Pontine autosomal dominant microangiopathy with leukoencephalopathy: Col4A1 gene variants in the original family and sporadic stroke.

BACKGROUND: (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients. PATIENTS AND METHODS: Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients. RESULTS: PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients. CONCLUSION: Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.

KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.

A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke.

BACKGROUND AND PURPOSE: We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. METHODS: We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed. RESULTS: Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09-1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59-2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13-1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P=0.065; 29.1% versus 16.5% for old lesions, P<0.001), infarct location in the brain stem (12.4% versus 6.9%, P<0.001), and in white matter (27.8% versus 21.1%, P=0.001). Microbleeds (16.3% versus 4.7%, P=0.001), higher grades of white matter hyperintensities (P<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST (P=0.018) were more often present in patients with dolichoectasia. CONCLUSIONS: Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Family History in Young Patients With Stroke.

BACKGROUND AND PURPOSE: Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. METHODS: We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed. RESULTS: A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage (P=0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P=0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P=0.047). CONCLUSIONS: Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Characteristics of Susac syndrome: a review of all reported cases.

In Susac syndrome, occlusions of microvessels--presumed to be mediated by an autoimmune response to an as yet unknown antigen--lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome.

Prevalence of unknown atrial fibrillation in patients with risk factors.

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. 'Silent', undiagnosed AF is often only detected with the first complication, e.g. a stroke. Detection of 'silent' AF prior to the first cerebrovascular event would be valuable to institute adequate therapy and prevent complications related to AF. We performed a simple electrocardiography (ECG) screening for silent AF in patients at risk for AF. METHODS AND RESULTS: One hundred and thirty-two adult patients (76 male; age: 64 ± 14, mean ± SD) without known AF presenting to the diabetes, hypertension, and dyslipidaemia clinics (76 outpatients in the different clinics), or to the stroke unit (56 stroke survivors) at the University Hospital Muenster were screened for unknown AF using a simple patient-operated, single-channel ECG recorder (Omron hcg-801-e, Germany). Silent AF was found in 7/132 patients (5.3%; four stroke survivors, two diabetics, one patient with hypertension, median CHADS2 score: 2 (25-75 quartiles 1-3). The prevalence of AF was higher in patients with multiple risk factors for stroke and AF: AF was found in 3% (1/32) patient with hypertension and no other risk factors for AF, but in 7% (5/71) patients with two risk factors including stroke patients (diabetes and hypertension, stroke, or stroke and hypertension), and in 11% (1/9) with stroke, hypertension, and diabetes. Standard ECG did not detect further patients with AF. CONCLUSION: A simple ECG screening could help to detect 'silent' AF prior to the first cerebrovascular events, especially in patients with multiple cardiovascular conditions. Larger studies of such a screening are warranted.

Serum from interferon-ß-1b-treated patients with early multiple sclerosis stabilizes the blood-brain barrier in vitro.

Interferon-ß (IFN-ß) stabilizes the blood-brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-ß-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-ß-treated patients resulted in a significantly (p < 0.05) reduced permeability as compared with untreated patients. Our findings show that sera from IFN-ß-1b-treated MS patients have a stabilizing effect on the in vitro BBB. We suggest an unknown potentially pro-inflammatory factor in the serum of MS patients that may lead to a BBB dysfunction and can be modulated by IFN-ß.

Intravenous lacosamide--an effective add-on treatment of refractory status epilepticus.

Status epilepticus (SE) is a frequent neurological emergency requiring immediate treatment. Therapy usually requires intravenous anticonvulsive medication. Lacosamide is a novel anticonvulsant drug that is available as infusion solution. We describe seven patients with focal SE who were treated with intravenous Lacosamide. All patients in our case series were unsuccessfully treated with other antiepileptic drugs before Lacosamide i.v. was added. In all cases, SE was terminated within 24 h after Lacosamide. There were no serious side effects or adverse events attributable to Lacosamide i.v. Our data suggest that Lacosamide might be an effective add-on treatment, if standard drugs fail or are unsuitable.

Arterial elongation ("redundancy") is not a feature of spontaneous cervical artery dissection.

