Complications of reversible cerebral vasoconstriction syndrome in relation to age.

INTRODUCTION: Reversible cerebral vasoconstriction syndrome (RCVS) has a heterogenous clinical and radiological presentation. We investigated whether RCVS complications vary according to age. PATIENTS AND METHODS: In a pooled French cohort of 345 patients with RCVS, we assessed (1) rates of clinical and radiological complications, and (2) the functional outcome at 3 months according to age as a continuous variable, and in young patients aged ≤ 49 years versus those aged ≥ 50 years. The Commission Nationale Informatique et Liberté and the local ethics committee approved this study (registration number: 202100733). RESULTS: The risk for any focal deficit and for any brain lesion were independently associated with increasing age (OR 1.4, 95% CI 1.1-1.8; p = 0.014, and OR 1.6, 95% CI 1.2-2.1; p < 0.001, respectively). Subtypes of brain lesions independently associated with increasing age were subarachnoid haemorrhage (OR 1.7, 95% CI 1.3-2.3; p < 0.001) and intracerebral haemorrhage (OR 1.5, 95% CI 1.1-2.2; p = 0.023). Frequency of cervical artery dissections peaked at age 30-39, and young age was independently associated with cervical artery dissections (OR 13.6, 95% CI 2.4-76.6; p = 0.003). Age had no impact on the functional outcome, with a modified Rankin scale score of 0-1 in > 96% of patients. CONCLUSION: Age seems to influence rates and types of complications of RCVS, with young age being associated with cervical artery dissections, and increasing age with haemorrhagic complications. If confirmed in larger prospective studies, recognition of age-specific patterns might help to guide clinical management and to identify complications in cases of RCVS and vice versa.

Type of headache at onset and risk for complications in reversible cerebral vasoconstriction syndrome.

BACKGROUND: In a recent Italian study, 30% of patients with reversible cerebral vasoconstriction syndrome (RCVS) presented without thunderclap headache (TCH), and tended to present more severe forms of RCVS than patients with TCH. We aimed to analyze the risk for complications of RCVS in patients with and without TCH at onset. METHODS: In a pooled cohort of 345 French patients with RCVS, we compared patients with and without TCH at onset regarding rates of neurological complications, and the functional outcome at 3 months. RESULTS: As compared to the 281 patients with TCH at onset, the 64 patients without TCH had a higher risk for any neurological complication (61% vs. 24%, OR 4.9, 95% CI 2.8-8.7, p < 0.001). The association was strongest for cervical artery dissections (28% vs. 5%, OR 8.1, 95% CI 3.7-17.6, p < 0.001), followed by posterior reversible encephalopathy syndrome (17% vs. 3%, OR 7.1, 95% CI 2.7-18.4, p < 0.001), seizures (9% vs. 2.5%, OR 4.1, 95% CI 1.3-12.5, p = 0.019), and subarachnoid hemorrhage (41% vs. 16%, OR 3.5, 95% CI 1.9-6.3, p < 0.001). In multivariable analysis, the risk for any neurological complication remained significantly elevated in the absence of TCH (OR 3.5, 95% CI 1.8-6.8, p < 0.001). The functional outcome was equal in both groups, with a modified Rankin scale score of 0-1 in ≥90% of patients. CONCLUSIONS: Absence of TCH at onset might predict a higher risk of complications in RCVS. Our results warrant further multicentric studies to prove this finding.

Long-Term Outcomes After Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- We aimed to further investigate the long-term outcomes after reversible cerebral vasoconstriction syndrome (RCVS). Methods- A longitudinal follow-up study was conducted in 173 RCVS patients. Results- Of the 172 patients who completed a mean follow-up of 9.2±3.3 years, 10 had a recurrent RCVS that was benign in all. Independent predictors of relapse were having a history of migraine and having exercise as a trigger for thunderclap headache during initial RCVS. After new delivery, the rate of postpartum RCVS was 9%. Conclusions- Overall, long-term outcome after RCVS is excellent.

Primary angiitis of the CNS and reversible cerebral vasoconstriction syndrome: A comparative study.

