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Journal of Neurology, Neurosurgery, and... Jul 2004CADASIL is an inherited small vessel disease related to Notch3 gene mutations.
BACKGROUND
CADASIL is an inherited small vessel disease related to Notch3 gene mutations.
AIM
To report retinal findings in symptomatic CADASIL patients.
METHODS
Assessment of visual acuity (VA), testing of visual fields (VF), funduscopic examination (FE), and fluorescein angiography (FA) were carried out in 18 symptomatic patients.
RESULTS
No visual symptoms were presented by our patients. VA was normal in all. Ophthalmologic abnormalities were found in 8 patients. VF were normal except for a right hemianopia in one subject due to ischemic stroke. FE and FA revealed significant abnormalities in seven other subjects (mean age: 55 years; range: 39-74): nerve fibre loss (n = 4), cotton wool spots (n = 3), sheathed arteries (n = 1), and tortuous arteries (n = 1). Only one patient with both tortuous arteries and nerve fibre loss had multiple vascular risk factors, and another patient with cotton wool spots was a current smoker.
DISCUSSION
FE and FA revealed silent retinal abnormalities in CADASIL patients with nerve fibre loss in 22% and cotton wool spots in 17%. The presence of these abnormal retinal findings does not seem related to the severity of the disorder but may be considered as peripheral markers of this genetic disease.
Topics: Adult; Aged; Cerebral Angiography; Dementia, Multi-Infarct; Female; Fluorescein Angiography; Hemianopsia; Humans; Male; Middle Aged; Point Mutation; Proto-Oncogene Proteins; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch; Retina; Retrospective Studies; Visual Acuity; Visual Fields
PubMed: 15201374
DOI: 10.1136/jnnp.2003.024307 -
CMAJ : Canadian Medical Association... Apr 2004
Topics: Dementia, Multi-Infarct; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Proto-Oncogene Proteins; Receptor, Notch4; Receptors, Cell Surface; Receptors, Notch
PubMed: 15111470
DOI: 10.1503/cmaj.1031673 -
Journal of Neurology, Neurosurgery, and... Apr 2004Although stroke associated with small vessel disease (SSVD) can induce both motor and cognitive impairment, the latter has received less attention. We aimed to evaluate...
OBJECTIVES
Although stroke associated with small vessel disease (SSVD) can induce both motor and cognitive impairment, the latter has received less attention. We aimed to evaluate the frequency of the varying severity levels of cognitive impairment, the determinants of severe cognitive impairment, and the association of cognitive impairment with functional outcome after SSVD.
METHODS
Consecutive patients admitted to hospital because of SSVD were assessed at 3 months after stroke. We performed a semi-structured clinical interview to screen for cognitive symptoms. Severity of cognitive symptoms was graded according to the Clinical Dementia Rating Scale (CDR). Performance on psychometric tests (Mini-Mental State Examination, Alzheimer's Disease Assessment Scale (cognition subscale), Mattis Dementia Rating Scale (initiation/perseverence subscale; MDRS I/P)) of patients of different CDR gradings was compared with that of 42 healthy controls. Basic demographic data, vascular risk factors, stroke severity (National Institute of Health Stroke Scale; NIHSS), pre-stroke cognitive decline (Informant Questionnaire on Cognitive Decline in the Elderly; IQCODE), functional outcome (Barthel index; BI), Instrumental Activities Of Daily Living; IADL), and neuroimaging features (site of recent small infarcts, number of silent small infarcts, white matter changes) were also compared among the groups. Regression analyses were performed to find predictors of severe cognitive impairment and poor functional outcome.
RESULTS
Among the 75 included patients, 39 (52%) complained of cognitive symptoms. The number of patients in each CDR grading was as follows: 39 (52%) had a CDR of 0, 26 (34.7%) had a CDR of 0.5, 10 (13.3%) had a CDR of > or =1. Pre-stroke IQCODE and previous stroke predicted CDR> or =1. The NIHSS was associated with more impaired BI. The NIHSS and MDRS I/P contributed most to impaired IADL.
CONCLUSIONS
Half of the patients with SSVD complained of varying severity of cognitive problems 3 months after stroke. Pre-stroke cognitive decline and previous stroke predict severe cognitive impairment post stroke. Stroke severity and executive dysfunction contribute most to a poor functional outcome.
