Marta Carvalho

Mutations of the GLA Gene in Young Patients With Stroke The PORTYSTROKE Study—Screening Genetic Conditions in PORTuguese Young STROKE Patients

Background and Purpose— Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. Methods— During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. Results— Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte &agr;-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). Conclusions— Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

Intracranial Arterial Stenosis

Intracranial arterial stenosis (IAS) is usually attributable to atherosclerosis and corresponds to the most common cause of stroke worldwide. It is very prevalent among African, Asian, and Hispanic populations. Advancing age, systolic hypertension, diabetes mellitus, high levels of low-density lipoprotein cholesterol, and metabolic syndrome are some of its major risk factors. IAS may be associated with transient or definite neurological symptoms or can be clinically asymptomatic. Transcranial Doppler and magnetic resonance angiography are the most frequently used ancillary examinations for screening and follow-up. Computed tomography angiography can either serve as a screening tool for the detection of IAS or increasingly as a confirmatory test approaching the diagnostic accuracy of catheter digital subtraction angiography, which is still considered the gold (confirmation) standard. The risk of stroke in patients with asymptomatic atherosclerotic IAS is low (up to 6% over a mean follow-up period of approximately 2 years), but the annual risk of stroke recurrence in the presence of a symptomatic stenosis may exceed 20% when the degree of luminal narrowing is 70% or more, recently after an ischemic event, and in women. It is a matter of controversy whether there is a specific type of treatment other than medical management (including aggressive control of vascular risk factors and antiplatelet therapy) that may alter the high risk of stroke recurrence among patients with symptomatic IAS. Endovascular treatment has been thought to be helpful in patients who fail to respond to medical treatment alone, but recent data contradict such expectation.

Stroke and multiple peripheral thrombotic events in an adult with varicella

Sirs, Varicella is typically a benign childhood disease caused by varicella zoster virus (VZV), though serious complications can arise [1,2]. Varicella has been commonly associated with stroke in children [3], but exceptional reports have described afflicted immunocompetent adults, repeatedly relating vasculitis with this condition [4–8]. A 39-year-old right-handed male, smoker (10 cigarettes/day), developed varicella 2 weeks after his 4-year-old daughter showed the characteristic rash. Acute pain and pallor of the left lower limb and absent ipsilateral foot pulses suddenly emerged 1 week later, as well as left hemiplegia, left homonymous hemianopia and hemineglect. Emergent lower limb angiography (Fig. 1a and b) showed one occlusive (left femoral artery) and two sub-occlusive thrombi (left common iliac and right femoral arteries); thromboembolectomy was carried out. Intravenous non-fractionated heparin, acyclovir and methylprednisolone (5-day course, followed by oral prednisone and tapering) were prescribed. Acyclovir and corticosteroids were employed because of suspected VZV-related vasculitis. Central retinal artery occlusion of the right eye, probably the first event according to the patient, was later perceived. Laboratory examinations revealed: increased leucocytes (16.87 · 10/l), C-reactive protein (19.3 mg/l) and erythrocyte sedimentation rate (49 mm/h), low protein S (0.18 U/ml, normal range 0.60–1.40), positive anticardiolipin IgM and antibeta2-glycoprotein-I IgM (25.3 MPL and 45.5 SMU, respectively; normal <15), positive VZV-specific IgM and positive VDRL at 1:8 dilutions (TPHA negative). Other blood tests were normal, including folic acid, vitamin B12, homocysteine, thyroid function tests; microbial cultures; screening for HIV, HBV and HCV; immunological screening; other basic coagulation tests and inherited prothrombotic disorders screening. Cerebrospinal fluid examination disclosed 9 cells/ mm, normal protein and glucose levels; negative VZV DNA, anti-VZV antibodies (IgM, IgG), VDRL, TPHA and cultures. Transesophageal echocardiography and ECG were normal. Carotid and transcranial ultrasound showed eccentric luminal stenosis (40%) of the proximal right internal carotid artery with hypoechoic material; on serial testing, gradual shrinkage (to 20% 20 days later) and distal progression were demonstrated – findings that cannot be attributed to an atherosclerotic plaque. Brain MRI (1.5 T) was conducted 1 week after admission, showing the lesions observed in Fig. 1c. On discharge the patient presented right eye blindness, left hemiparesis and hemianopia; 3 months later he walked autonomously using one crutch. All abnormal laboratory findings returned to normal and so remained. Warfarin was stopped 6 months later; his current medication consists of antiplatelet drug and statin. We believe that these data strongly suggest that the vascular events sustained by this patient were associated with VZV, and occurred in the setting of a transitory prothrombotic condition, which also finds support in the fact that anticardiolipin antibodies and protein S ultimately returned to normal values. Nonetheless, analysing all data, we find ourselves unable to further theorize on the pathophysiology of the processes leading to intravascular thrombi formation in this patient. To the best of our knowledge, this case is unique, as previous reports mention VZV-related stroke, without concomitant extracerebral vascular events.

Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine

Disabling orthostatic hypotension, due to insufficiency of the autonomic nervous system, is a common complication of type I familial amyloidotic polyneuropathy (FAP). We investigated whether oral treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-Dops), a noradrenaline precursor, might be of therapeutical benefit. In twenty untreated FAP patients, aged 33 to 44 years, who, because of severe orthostatic hypotension, were bedridden or constrained to a sitting life, supine and erect blood pressure (BP), plasma noradrenaline and tilting time, defined as the interval (s) between the beginning of a 60 degrees head-up tilt and the occurrence of orthostatic symptoms (dizziness, blurred vision or near syncope) were determined before and at repeated intervals during oral treatment with L-threo-Dops, 100 mg bid, for 6 months. Before treatment supine mean BP was 80 (76-85) mmHg (mean and 95% CI), supine plasma noradrenaline was low, 59 (41-77) pg/ml and tilting time ranged from 38 to 118 s. In response to tilt, mean BP immediately fell by 36 (31-41) mmHg, whereas plasma noradrenaline increased by only 11 (0-21) pg/ml (p = 0.05). After 3 to 5 days of treatment with L-threo-Dops all patients experienced marked improvement of their orthostatic tolerance as reflected by their ability to walk freely around. This effect sustained throughout the six months of treatment. Plasma noradrenaline increased moderately by 37 (11-63) pg/ml (p = 0.02) and supine mean BP increased by 8.6 (5.8-12.4) mmHg (p < 0.001) during chronic treatment. Supine or nocturnal hypertension did not develop, the fall in mean BP in response to tilt diminished by 12.5 (6.5-17.3) mmHg (p < 0.001) and tilting time became longer than 600 s in all patients. Because of its efficacy, its sustained duration of action and the lack of side effects, L-threo-Dops is advocated to improve orthostatic tolerance in patients with autonomic insufficiency due to FAP.

Mitochondrial Encephalomyopathy With Lactic Acidosis and Strokelike Episodes Presenting Before 50 Years of Age: When a Stroke Is Not Just a Stroke.

Mitochondrial Encephalomyopathy With Lactic Acidosis and Strokelike Episodes Presenting Before 50 Years of Age: When a Stroke Is Not Just a Stroke Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most common maternally inherited mitochondrial diseases. However, its pleomorphic clinical manifestations and the fact that the maternal relatives carrying the same mutation may be asymptomatic or only oligosymptomatic makes the diagnosis sometimes elusive.