OBJECTIVES: To further improve the distinction between primary angiitis of the CNS (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We compared 2 large French cohorts of patients with PACNS (n = 110, retrospectively and prospectively enrolled) and RCVS (n = 173, prospectively enrolled). RESULTS: Patients with RCVS were predominantly female (p < 0.0001), with migraines (p < 0.0001), and were more often exposed to vasoactive substances (p < 0.0001) or postpartum (p = 0.002) than patients with PACNS. Headache, especially thunderclap headache, was more frequent in RCVS (both p < 0.0001). Thunderclap headache was absent in only 6% of patients with RCVS and was mainly recurrent (87%) and provoked (77%) mostly by sexual intercourse, exertion, or emotion. All other neurologic symptoms (motor deficit, seizure, cognitive disorder, or vigilance impairment, all p < 0.0001) were more frequent in PACNS. At admission, brain CT or MRI was abnormal in all patients with PACNS and in 31% of patients with RCVS (p < 0.0001). Acute ischemic stroke was more frequent in PACNS than in RCVS (p < 0.0001). Although intracerebral hemorrhage was more frequent in PACNS (p = 0.006), subarachnoid hemorrhage and vasogenic edema predominated in RCVS (p = 0.04 and p = 0.01, respectively). Multiple small deep infarcts, extensive deep white matter lesions, tumor-like lesions, or multiple gadolinium-enhanced lesions were observed only in PACNS, whereas cervical artery dissection was found only in RCVS. CONCLUSIONS: Our study confirms that careful analysis of clinical context, headache features, and patterns of brain lesions can distinguish PACNS and RCVS within the first few days of admission in most cases. However, diagnosis remains challenging in a few cases.

Phospholipase A2 in patients with noncardioembolic ischemic stroke and severe inflammatory reaction.

The inflammatory reaction is characterized by increased circulatory levels of various indicators of the severity of inflammation. The objective was to investigate the value of lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with noncardioembolic ischemic stroke and severe proinflammatory reaction. There were investigated prospectively Lp-PLA2 levels in sera from 47 patients with ischemic stroke and severe inflammatory reaction (32 men and 15 women, mean age 63 +/- 4.23 years) as compared to 38 patients with ischemic stroke without inflammatory reaction (21 men and 17 women, mean age 61 +/- 5.52 years) and 114 healthy elderly controls. Lp-PLA2 levels were assessed using the diaDexus PLAC test (a noncompetitive ELISA). Out of 47 patients with ischemic stroke and severe inflammatory reaction 36 presented Lp-PLA2 high levels (79%). Lp-PLA2 was detected with high levels in 17 out of 30 patients with ischemic stroke without inflammatory reaction (45%). Patients with ischemic stroke and severe inflammatory reaction presented Lp-PLA2 with high levels more frequently than the healthy controls (RR 12.1 [95% CI. 6.22 to 19.333], p<0.0001). Levels of Lp-PLA2 were higher in subjects who experienced a stroke as compared to controls. Lp-PLA2 is a strong predictor of recurrent stroke risk and of increased risk of dying. The determination of Lp-PLA2 should be used to predict patient risk of cardiovascular disease and stroke; it does provide additional risk of inflammation when used in conjunction with the traditional markers. Lp-PLA2 might be used not only for risk stratification of stroke patients, but also as target for treatment.

Some clinico-immunological aspects in patients with ocular myasthenia gravis associated with inflammatory bowel disease.