Topics: Activities of Daily Living; Aged; Alzheimer Disease; Brain; Cerebral Infarction; Cognition Disorders; Dementia, Multi-Infarct; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Magnetic Resonance Angiography; Male; Microcirculation; Middle Aged; Neuropsychological Tests
PubMed: 15026497
DOI: 10.1136/jnnp.2003.015107 -
Revista de NeurologiaThe term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) refers to an autosomal dominant hereditary arteriopathy of...
INTRODUCTION
The term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) refers to an autosomal dominant hereditary arteriopathy of the brain that is characterised by headache, recurring strokes and progressive cognitive deterioration. We report the case of another family with CADASIL and emphasise the importance of a genetic study in its diagnosis.
CASE REPORT
A 62-year-old female patient with repeating lacunar strokes, subcortical dementia and a family history of dementia and strokes. Neuroimaging studies conducted on the patient and her siblings showed signs of leukoencephalopathy and lacunar infarctions. The ultrastructural study of the biopsy performed on a sample of the patient's skin, which included five dermal vessels, did not show any electron-dense deposits. The genetic study revealed the presence of mutation C475T in exon 4 of NOTCH3.
CONCLUSIONS
The possible presence of CADASIL must be suspected in patients with symptoms of cerebrovascular disease or dementia who present characteristic alterations in the magnetic resonance brain scan, especially when there is a compatible family history. The first choice diagnostic procedure must be a genetic study.
Topics: Dementia, Multi-Infarct; Female; Humans; Middle Aged; Mutation; Pedigree; Proto-Oncogene Proteins; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch
PubMed: 14730489
DOI: No ID Found -
American Journal of Human Genetics Feb 2004Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterized by the degeneration...
Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling Pathway.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular dementia characterized by the degeneration of smooth-muscle cells in small cerebral arteries. CADASIL is caused by mutations in NOTCH3, one of the four mammalian homologs to the Drosophila melanogaster NOTCH gene. Disease-associated mutations are distributed throughout the 34 epidermal growth factor-like repeats (EGFRs) that compose the extracellular domain of the Notch3 receptor and result in a loss or a gain of a cysteine residue in one of these EGFRs. In human adults, Notch3 expression is highly restricted to vascular smooth-muscle cells. In patients with CADASIL, there is an abnormal accumulation of Notch3 in the vessel. Molecular pathways linking NOTCH3 mutations to degeneration of vascular smooth-muscle cells are as yet poorly understood. In this study, we investigated the effect of CADASIL mutations on Notch3 activity. We studied five naturally occurring mutations: R90C and C212S, located in the previously identified mutational hotspot EGFR2-5; C428S, shown in this study to be located in the ligand-binding domain EGFR10-11; and C542Y and R1006C, located in EGFR13 and EGFR26, respectively. All five mutant proteins were correctly processed. The C428S and C542Y mutant receptors exhibited a significant reduction in Jagged1-induced transcriptional activity of a RBP/JK responsive luciferase reporter, relative to wild-type Notch3. Impaired signaling activity of these two mutants arose through different mechanisms; the C428S mutant lost its Jagged1-binding ability, whereas C542Y retained it but exhibited an impaired presentation to the cell surface. In contrast, the R90C, C212S, and R1006C mutants retained the ability to bind Jagged1 and were associated with apparently normal levels of signaling activity. We conclude that mutations in Notch3 differently affect Jagged1 binding and Notch3 signaling via the RBP/JK pathway.
Topics: Calcium-Binding Proteins; Dementia, Multi-Infarct; Drosophila Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mutation; Protein Binding; Proteins; Proto-Oncogene Proteins; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction; Transcription Factors
PubMed: 14714274
DOI: 10.1086/381506 -
Tidsskrift For Den Norske Laegeforening... Nov 2003CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a neurovascular disease caused by mutations of the notch3 gene,...
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a neurovascular disease caused by mutations of the notch3 gene, manifesting with strokes or stroke-like episodes, psychiatric symptoms, migraine and dementia. The diagnosis can be confirmed by screening exons of this gene. Involvement of the anterior temporal lobe and external capsule on MRI and presence of granular osmiophilic material on skin biopsy may help in diagnosis. We present two Norwegian families with eight members who have symptoms indicating CADASIL. The mutation R182C was demonstrated in exon 4 in seven; one refused gene testing. Two brothers without symptoms also tested positively for this gene mutation.