The prevalence of elongation of the internal carotid arteries (ICA) is suggested to be significantly higher in patients with spontaneous cervical artery dissection (sCAD) than in other stroke patients. We reassessed this hypothesis in a case-control study by means of an improved semiautomated MR imaging technique. We compared the length of the cervical arteries in patients with and without sCAD. In 40 consecutive patients with MRI proven sCAD, we measured the arterial lengths of both ICA from the cervical bifurcation to the carotid-T, as well as both vertebral arteries (VA) from their origin to the vertebro-basilar junction. The measurements were performed on the basis of high-resolution, three-dimensional (3D) MR-angiographies with the use of specialized software calculating the length of the coaxial line of these arteries. These results were compared to the findings of 40 age-matched controls with an ischemic stroke due to other etiologies. The mean arterial lengths in patients with sCAD (left ICA 169.62 mm, right ICA 170.05 mm, left VA 233.56 mm, right VA 224.57 mm) compared to patients without sCAD (left ICA 171.07 mm, right ICA 171.88 mm, left VA 232.54 mm, right VA 222.08 mm) did not differ significantly. In our case-control study, cervical arteries are not elongated in patients with sCAD when compared to age-matched stroke patients due to other etiologies. The finding of an arterial elongation is not a distinct clinical marker in patients with suspected sCAD. The macroscopic appearance of the cervical arteries on MR-angiograms does not suggest an underlying elongative or dilatative arteriopathy.

Endoscopic characteristics and levodopa responsiveness of swallowing function in progressive supranuclear palsy.

Dysphagia is a frequent and early symptom in progressive supranuclear palsy (PSP) predisposing patients to aspiration pneumonia. Fiberoptic endoscopic evaluation of swallowing (FEES) has emerged as a valuable apparative tool for objective evaluation of neurogenic dysphagia. This is the first study using FEES to investigate the nature of swallowing impairment in PSP. Eighteen consecutive PSP patients (mean age 69.7 +/- 9.0 years) were included. The salient findings of FEES in PSP patients were compared with those of 15 patients with Parkinson's disease (PD). In 7 PSP patients, a standardized FEES protocol was performed to explore levodopa (L-dopa) responsiveness of dysphagia. Most frequent abnormalities detected by FEES were bolus leakage, delayed swallowing reflex, and residues in valleculae and piriformes. Aspiration events with at least one food consistency occurred in nearly 30% of PSP patients. Significant pharyngeal saliva pooling was observed in 4 PSP patients. We found no difference of salient endoscopic findings between PSP and PD patients. Endoscopic dysphagia severity in PSP correlated positively with disease duration, clinical disability, and cognitive impairment. No correlation was found with dysarthria severity. In early PSP patients, swallowing dysfunction was solely characterized by liquid leakage with the risk of predeglutitive aspiration during the oral phase of swallowing. Two PSP patients showed relevant improvement of swallowing function after L-dopa challenge. Chin tuck-maneuver, hard swallow, and modification of food consistency were identified as the most effective therapeutic interventions. In conclusion, FEES assessment can deliver important findings for the diagnosis and refined therapy of dysphagia in PSP patients.

Methodological quality of preclinical stroke studies is not required for publication in high-impact journals.

Omitting quality characteristics in animal stroke studies leads to an overestimation of the efficacy of candidate stroke drugs. Nevertheless, the methodological quality of preclinical stroke studies is often limited. As publishing of research results in high-impact journals is an important motivation for scientists, we analyzed whether study quality predicts high-impact publishing. Animal stroke studies of neuroprotective drugs that were recently investigated in clinical phase II/III trials were included in the analysis. Data on the study quality and other important study characteristics were extracted. Regression analyses were performed to estimate the effect of the study characteristics on the journal's impact factor. We identified 117 studies that investigated 12 different drugs. Study quality was not associated with the impact factor before (beta=-0.2, P=0.50) and after adjustment for other study characteristics (beta=-0.3, P=0.19). There was a significant association of the number of investigated mechanisms and applied techniques with the impact factor (beta=1.4, P<0.0001). Our findings show that the quality of animal experimental stroke studies is not relevant for publishing in high-impact journals. The major predictor for accepting preclinical stroke studies in high-impact journals is the complexity of the investigation into a stroke drug's mode of action.

The impact of lesion location and lesion size on poststroke infection frequency.

OBJECTIVES: Infections in patients with stroke are common and significantly affect outcome. Various predictors of poststroke infections were determined, such as degree of neurological impairment and implementation of therapeutic interventions. The authors investigated whether stroke location and stroke size are independent risk factors for poststroke infections. METHODS: 591 patients with acute stroke who were treated on our stroke unit were included in a prospective observational study. Predefined endpoints were pneumonia, urinary-tract infection (UTI) and other infections. The OR of infections was calculated for various stroke locations, stroke lateralisation and three categories of stroke size. Logistic regression models were used to adjust for factors significantly associated with poststroke infections in a single-factor analysis. RESULTS: In the single-factor analysis, the left anterior cerebral artery territory was associated with pneumonia. After adjustment for relevant covariates, this association was no longer statistically significant. Stroke lateralisation showed no association with infection frequency. The largest stroke size was positively associated with pneumonia (OR 3.5, p<0.001). The smallest lesion size was significantly less associated with the occurrence of UTI (OR 0.4, p<0.01). CONCLUSION: In this study, lesion size is an independent risk factor for the development of poststroke infection. Particular brain regions associated with infections could not be determined.

