Catastrophic relapses following initiation of dimethyl fumarate in two patients with neuromyelitis optica spectrum disorder.

We report two cases of neuromyelitis optica spectrum disorder (NMOSD) who were misdiagnosed as multiple sclerosis (MS) and developed catastrophic relapses following initiation of dimethyl fumarate. Both patients developed a severe myelitis extending from the cervical cord to the medulla with significant cord swelling, resulting in complete quadriplegia and respiratory difficulties, in addition to severe bilateral visual loss in one patient. It is of note that both catastrophic relapses occurred 2 and 3 months following initiation of dimethyl fumarate.

Real-world retrospective study of effectiveness and safety of FINgOlimod in relapsing remitting multiple sclerosis in the Middle East and North Africa (FINOMENA).

OBJECTIVES: Evidence on the effectiveness and safety of fingolimod in real-world clinical practice in the Middle East and North African (MENA) region is limited. This study aimed to evaluate the effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) in real-world setting in the MENA region. PATIENTS AND METHODS: RRMS patients who had been treated with fingolimod for at least 12 months were retrospectively identified from the databases of 34 centers across the MENA region. Study outcomes included the annualized relapse rate (ARR), relapse-free rate (RFR), time to first and second relapses, mean change in Expanded Disability Status Scale (EDSS), proportion of patients with Magnetic Resonance Imaging (MRI) activity and no evidence of disease activity (NEDA)-3, retention of patients on treatment, as well as all safety measures. RESULTS: A total of 806 patients were included: 66.34 % female; mean age 32.97 ± 9.62 years; mean disease duration 4.92 ± 4.66 years; mean fingolimod use 37.2 ± 16.7 months. Most patients had received previous disease-modifying therapy (79.65 %). Compared to the year preceding fingolimod initiation, RFR improved (33.00%-86.35%; p < 0.001), ARR decreased (0.84 ± 0.73 to 0.16 ± 0.45; p = 0.005), EDSS decreased (2.69 ± 1.74-2.01 ± 1.66; p < 0.001), and the proportion of patients with Gadolinium-enhancing T1 lesions decreased (57.84 % to 12.93 %; p < 0.001), after 12 months of fingolimod treatment. NEDA-3 was achieved in 41.3 % of patients. Median time to first and second relapses was not reached since 86.35 % and 98.39 % of patients had not experienced relapses for the first time and second time, respectively. Eight-hundred one (99.38 %) patients continued fingolimod treatment beyond 12 months. One-hundred thirty patients (16.13 %) experienced adverse events, mainly lymphopenia (5.46 %) and leukopenia (2.11 %), while 13 patients (1.61 %) experienced serious adverse events. CONCLUSION: This study confirms the effectiveness and safety profile of fingolimod in real-world setting in the Middle East and North African (MENA) region.

Polyglycolide/polylactide-coated platinum coils for patients with ruptured and unruptured cerebral aneurysms: a single-center experience.

BACKGROUND AND PURPOSE: Recanalization of cerebral aneurysm is a limitation of bare platinum coils (BPCs). In a swine aneurysm model, polyglycolide/polylactide (a polymer)-coated platinum coils (Matrix) accelerated clot fibrosis and reduced recanalization rate and aneurysmal volume. We aimed to evaluate the safety of Matrix coils in patients with intracranial aneurysm. METHODS: This is a single-center, prospective study of patients with intracranial aneurysms treated with Matrix alone or in combination with BPCs. Follow-up evaluation included a 1-month clinical evaluation and a 6- and 12-month clinical and angiographic examination. Primary adverse events included death, stroke, and permanent neurological deficits. RESULTS: Between May 2002 and January 2004, 52 patients (range 34 to 79 years of age; 38 females) were treated for 54 aneurysms (size 7.9+/-4.6 mm; neck 3.9+/-1.5 mm; 26 ruptured). Matrix alone was used in 13 aneurysms. In 39, we used a combination of Matrix and BPCs. Twenty-one aneurysms had a 6-month follow-up examination (11 Matrix; 10 Matrix combined with bare platinum), and 11 completed the 12-month follow-up evaluation (Matrix only). Adverse events not related to the procedure were 2 deaths (ruptured basilar aneurysms) and 1 stroke at day 10 postcoiling secondary to vasospasm. Procedure-related adverse events were 2 strokes. At 6-month follow-up (n=21) evaluation, 2 of 3 recanalizations needed retreatment. At 12-month follow-up (n=11), there was no recanalization in patients treated with Matrix alone and no significant reduction in aneurysmal size. CONCLUSIONS: Polyglycolide/polylactide-coated coils had a satisfactory safety profile. Significant aneurysmal size reduction after coiling was not observed.