Topics: Aged; Dementia, Multi-Infarct; Female; Humans; Male; Middle Aged; Mutation
PubMed: 14618173
DOI: No ID Found -
British Journal of Anaesthesia Sep 2003We report the anaesthetic management of a patient suffering from an ischaemic arteriopathy of the CADASIL (cerebral autosomal dominant arteriopathy with subcortical...
We report the anaesthetic management of a patient suffering from an ischaemic arteriopathy of the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) type. The anaesthetic implications of this pathology are discussed. By analogy with other cerebral arteriopathies, the aim of our management was to keep mean arterial blood pressure and end-tidal carbon dioxide so as to prevent any cerebral ischaemic or vasospastic phenomenon. We preserved the cerebral venous return by avoiding excessive head-down position. We used a balanced anaesthetic technique because it allows easier titration of the depth of anaesthesia with regard to mean arterial pressure. There is no contraindication to the use of loco-regional anaesthesia.
Topics: Adult; Anesthesia, General; Brain Ischemia; Dementia, Multi-Infarct; Emergencies; Female; Humans; Laparoscopy; Ovarian Diseases; Perioperative Care; Torsion Abnormality
PubMed: 12925491
DOI: 10.1093/bja/aeg182 -
The Cochrane Database of Systematic... 2003Transcutaneous electrical nerve stimulation (TENS) is the application of an electrical current through electrodes attached to the skin. The commonest clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Transcutaneous electrical nerve stimulation (TENS) is the application of an electrical current through electrodes attached to the skin. The commonest clinical application of TENS is pain control. TENS is also used occasionally for the treatment of a range of neurological and psychiatric conditions including drug and alcohol dependence, headaches, and depression. TENS is rarely used for the treatment of dementia. However, since the early 1990s a number of studies carried out by a group in the Netherlands, and one study carried out by a group in Japan, suggest that TENS applied to the back or head may improve cognition and behaviour in patients with Alzheimer's disease or multi-infarct dementia. It was claimed that applying TENS could benefit patients with dementia by altering the activity of various neurotransmitters, or by increasing brain activity and thereby retarding neural degeneration and stimulating regenerative processes. It is claimed that application of TENS to the head may also alleviate the sleep disorders associated with dementia.
OBJECTIVES
The aim of this review is to determine the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) in the treatment of dementia. Secondary objectives of this review are to determine whether any effect of treatment of dementia with TENS is influenced by any treatment parameters or patient features, including: the duration of treatment, electrical waveform, current amplitude, pulse duration and frequency and the patient's type or severity of cognitive impairment.
SEARCH STRATEGY
The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 December 2002 using the terms TENS, transcutaneous, "transcutaneous electrical nerve stimulation", and "electric stimulation". The CDCIG Specialized Register contains records from all major health care databases and many ongoing trials databases and is regularly updated.
SELECTION CRITERIA
All RCTs in which TENS was used as an intervention for people with dementia were included in this review. This included peripherally applied transcutaneous electrical stimulation as well as transcutaneous electrical stimulation applied to the head (also known as cranial electrical stimulation (CES)).
DATA COLLECTION AND ANALYSIS
All RCTs that fulfilled the inclusion criteria for the review and for which sufficient data were available were included in this meta-analysis. Two reviewers extracted the data from the included trials. All except one of the included trials used similar outcome measures. Data of the same outcome measures were combined for analysis.
MAIN RESULTS
Eight trials were included in the review but only 3 trials could be included in the meta-analysis. Sufficient data to include the other trials in the meta-analysis could not be obtained. From this limited analysis it appears that TENS produced a statistically significant improvement directly after treatment in: delayed recall of 8 words in one trial, face recognition in two trials and motivation in one trial however, no effect of TENS was found on any of the many other neuropsychological and behavioural measures evaluated either directly after TENS treatment or 6 weeks after treatment was completed.