A Neurologist’s Hard Day’s Work: Impact of Inpatient Neurology Consultation in a Tertiary Hospital

INTRODUCTION Consultation of hospitalized patients under the responsibility of other specialties is a very demanding work. However, it is often under-recognized and poorly documented. The aim of the present study was to assess the burden of the inpatient neurology consultation in a Portuguese hospital and to evaluate the performance of our Neurology department regarding this issue. MATERIAL AND METHODS A retrospective study was conducted during 2013, reviewing clinical and demographic data. RESULTS Over one year, the neurologists of our department evaluated 632 inpatients. The commonest reasons for consultation were altered mental state/behavior, focal neurological deficit and seizures. Requests came mainly from medical departments but also from Intermediate and Intensive Care Units. Neurologists suggested further investigation in almost one half of patients and management changes in a similar proportion of patients. A new diagnosis could be established in 63% of cases and the most frequent diagnosis were neurological manifestations of systemic disorders, epilepsy and cerebrovascular disease. Our intervention had impact on the care of 68% of patients. DISCUSSION AND CONCLUSION Different studies in the literature support our findings and highlight the economic and patient care benefits of this activity. Our results suggest that neurological inpatient observation generates useful interventions for the clinical management of these patients.

Cerebral vasoconstriction after carotid endarterectomy

Carotid endarterectomy carries the risk of several complications. We report a 55-year-old woman with recurrent cerebral vasoconstriction postoperatively. She had bilateral high-grade internal carotid artery stenosis and underwent right endarterectomy because of transient left-sided sensory symptoms. She developed a reperfusion syndrome with severe right-sided headache, right frontotemporal oedema and increased velocities in transcranial Doppler ultrasound. Given her gradual increase of velocities and Lindegaard index, together with fixed left sensory and motor deficits, we performed CT angiography, which suggested cerebral vasoconstriction syndrome. A subsequent left carotid endarterectomy triggered a similar cerebrovascular response. We highlight the need for continuous monitoring of cerebral haemodynamics following carotid endarterectomy.

The benefit of EXtending oral antiCOAgulation treatment (EXCOA) after acute cerebral vein thrombosis (CVT): EXCOA-CVT cluster randomized trial protocol:

Rationale After a cerebral vein thrombosis, there is an increased risk of further venous thromboembolic events. The optimal duration of anticoagulation after cerebral vein thrombosis is unknown. Aim To compare efficacy and safety of a policy of short- (3–6 months) versus long-term (12 months) anticoagulation (any type venous thromboembolic events) after cerebral vein thrombosis for the prevention of venous thromboembolic events. Sample size estimates A sample of 1428 patients (749 per arm) allows detecting a reduction from 10 to 5% in the risk of venous thromboembolic event recurrence with 80% power at 5% significance, with 3% dropout rate. Methods and design An international multicenter, prospective cluster-randomized trial with equal allocation between both interventions (ISRCTN25644448). Each cluster is a participating center, which accepted to be randomly allocated to one of the anticoagulation policies. Eligible patients are adults with radiologically confirmed cerebral vein thrombosis within 30 days, and stable to initiate post-acute anticoagulation. Patients judged by the investigator to be an absolute indication for permanent anticoagulation are excluded. Follow-up is at 6, 12 and 24 months. Study outcomes Primary efficacy outcome is any symptomatic and confirmed fatal/nonfatal venous thromboembolic event (recurrent-cerebral vein thrombosis or non-cerebral venous thromboembolic event). Primary safety outcomes include bleeding events during treatment periods and death from any cause. Discussion This study responds to a knowledge gap in the post-acute management of cerebral vein thrombosis patients by comparing short- versus long-term anticoagulation for the prevention of venous thromboembolic event recurrence.

PORTYSTROKE: Screening genetic conditions in portuguese young stroke patients

Miguel Viana-Baptista, MDt; Susana Ferreira, BS2; Teresa Pinho-e-Melo, MD3; Marta Carvalho, MD4; Vitor Tedim Cruz, MD5; c.itia Carmona, MDt; Fernando Silva, MD6; Assun~ao Tuna, MD7; Miguel Rodrigues, MD8; Carla Ferreira, MD9; Ana Amelia Nogueira Pinto, MDlO; Andre Leitao, MDll; Joao Paulo Gabriel, MDt2; Sofia Calado, MD13; J.P. Oliveira, PhD2; and J.M. Ferro, PhD3; for the PORTYSTROKE Investigators