The link between inflammatory bowel disease (IBD) and ocular myasthenia gravis (OMG) is thought to be related to the production of autoantibodies. The aim of this study was to determine the incidence of some antibodies in OMG patients with IBD. Sixty-four patients with IBD and neurological symptoms were examined neurologically and immunologically (41 men and 23 women, mean age 43-5.4 years); mean duration of IBD before the diagnosis of OMG was 7.5 years. The following immunological investigations were performed: anti-acetylcholine receptor antibodies (AChR Abs) (ELISA), anti-smooth muscle antibodies (ASMA) (indirect immunofluorescence), perinuclear anti-neutrophilic cytoplasmic antibodies (p-ANCA) (indirect immunofluorescence), carcinoembryonic antigen (CEA) (ELISA), Saccharomyces cerevisiae antibodies IgA and IgG (ASCA) (ELISA), peripheral lymphocyte counts, immature CD4, CD4/CD8 ratio. Five patients out of 64 with IBD presented OMG. The following antibodies were observed: anti-AChR in 4 OMG patients, ASMA in 4 OMG patients, p-ANCA in 4 OMG patients, CEA in 5 OMG patients, ASCA IgA and IgG in 3 OMG patients. Of 5 OMG patients 4 were positive for >3 antibodies. The peripheral lymphocytic counts were reduced in 5 OMG patients, a decline in CD8 cells and an increase in immature CD4 cells in 5 OMG patients, an increased CD4/CD8 ratio in 5 OMG patients were observed. The association of IBD with OMG was rare. Autoimmune dysregulation is the central defect in both MG and IBD. Further studies are required to define the nature of this association.

Detecting anti-prothrombin antibodies in young women with acute ischemic stroke.

Prothrombin (PT) is a target for antibodies with lupus anticoagulant (LA) activity. Anti-prothrombin antibodies (aPT) were recently identified as antibodies directed toward a phospholipid-binding protein. aPT are a new serologic marker of antiphospholipid syndrome. The objective was to detect aPT in a group of 46 patients with acute ischemic stroke in order to correlate their presence with clinical diagnosis, laboratory and neuroradiological findings. We tested aPT, lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2-glycoprotein I antibodies (anti-bbeta2-GPI) in 46 young women with acute ischemic stroke aged 34-45 years and 43 patients with nonischemic neurologic diseases and 141 normal controls. Anti-prothrombin antibodies were detected by calcium-containing aPT ELISA, aCL and anti-beta2-GPI by ELISA. All samples were screened using the activated partial thromboplastin time (aPTT); the dilute Russell viper venous time (dRVV) coagulation test was performed. The results were statistically analyzed. Anti-prothrombin antibodies were found in 26 (57%) of 46 stroke patients. Out of 43 patients with nonischemic neurological disorders, 2 (4.18%) were positive for aPT. aPT were detected in one (0.70%) of the normal controls. Ten stroke patients (21%) were positive for IgG aPT only, 9 stroke patients (18.2%) for IgM aPT only, and 8 stroke patients (16.9%) for both IgG and IgM isotypes of aPT. Two nonischemic neurological disorders patients (4.18%) presented IgM isotype of aPT. Patients with ischemic stroke presented aPT much more frequently than the healthy controls (OR 182.00 [95% CI 23.382-1416.6]. p < 0.0001). Patients with ischemic stroke presented aPT much frequently than the nonischemic neurological disorders patients (OR 26.650 [95% CI 5.743-123.66], p < 0.0001). When IgG or IgM aPT were considered separately, they were more frequently found in patients with ischemic stroke than in healthy control group (OR 38.889 [95% CI 4.817-313.95], p < 0.0001) and (OR 34.054 [95% CI 4.178-277.5], p < 0.0001), respectively. Simultaneous positive titers for both isotypes of aPT (IgG and IgM) were more frequently found in patients with ischemic stroke than in healthy control group (OR 29.474 [95% CI 3.573-243.12], p < 0.0001). Eleven stroke patients (43%) were negative for aCL, LA and anti-beta2-GPI, but positive for aPT (OR 0.03287 [95% CI 0.001794-0.6022], p < 0.001). aCL, LA and anti-beta2-GPI were not found both in nonischemic neurological disorders patients and in healthy controls.

Changes in plasma levels of complement in patients with acute ischemic stroke.