How much does hypertension affect cognition?: explained variance in cross-sectional analysis of non-demented community-dwelling individuals in the SEARCH study.

Vascular pathology impairs cognition and impaired cognition increases the risk of dementia. Hypertension is arguably the vascular risk factor that can be reverted best. Here we estimated the effect magnitude of hypertension by determining the variance in cognition explained by systolic blood pressure (sBP) in non-demented community-dwelling individuals. We recruited 525 individuals (mean age 65, range 40-85) selected from the city registry of Muenster, Germany, measured cognitive performance with a comprehensive test battery and assessed vascular risk based on glycosylated hemoglobin, serum cholesterol, high sensitive C-reactive protein, body mass index, smoking pack years, and blood pressure. Including gender and education as well as the vascular risk factors, multiple linear regression analysis for different age groups showed that in midlife age groups systolic blood pressure explained up to 11% of the variance in cognitive performance. These findings suggest that in non-demented community-dwelling individuals hypertension may account for one tenth of cognitive impairment and thus for an increased risk for dementia.

Cortical compensation associated with dysphagia caused by selective degeneration of bulbar motor neurons.

According to recent neuroimaging studies, swallowing is processed within multiple regions of the human brain. In contrast to this, little is known about the cortical contribution and compensatory mechanisms produced by impaired swallowing. In the present study, we therefore investigated the cortical topography of volitional swallowing in patients with X-linked bulbospinal neuronopathy (Kennedy disease, KD). Eight dysphagic patients with genetically proven KD and an age-matched healthy control group were studied by means of whole-head magnetoencephalography using a previously established swallowing paradigm. Analysis of data was carried out with synthetic aperture magnetometry (SAM). The group analysis of individual SAM results was performed using a permutation test. KD patients showed significantly larger swallow-related activation of the bilateral primary sensorimotor cortex than healthy controls. In contrast to the control group, in KD patients the maximum activity was located in the right sensorimotor cortex. Furthermore, while in nondysphagic subjects a previously described time-dependent shift from the left to the right hemisphere was found during the one second of most pronounced swallow-related muscle activity, KD patients showed a strong right hemispheric activation in each time segment analyzed. Since the right hemisphere has an established role in the coordination of the pharyngeal phase of swallowing, the stronger right hemispheric activation observed in KD patients indicates cortical compensation of pharyngeal phase dysphagia.

Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: lessons from acrylamide-induced neuropathy.

Endoneurial macrophages are crucially involved in the pathogenesis of neuropathies. Historically, the macrophage response in neuropathies is believed to be of hematogenous origin. However, recent studies could demonstrate an intrinsic generation of the early macrophage response by resident endoneurial macrophages after traumatic nerve injury and in a model of hereditary neuropathy. We hypothesized that the local macrophage response might suffice to generate an appropriate macrophage response in mild neuropathies, supplemented by infiltrating macrophages only in severe nerve pathology. To clarify this assumption, we investigated the macrophage response in acrylamide-induced neuropathy as a model of a slowly progressive neuropathy with a defined onset. We induced the neuropathy in bone marrow chimeric mice carrying green fluorescent protein transgenic bone marrow, allowing the differentiation of resident (GFP(-)) and invading hematogenous endoneurial (GFP(+)) macrophages. Quantification of GFP(-) and GFP(+) endoneurial macrophages in the sciatic nerve revealed an increase only of resident macrophages in proximal parts, whereas in distal parts a minor additional influx of hematogenous macrophages was observed. The immunohistochemical profile of GFP(-) and GFP(+) macrophages was similar but distal GFP(-) macrophages were differentially activated than their GFP(+) counterparts. Characterization of CCR2-deficient mice revealed a function for this chemokine system in attracting hematogenous macrophages but not in generating the intrinsic macrophage response. In conclusion, we provide evidence for a role of resident macrophages in acrylamide-induced neuropathy. Resident endoneurial macrophages intrinsically generate the macrophage response in this slowly progressive neuropathy, which only becomes supplemented by hematogenous macrophages in distal areas of more pronounced damage.

Early recovery and functional outcome are related with causal stroke subtype: data from the tinzaparin in acute ischemic stroke trial.