REVIEWER'S CONCLUSIONS
Although a number of studies suggest that TENS may produce short lived improvements in some neuropsychological or behavioural aspects of dementia, the limited presentation and availability of data from these studies does not allow definite conclusions on the possible benefits of this intervention. Since most of the currently published studies are well designed, although the numbers of subjects in each study is small, analysis of the complete original data from these and/or future studies may allow more definitive conclusions to be drawn.
Topics: Aged; Dementia; Humans; Randomized Controlled Trials as Topic; Transcutaneous Electric Nerve Stimulation
PubMed: 12917999
DOI: 10.1002/14651858.CD004032 -
AJNR. American Journal of Neuroradiology Aug 2003Small vessel cerebrovascular disease is an important cause of vascular cognitive impairment. It is usually sporadic but also occurs secondary to the genetic disorder... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
Small vessel cerebrovascular disease is an important cause of vascular cognitive impairment. It is usually sporadic but also occurs secondary to the genetic disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Recurrent lacunar stroke is a characteristic feature, although symptomatic events are relatively rare, making large numbers necessary for evaluation of potential therapies. Diffusion-weighted imaging is sensitive to acute ischemic lesions and differentiates them from chronic infarcts. Detection of asymptomatic lacunar infarcts with diffusion-weighted imaging is a potential surrogate marker for treatment trials. In this study, the frequency of asymptomatic new lesions in ischemic leukoaraiosis and CADASIL was determined as a step toward assessing the potential of this technique as a surrogate marker of disease activity.
METHODS
Fifty patients with sporadic small vessel disease and 19 patients with CADASIL underwent diffusion-weighted imaging. All had been asymptomatic for 3 months before imaging. Diffusion-weighted images were screened by two raters for new lesions; lesions were confirmed as recent by a visible reduction of diffusivity on the corresponding apparent diffusion coefficient maps.
RESULTS
Recent ischemic lesions were identified in four patients with sporadic small vessel disease (8.0%) and two patients with CADASIL (10.5%).
CONCLUSION
Asymptomatic new lesions are found in cases of sporadic small vessel disease and CADASIL. The frequency of new lesions suggests that this approach has a potential role as a surrogate marker in therapeutic trials that warrants further investigation.
Topics: Adult; Aged; Aged, 80 and over; Brain Infarction; Brain Ischemia; Cerebral Arterial Diseases; Cerebral Infarction; Cohort Studies; Dementia, Multi-Infarct; Dementia, Vascular; Diffusion Magnetic Resonance Imaging; Dystonic Disorders; Female; Humans; Male; Middle Aged; Mutation; Prevalence; United Kingdom
PubMed: 12917126
DOI: No ID Found -
Medicine Jul 2003Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical microvascular changes are found throughout the arterial tree, but the documented disease expression is confined to the central nervous system. In an ongoing CADASIL study, we noted a number of patients with early acute myocardial infarction (before the age of 50 years), as well as patients with electrocardiogram (ECG) abnormalities. We analyzed these data to determine whether myocardial ischemia is associated with NOTCH3 mutations. ECGs were recorded in mutated (n = 41) and nonmutated (n = 22) individuals from 15 genetically confirmed CADASIL families, and blindly classified according to the Minnesota code. Cardiologic history was assessed and cardiovascular disease risk factors were determined. Evidence for myocardial infarction was defined as a positive history for acute myocardial infarction and/or a Minnesota Code 1 (Q-waves) on ECG. We examined CADASIL myocardial tissue ultrastructurally and immunohistochemically for evidence of microangiopathy. We found that almost 25% (10/41) of mutation carriers had evidence of myocardial infarction, versus none of the 22 nonmutation carriers (p = 0.011). Five had a medical history of acute myocardial infarction, and 5 had current pathologic Q-waves on ECG. Acute myocardial infarction occurred at a mean age of 39.6 +/- 5.22 years, and predated major neurologic symptoms of CADASIL in all cases. Pathologic examination of myocardial tissue revealed typical CADASIL arteriopathic changes of the coronary microvasculature. To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart.
Topics: Acute Disease; Adult; Dementia, Multi-Infarct; Electrocardiography; Female; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Infarction; Myocardium; Point Mutation; Proto-Oncogene Proteins; Receptor, Notch3; Receptors, Cell Surface; Receptors, Notch
PubMed: 12861102
DOI: 10.1097/01.md.0000085054.63483.40