 (0.8 to 3.9) and with occurrence of spontaneous DCI (crude HR = 3.5 (0.9 to 13.1); adjusted HR = 2.2 (0.5 to 9.8). None of the other markers showed any associations. CONCLUSIONS: Concentrations of sICAM-1, sP-selectin, sE-selectin, and ED1-fibronectin do not predict the occurrence of DCI or outcome. The positive associations of raised early vWf concentrations with ischaemic events and poor outcome after SAH may reflect a predisposition to further ischaemic injury through formation of microthrombi in the cerebral circulation.

Genes and outcome after aneurysmal subarachnoid haemorrhage.

OBJECTIVES: Initial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery.We investigated whether functional polymorphisms in the apolipoprotein E (APOE), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-A (TNF-A), interleukin-1A (IL-1A), interleukin-1B (IL-1B), and interleukin-6 (IL-6) genes are related with outcome after aneurysmal SAH. METHODS: Genotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference. RESULTS: Patients carrying any IGF-1 non-wild type allele had a lower risk of a poor outcome (OR 0.4, 95% CI 0.2-1.0), while carriers of the TNF-A non-wild type allele had a higher risk (OR 2.3, 95% CI 1.0-5.4). We could not demonstrate an association with outcome for APOE (APOE epsilon4 OR 0.4, 95% CI 0.1-1.2; APOE epsilon2 OR 0.7, 95% CI 0.2-2.4), IL-1A (OR 1.8, 95% CI 0.8-4.0), IL-1B (OR 0.7, 95% CI 0.3-1.5) and IL-6 (OR 0.7, 95% CI 0.3-1.8) polymorphisms. CONCLUSIONS: Variation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF-1 wild type allele or carriers of the TNF-A non-wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.

Plasminogen activator inhibitor-1 4G allele in the 4G/5G promoter polymorphism increases the occurrence of cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: In several acute life-threatening diseases, the 4G-allele in the 4G/5G-promotor polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene is associated with higher PAI-1 levels and increased poor outcome, probably by promoting the formation of microthrombi. The aim of the present study was to investigate whether the PAI-1 4G/5G polymorphism is associated with the occurrence of cerebral ischemia, rebleeding, and other events, and clinical outcome after aneurysmal subarachnoid hemorrhage. METHODS: DNA was collected and analyzed in 126 patients with aneurysmal subarachnoid hemorrhage admitted to the Academic Medical Centre Amsterdam and University Medical Centre Utrecht in the Netherlands. All episodes of deterioration were classified according to predefined criteria. Causes of poor outcome and functional outcome were assessed 3 months after the initial bleeding according to the 5-point Glasgow Outcome Scale (GOS). RESULTS: Secondary ischemia occurred more often in patients with the 4G genotype than in patients homozygous for the 5G allele (RR: 3.3; 95% CI: 1.1 to 10.0). No significant differences were found between the groups for rebleeding or other events. Patients with the 4G genotype tended to have a higher risk for poor outcome than patients with the 5G/5G genotype (RR 1.2; 95% CI 0.7 to 2.2). CONCLUSIONS: The 4G allele in the PAI-1 gene increases the risk for cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH) and probably also the risk for poor outcome. After early aneurysm occlusion, treatment aimed at enhancing fibrinolysis might be effective to prevent and treat cerebral ischemia in patients with aneurysmal SAH.

[Diagnostic image (171). A man with a painful red ear. Relapsing polychondritis]. / Diagnose in beeld (171). Een man met een pijnlijke, rode oorschelp. Recidiverende polychondritis.

A 50-year-old man presented with a painful and red swollen right ear, fever, iridocyclitis and a peripheral facial nerve palsy, due to relapsing polychondritis. Immunosuppressive therapy was successful.

Endothelial cell activation is associated with cerebral white matter lesions in patients with cerebrovascular disease.

Cerebral MRI scanning frequently shows white matter lesions in elderly people. They are related to cognitive impairment and may result in dementia. Although vascular risk factors are associated with the presence of white matter lesions, the exact pathogenesis remains unclear. Animal studies have indicated involvement of endothelial cells in the pathogenesis of white matter lesions and possibly dementia. We investigated the relation between endothelial cell activation and white matter lesions in individuals with cerebrovascular disease. In 29 patients with an acute stroke (n = 11) or TIAs associated with a symptomatic internal carotid artery stenosis (n = 18), markers of endothelial cell activation such as intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin, and sP-selectin were measured by means of ELISA. All individuals underwent 1.5-T MRI scanning. White matter lesions were rated for the periventricular and the subcortical region separately. Individuals with severe periventricular white matter lesions had higher levels of sP-selectin (245.5 ng/mL vs. 172.7 ng/mL, p = 0.01) and sVCAM-1 (547.8 ng/mL vs. 454.0 ng/mL, p = 0.04) than those without. This association was only found in individuals with a symptomatic carotid artery stenosis. No such association was found for subcortical white matter lesions. We did not detect any relation between sICAM-1 and sE-selectin and white matter lesions. Endothelial cell activation may play a role in the pathogenesis of white matter lesions, especially in periventricular white matter. Possibly, this activation represents the influence of vascular factors on the cerebral endothelium as a prelude to increasingly severe small vessel disease.

[Treatment of patients with a TIA or a stroke]. / Behandeling van patiënten met een TIA of een herseninfarct.

Patients in the acute phase of a stroke ought to be sent to a centre with a well-organised 'stroke unit' where thrombolysis is possible. The integrated approach at a stroke unit is associated with a better outcome than treatment in a general neurology ward. Intravenous thrombolysis can be carried out responsibly if the treatment is started within 3 hours of the onset of clinical symptoms and if certain conditions are satisfied. However, preventive measures provide the greatest benefit to patients who have experienced a transient ischaemic attack (TIA) or a minor stroke. The treatment of vascular risk factors should therefore receive the greatest priority. In addition to the classical risk factors, hyperhomocysteinaemia, infection with Chlamydia pneumoniae and obesity have all recently been indicated as potential risk factors. For patients with a potential source of embolism in the heart, oral anticoagulants are the treatment of choice, whereas platelet aggregation inhibitors should be the first choice for patients with atherosclerotic lesions in the extracranial vessels. Carotid endarterectomy is now a regular form of secondary prevention, whereas the role of endovascular treatment is currently under investigation.