INTRODUCTION: Baseline severity and causal subtype are predictors of outcome in ischemic stroke. We used data from the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) to further assess the relationship among stroke subtype, early recovery, and outcome. METHODS: Patients with ischemic stroke (<48 hours ictus) and enrolled into TAIST were included. Severity was measured prospectively as the Scandinavian Neurological Stroke Scale (SNSS) at days 0, 4, 7, and 10. Causal subtype as large artery atherosclerosis (LAA), cardioembolism (CE), or small vessel occlusion (SVO) was assigned after standard investigations. The rate of recovery was calculated as the change in SNSS at each time point. Functional outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index at day 90. RESULTS: Analyses were performed on the 1190 patients in TAIST who met criteria for LAA, CE, and SVO. The largest change in SNSS score occurred between baseline and day 4 and was greatest in SVO (median improvement 4 U), compared with LAA (median improvement 2 U) and CE (median improvement 2 U) (P < .0001). If no improvement in SNSS had occurred by day 4, irrespective of subgroup, then early recovery (median SNSS improvement by day 10: 2) and functional outcome (mRS 4) tended to be limited; patients who recovered early tended to continue to improve (median SNSS improvement by day 10: 11) and had a better outcome at day 90 (median, mRS 2). CONCLUSIONS: Recovery is related to causal subtype. In all subtypes most recovery occurred by day 4, and was predictive of longer-term functional outcome.

Stroke severity, early recovery and outcome are each related with clinical classification of stroke: data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST).

INTRODUCTION: Baseline severity and clinical stroke syndrome (Oxford Community Stroke Project, OCSP) classification are predictors of outcome in stroke. We used data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST) to assess the relationship between stroke severity, early recovery, outcome and OCSP syndrome. METHODS: TAIST was a randomised controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Severity was measured as the Scandinavian Neurological Stroke Scale (SNSS) at baseline and days 4, 7 and 10, and baseline OCSP clinical classification recorded: total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) and posterior circulation infarction (POCI). Recovery was calculated as change in SNSS from baseline at day 4 and 10. The relationship between stroke syndrome and SNSS at days 4 and 10, and outcome (modified Rankin Scale at 90 days) were assessed. RESULTS: Stroke severity was significantly different between TACI (most severe) and LACI (mildest) at all four time points (p<0.001), with no difference between PACI and POCI. The largest change in SNSS score occurred between baseline and day 4; improvement was least in TACI (median 2 units), compared to other groups (median 3 units) (p<0.001). If SNSS did not improve by day 4, then early recovery and late functional outcome tended to be limited irrespective of clinical syndrome (SNSS, baseline: 31, day 10: 32; mRS, day 90: 4); patients who recovered early tended to continue to improve and had better functional outcome irrespective of syndrome (SNSS, baseline: 35, day 10: 50; mRS, day 90: 2). CONCLUSIONS: Although functional outcome is related to baseline clinical syndrome (best with LACI, worst with TACI), patients who improve early have a more favourable functional outcome, irrespective of their OCSP syndrome. Hence, patients with a TACI syndrome may still achieve a reasonable outcome if early recovery occurs.

Development and implementation of evidence-based indicators for measuring quality of acute stroke care: the Quality Indicator Board of the German Stroke Registers Study Group (ADSR).

BACKGROUND AND PURPOSE: There is no consensus about indicators for measuring quality of acute stroke care in Germany. Therefore, a standardized process was initiated recently to develop and implement evidence-based indicators for the measurement of quality of acute hospital stroke care. METHODS: Quality indicators were developed by a multidisciplinary board between November 2003 and December 2005. The process was initiated by the German Stroke Registers Study Group in cooperation with the German Stroke Society, the German Society of Neurology, the German Stroke Foundation, Regional Offices for Quality Assurance and other experts proven in the field. National and international recommendations were considered during the development process. The process was based on a systematic literature review, an independent external evaluation of the process and its results, and a prospective pilot study to evaluate the defined indicators in clinical practice. RESULTS: Overall a set of 24 indicators was developed to measure performance of acute care hospitals in the 3 health care dimensions structure, process and outcome as well as in 3 treatment phases prehospital, in-hospital/acute and postacute. Practicability of the derived indicators was tested in a prospective pilot study. During a 2-month period, 1006 patients in 13 hospitals were documented. Application of the new indicator set was found to be feasible by participating physicians and hospitals. Median time to document the required information for 1 patient was 5 minutes. Nationwide implementation of the new indicator set within regional registers in Germany started since April 2006. CONCLUSIONS: The development of indicators to measure hospital performance in stroke care is an important step toward improving stroke care on a national level. The chosen standardized evidence-based approach ensures maximal transparency, acceptance and sustainability of the developed indicators in Germany.