Volume cerebral blood flow reduction in pre-clinical stage of Alzheimer disease: evidence from an ultrasonographic study.

The association of decreased cerebral blood flow with the development of Alzheimer's disease (AD) has been a recent target of interest. By using neuroimaging techniques, growing attention has been devoted to the identification of preclinical AD. In this study, color duplex sonography of cervical arteries was used to measure mean cerebral blood flow (CBF) on 55 amnestic Mild Cognitive Impairment (MCI) patients. Two years after enrollment, excluding patients who progressed to dementia other than AD, two subgroups were identified, patients who developed AD (MCI converters) and patients with preserved cognitive and functional level (MCI non-converters). Examining the mean difference of CBF measured at baseline in the two subgroups obtained, a significant difference was noticed (MCI converters 539.3 +/- 114.3 vs MCI non converters 636.0 +/- 143.9, p < 0.05). MCI patients with CBF higher than median value (558 ml/min) had lower risk of developing AD (specificity 72.2%, sensitivity 68.4%) within a two year follow-up. Ultrasonography of the cervical arteries is a simple, non invasive and widespread technique useful in detecting CBF decline during the MCI stage, thus identifying patients who later will convert to AD.

Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults.

BACKGROUND AND PURPOSE: The effect of apolipoprotein E (APOE) polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of APOE genotypes and conventional risk factors in a case-control study of young adults with cerebral infarct. METHODS: We analyzed 124 consecutive patients (age, 34.7+/-7.3 years) and 147 age- and sex-matched controls. APOE genotypes were determined by restriction fragment-length polymorphism analysis. RESULTS: The prevalence of the epsilon4 allele and epsilon34 genotype was slightly higher in cases than in controls (0.125 versus 0.071 and 0.242 versus 0.136, respectively). Carriers of the epsilon34 genotype and epsilon4 allele were associated with an increased risk of stroke on multivariate analysis compared with the epsilon33 genotype and non-epsilon4 carriers, respectively (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.10 to 4.76; and OR, 2.27; 95% CI, 1.13 to 4.56). ORs for stroke were 2.99 (95% CI, 1.64 to 5.45), 2.69 (95% CI, 1.25 to 5.77), and 5.39 (95% CI, 1.59 to 18.30) for smokers with the epsilon33 genotype, nonsmokers with the epsilon34 genotype, and smokers with the epsilon34 genotype, respectively, compared with nonsmokers with the epsilon33 genotype. Similar results were obtained when epsilon4 carriers and non-epsilon4 carriers were compared in the same interaction model. No significant interaction between APOE and hypertension was found. CONCLUSIONS: In young adults, the APOE epsilon4 allele and cigarette smoking act synergistically, increasing an individual's propensity to have a cerebral ischemic event. This finding may help in determining an individual's predisposition to stroke and more targeted preventive interventions.

Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale.

BACKGROUND AND PURPOSE: The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study. METHODS: We investigated 125 consecutive subjects (age, 34.7+/-7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)(G1691A) mutation, the prothrombin (PT)(G20210A) variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. RESULTS: A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO-). The PT(G20210A) variant was more frequent in the PFO+ group compared with control subjects and the PFO- group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO-, 11% versus 1.1%; 95% CI, 1.09 to 109; P=0.047). A similar distribution was observed for subjects carrying either the PT(G20210A) variant or the FV(G1691A) mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO-, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1; P=0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66; P=0.015), and in 0 subjects in the PFO- group. A trend toward a difference in the frequency of the FV(G1691A) mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%; P=0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups. CONCLUSIONS: In young adults, the PT(G20210A) variant and, to a lesser extent, the FV(G1691A) mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.

Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators.

Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline.