Inflammatory processes are involved in cerebral ischemia. Patients with ischemic stroke may be predisposed to marked activation of the inflammatory system. The objective was to analyze the association between the level of complement at different stages after stroke and outcome. We collected blood samples from 179 patients (81 men and 98 women, mean age 73 +/- 5.6 years) within 24 hours after ischemic stroke, within 48 to 72 hours and at hospital discharge (16 +/- 7 days) as compared to 156 healthy controls, matching ischemic stroke patients with regard to sex and age. We measured levels of total hemolytic activity of serum complement (EIA method) and of C3, C4 (nephelometric measurements). The data were evaluated using chi 2 test. Within 24 hours after ischemic stroke in 38% patients mean value of CH50 was 148.4 +/- 57 CH50 U Eq/mL (p<0.05), of C3 was 1.49 +/- 0.24 mg/L (p<0.05) and of C4 was 0.32 +/- 0.08 mg/L (p<0.05). Within 48-72 hours after ischemic stroke in 34% patients mean value of CH50 was 167 +/- 5.9 CH50 U Eq/mL (p<0.01), of C3 was 1.58 +/- 0.27 mg/L (p<0.01) and of C4 was 0.38 +/- 0.08 mg/L (p<0.01). At hospital discharge in 31% patients mean value of CH50 was 192.8 +/- 64 CH50 U Eq/mL (p<0.001), of C3 was 1.66 +/- 0.28 mg/L (p<0.001) and of C4 was 0.49 +/- 0.07 mg/L (p<0.001). Patients with ischemic stroke who had elevated complement levels (inflammatory marker) at discharge had a worse neurological disability; complement might directly contribute to vascular damage.

Detection of autoantibodies to ribosome P in lupus patients with neurological involvement.

Autoantibodies to ribosome P react with the cytoplasmic ribosomes and are specific for the diagnostic of lupus with neurological involvement. The objective of this study was to assess prevalence of serum autoantibodies to ribosome P as a biomarker for lupus with neurological involvement. We measured serum autoantibodies in 47 lupus patients with neurological involvement (range 31-52 years, mean age 38.6 years) as compared to 31 patients with lupus without neurological involvement (range 28-56 years, mean age 41.2 years) and 56 healthy subjects matching with both groups with regard to sex and age. Serum autoantibodies to ribosome P were measured by means of ELISA test. The results were statistically analyzed using the Student t-test. A value of p < 0.05 was considered significant. Autoantibodies to ribosome P were detected in 43 (91%) oflupus patients with neurological involvement and in 7 (15%) lupus patients without neurological involvement (p < 0.001). The results confirm that these autoantibodies are released into the blood, they can be easily measured, and they correlate with outcome including neurological involvement. This study provides additional information with regard to autoantibodies to ribosome P in Romanian lupus population with neurological involvement. Detection of autoantibodies to ribosome P appears useful for diagnostic purpose. Higher peak of serum autoantibodies to ribosome P levels correlated well with neurological involvement (highly specific).

Ischemic stroke accompanied by anti-PR3 antibody-related cerebral vasculitis and hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection has been found to be strikingly associated with autoimmune phenomena. Autoantibodies are commonly found in patients with HCV infection. PURPOSE: The aim of the present study was to investigate the presence of anti-neutrophil cytoplasmic antibody (ANCA) in patients with ischemic stroke and HCV infection. MATERIAL AND METHODS: ANCA were determined in sera from 36 patients with ischemic stroke and HCV infection (18 females, 18 males, mean age 75+/-10 years) and 44 healthy controls. Assays employed were indirect immunofluorescence for detection of ANCA and ELISA for anti-proteinase 3 (anti-PR3-ANCA). No one of the patients studied received IFN-alpha treatment before blood collection. RESULTS: ANCA were positive in 21 out of 36 (58 %) patients with ischemic stroke and HCV infection. All sera with ANCA showed cANCA patterns and contained anti-PR3 specificity. HCV patients with ANCA showed a higher prevalence of cerebral vasculitis. CONCLUSION: HCV may be regarded as a possible causative factor in ANCA-related vasculitis.

Serum magnesium in patients with acute ischemic stroke.