Is transient global amnesia a risk factor for amnestic mild cognitive impairment?

Transient Global Amnesia (TGA) is a common condition of unknown aetiology characterised by the abrupt onset of severe anterograde amnesia, which lasts less than 24 hours. Some authors have suggested that subclinical impairment of memory functions may persist for much longer, but neuropsychological assessment lasting years after TGA attack has not been performed so far. The aim of this study was to evaluate longterm cognitive functions in patients with a previous TGA episode. Fifty-five patients underwent a standardised neuropsychological assessment after at least one-year from the TGA attack, and were compared with 80 age-matched controls. TGA patients showed worse performances on tests evaluating verbal and nonverbal long-term memory and attention, with comparable global cognitive functions. By applying current criteria for amnestic Mild Cognitive Impairment (MCI-a) on TGA subjects, a group consisting of 18/55 (32.7%) MCI-a subjects was identified. There was no association between the presence of MCI-a and demographic variables, vascular risk factors, years since the TGA episode, or ApoE genotype. This study demonstrates that TGA appears to be a relatively benign syndrome although objective memory deficits fulfilling MCI-a criteria persist over time, as detected by multidimensional neuropsychological tasks performed at long-term follow-up.

Serum cholesterol levels modulate long-term efficacy of cholinesterase inhibitors in Alzheimer disease.

The clinical, genetic or biological variables which regulate long-term efficacy of cholinesterase inhibitors (ChEIs) in Alzheimer disease (AD) are still unknown and it is not possible to predict who will benefit from the treatment. In this study we showed that high cholesterol levels correlated with faster decline at 1-year follow-up in AD patients on ChEIs. These findings suggest that serum cholesterol is a modulating factor of treatment response and additional therapies aimed at reducing treatable high cholesterol levels may represent an alternative strategy to improve ChEIs efficacy and slow down disease progression over time.

Microvascular damage and platelet abnormalities in early Alzheimer's disease.

Accumulating evidence from epidemiological and clinical studies suggests that vascular risk factors may be involved in Alzheimer disease (AD). Although the precise contribution of vascular disturbances to the pathogenesis of AD is still unclear, various biochemical and neuropathological data strengthen the view that cerebrovascular deficiencies such as reduced blood supply to the brain and disrupted microvascular integrity in brain parenchyma play a direct or intermediate role in the chain of events ending with a dementia syndrome. The present review focuses on platelet abnormalities and hemostatic alterations in AD. In particular, data from our group, along with current literature, are discussed with regard to the evidence of platelets amyloid precursor protein (APP) processing disturbances in early AD as well as to the recent observations of increased serum levels of thrombomodulin and sE-selectin, which are sensitive markers of endothelial dysfunction. These findings strongly indicate that platelet dysfunction and microvasculature deficiencies occur rather early during the course of AD, thus suggesting a further link between AD-related processes and vascular disorders.

Is mild vascular cognitive impairment reversible? Evidence from a study on the effect of carotid endarterectomy.

Mild vascular cognitive impairment (mVCI) is a broader term that is intended to detect cognitive loss before the development of dementia. The identification of preventable risk factors as well as therapeutic strategies of intervention is still unclear. It has been suggested that carotid endarterectomy (CEA) improves cognitive functions, beyond the well-known preventive effect upon future stroke events. In the present study, we evaluated the beneficial effect of CEA in restoring mVCI. Among a large sample of subjects, who underwent CEA for severe carotid stenosis, two groups were identified according to the absence (CON) or the presence of cognitive impairment (mVCI). A multidimensional neuropsychological and behavioural assessment was performed in the week prior, and at a 3-month follow-up after CEA. The incidence of mVCI in this sample was 38%. Seventy-eight patients completed the follow-up (48 CON, 30 mVCI). Both groups showed a clinical improvement after CEA, although the effect was significantly higher in the mVCI group in regard to verbal memory (short story, p < 0.05), and attention (digit span, p < 0.05) scores. At follow-up, 60% of mVCI subjects were classified as having normal cognitive functions. Index of disease severity and peripheral arterial disease were found to be the predictors of improvement. These findings support that mVCI represents a heterogeneous, in some cases reversible condition. CEA might be considered a therapeutic option to treat and prevent cognitive decline in mVCI patients.

Internal carotid artery stenting in patients over 80 years of age: single-center experience and review of the literature.

BACKGROUND: Thirty percent to 40% of strokes in the elderly are secondary to carotid bifurcation disease. The treatment of internal carotid artery (ICA) stenosis in this patient population is a clinical dilemma. Age more than 80 years is a risk factor for carotid endarterectomy (CEA). Carotid artery stenting (CAS) may be also associated with increased peri-procedural complications in this age group. DESIGN: This study was a single-center, retrospective database analysis evaluating CAS in patients more than 80 years old. Primary outcome included death, myocardial infarction (MI), or ipsilateral stroke. Secondary outcome included re-stenosis at 30 days, 6 months, and 1-year post-procedure. RESULTS: Between March 2001 and March 2004, CAS was performed in 178 patients. Twenty-four patients were more than 80 years old (range 80-91), and 16 men, 70.8%, were symptomatic. Success rate was 100% with residual stenosis of <20%. At the 30 days follow-up there was 1 non-Q wave MI (4.2%), 1 transitory ischemic attack (TIA), and 1 femoral occlusion in the symptomatic group. There were no deaths at 1-year follow-up evaluation as well as no ICA re-stenosis. CONCLUSIONS: CAS can be performed in patients more than 80 years old. Complications may be higher than in younger patients. However, because of the high prevalence of stroke in octogenarians, randomized trials should include this patient population.

Advances in treatment of acute ischemic stroke.

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, nonaggresive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.

Advances in treatment of acute ischemic stroke.

Stroke carries a severe toll in terms of loss of life and disability for patients and their families. Until 10 years ago, physicians, and in particular neurologists, had a conservative, non-aggressive approach to this devastating disease. The advent of thrombolytic therapy not only proved that acute ischemic stroke is treatable, but also that early reperfusion can dramatically change the outcome of acute stroke patients. As a result of these trials, intravenous (IV) tissue plasminogen activator (t-PA) has been approved for treatment of acute ischemic stroke within 3 hours after symptom onset in the United States, Canada, Australia, and the European Union. The near future is extremely promising. Imaging modalities, such as diffusion- and perfusion-weighted images, as well as CT perfusion and CT angiography, to better select patients for treatment are now routinely performed in most academic medical centers. Novel IV and intra-arterial (IA) agents have been developed and tested. Emerging therapies will soon be available to increase the therapeutic windows for thrombolysis both by better screening patients using MRI or CT and by new IV and IA treatments. Several multicenter controlled trials in both imaging-guided decisions and therapeutic agents are either completed or being performed. We review data on advancement in imaging and treatment of acute ischemic stroke, in particular focusing on pharmacologic and mechanical IA thrombolysis.

Jugular valve incompetence: a study using air contrast ultrasonography on a general population.

OBJECTIVE: Internal jugular valves are the only venous valves between the heart and the brain. Conditions such as coughing and other precipitating activities may result in retrograde cerebral venous flow because of the absence or presence of internal jugular valve incompetence, allowing brief transmission of high venous pressure and resulting in brain disturbance. Knowledge of these valves and their noninvasive evaluation might be useful in clinical practice. METHODS: We applied air contrast ultrasonographic venography to a large sample of healthy subjects (n = 125) to evaluate the ultrasonographic aspects of internal jugular valves and their competence. RESULTS: The valves were observed in 121 (96.8%) of 125 subjects and were present bilaterally in 107 (85.6%) and unilaterally in 14 (11.2%). In 4 subjects we did not detect the valves. Retrograde venous flow was present in 48 (38.4%) of 125 subjects. The frequency of internal jugular valve incompetence was significantly higher on the right side (36 [30.2%] of 119) than on the left (7 [6.4%] of 109; P < .0001). Retrograde venous flow due to incompetence of jugular valves was significantly more frequent at older ages (<50 years, 20%; and > or =50 years, 38.75%; P < .03) and was more frequent in men (33 [25%] of 132) than in women (10 [10.41%] of 96; P < .02). CONCLUSIONS: Air contrast ultrasonographic venography is a noninvasive method for evaluating internal jugular valves and identifying retrograde venous flow. This information may be useful in clinical and interventional care.