Magnesium (Mg) has important effects within the vascular system. Magnesium deficiency was shown to trigger vasoconstriction and enhance vascular endothelial injury, thus promoting the development and progression of atherosclerosis. However, it is still not completely understood whether low serum Mg also promotes the occurrence of stroke. We hereby intended to investigate Mg levels in serum in the early stage of ischemic stroke and to evaluate the relationship between serum Mg concentration and the development of neurological deficits. The study included forty patients with acute ischemic stroke (26 women and 14 men), mean age 56 +/- 4 years, without any other serious injuries. Twenty-one healthy subjects, sex- and age-matched were selected as controls. The serum Mg concentrations were measured colorimetrically on a Hitachi 917 autoanalyzer. Serum levels of Mg were checked on admission, and at 48 hours after the onset of ischemic stroke. Using NIHSS, the neurological deficit was assessed on the 1st day, and 48 hours later. Statistical analysis was performed using the Student t test. The results confirm that there is a relationship between a low Mg concentration in serum at 48 hours after onset of ischemic stroke and the intensity of the neurological deficit. Mean value was 1.39 +/- 0.213 mmol/L (on admission), 1.47 +/- 0.181 mmol/L (at 48 hours after the onset of stroke) versus 1.66 +/- 0.138 mmol/L (in controls). Severity of paresis degree was higher in the patients with low Mg levels (p < 0.05). The serum Mg concentration has been suggested to possibly affect the neurologic state. A decrease in the serum Mg concentration indicates the severity of the injury. A magnesium substitution therapy may be useful.

Evaluation of antiphospholipid antibodies in young women with ischemic stroke.

There is an association between antiphospholipid antibodies (aPL) and ischemic stroke. The detection of aPL in young women is to characterize a subset of patients with venous or/and arterial thrombotic complications, to describe whether aPL are a cause, a consequence, or an accompanying event. Cerebral ischemia is the most common arterial thrombotic manifestation associated with the presence of aPL. In patients with ischemic stroke, diagnostic value of aPL can be increased by patient testing for antibodies against cardiolipin. The aim of the study was to assess the prevalence of IgG-aCL in young women with ischemic stroke. IgG-aCL were screened by ELISA in 34 young women, under the age of 45 (mean age 36.7 years) with ischemic stroke without the common stroke risk factors: hypertension, diabetes, hyperlipidemia, vasculitis or arterial fibrillation, smoking. Other 20 healthy, age and sex matched adults with no evidence of disease were also included as a control group. Twelve of the 34 (35%) patients were found to have aCL of the IgG isotype. The present study confirmed that IgG-aCL may be associated with ischemic stroke; this phenomenon is however relevant only in a small subgroup of young women. They should be sought in all stroke patients under the age of 45, especially those with previous histories of deep venous thrombosis, spontaneous abortion or thrombocytopenia.

Detection of neopterin as parameter of potential monocyte activation in patients with acute ischemic stroke.

The mechanisms by which inflammation may induce endothelial dysfunction are not fully understood. It was analyzed if neopterin (a by-product of activated macrophage metabolism) is elevated in patients with systemic inflammatory insult at the time of ischemic stroke. There were investigated 86 consecutive patients with mean age 67 +/- 7.8 years who were admitted within 24 h after ischemic stroke. A control group of 37 patients with mean age 58 +/- 4.9 years without ischemic stroke was also tested. Measurements of serum neopterin levels were performed using enzyme linked immunosorbent assay. Patients with acute ischemic stroke had significantly higher serum levels of neopterin (mean value +/- SD) than controls: 9.6 +/- 1.2 vs. 7 +/- 0.8 nmol/L (p < 0.01). Immune mechanisms contribute to cerebral ischemic injury. The finding of higher serum levels of neopterin, which is regarded as a humoral component of the immune-mediated inflammatory response, sustains the hypothesis that patients with ischemic stroke may show higher levels of inflammatory markers like neopterin. Our results indicate increased monocyte activation after ischemic stroke. In patients with stroke it has been shown that neopterin was determinant of endothelium-dependent vascular dysfunction. However, these preliminary results need to be confirmed by controlled studies.

Evaluation of granulocyte elastase as a sensitive diagnostic parameter of inflammation in first ischemic stroke.

Several traditional vascular risk factors are associated with proinflammatory alterations, including leukocyte activation, and predispose cerebral vasculature to thrombogenesis on inflammatory stimulation. PMN elastase derived from the activated neutrophils might play an important role in injury. This study tries to elucidate the involvement of activated polymorphonuclear neutrophil proteolytic activity in the pathophysiology of ischemic stroke. Levels of PMN elastase/alpha 1-proteinase inhibitor complex (PMN-E/alpha1-PI) were measured in 145 patients (mean age 72.4+/-6.3) with first ischemic stroke from the onset day (day 0) to 7 days after onset (day 7) and 260 control subjects drawn matched for age, sex. Quantitative estimation of the plasma levels of the PMN-E/alpha1-PI complex was carried out with a highly sensitive enzyme-linked immunoassay (ELISA). Plasma PMN elastase levels were statistically significantly higher on 7 day patients (384.7+/-31.4 microg/L vs 216.5+/-26.8 microg/L on day 0; p<0.01) than in those without ischemic stroke (67.4+/-5.2 microg/L). Plasma PMN elastase may be a well-characterised and sensitive inflammation marker, and it is associated with endothelial dysfunction. PMN elastase can be used as a measure for the activity of granulocytes during an inflammatory response. Furthermore it may be possible to treat such disorders with proteinase inhibitors.

IgG-autoantibodies against oxidized low-density lipoprotein in ischemic stroke onset.

In the arterial wall oxidized Low Density Lipoprotein is a pro-inflammatory chemotactic factor for macrophages and immunoreactive cells. The association between oxidized low density lipoprotein (oxLDL) and stroke is suspected, but not established. The plasma oxLDL level in patients with ischemic stroke would be increased and could serve as a marker of ischemic stroke. Serum oxLDL concentrations were determined in 267 ischemic stroke patients (mean age of 72.6.6 +/- 8.6 years) and in 125 age matched controls. Anti-oxLDL antibodies were measured by ELISA. It was investigated the relationship between the serum titers of anti-oxLDL and ischemic stroke onset (within 24 hours) as compared to healthy control subjects. Thirty-one percent (82/267) of the patients tested had higher anti-oxLDL levels than controls. Mean anti-oxLDL titer was 544.6 +/- 48.2 mU/mL vs 416.2 +/- 31.4 mU/mL respectively, statistically significantly higher than those of controls (p < 0.001). The high concentrations of IgG anti-oxLDL contribute to a cascade of events characterized as immunoinflammatory reactions of ischemic stroke. It is probable that humoral immunity plays a significant role in the very initial stages of ischemic stroke. We can deduce that immune response to oxLDL is of variable importance, regarding pathophysiologic process in the ischemic stroke.

Cerebral ischemic attack secondary to hepatitis C virus infection.

Hepatitis virus C (HCV) is worldwide a health problem, which may lead to serious complications. The aim of this study was to correlate the onset of the cerebral ischemic attack accompanied by mixed cryoglobulinemia, with the chronic hepatitis C virus infection. These studies were carried out in 12 patients with serologic/virusologic confirmed chronic HCV infection associated with ischemic stroke. Ischemic stroke occurred in equal proportion in women and men. The patients did not know of HCV infection diagnosis at that moment. All patients had type II mixed monoclonal cryoglobulinemia, hypergammaglobulinemia with polyclonal IgG and monoclonal IgM, blood hyperviscosity, high level of cryocrit, positive rheumatoid factor, normal levels of serum transaminases, negative serum hepatitis B surface antigen (HBs Ag), negative anti HBc antibodies, positive HCV antibodies, positive serum RNA HCV, decreased serum C3 and C4 levels, antinuclear antibodies-false positive. Immunological tests for autoantibodies, namely, anti-Sm antibody, anti-RNP antibody, anti-SS-A and -B antibodies, and anti-Scl antibody were not detectable due to high level serum cryoglobulin. Cryoglobulin was washed several times with an isotonic chloride solution for purification, then subject to immunological analyses. The purified cryoglobulin contained monoclonal IgM-kappa, polyclonal IgG. Cryoglobulinemia is a risk factor for ischemic stroke, as it causes arterial thrombosis.