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CADASIL Syndrome


Presentation

  • To describe an Asian patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with schizophreniform organic psychosis. Case report.[ncbi.nlm.nih.gov]
  • This can positively diagnose CADASIL, though a negative result on this test does not necessarily mean that the disease is not present.[web.archive.org]
  • Family history suggesting an autosomal dominant inheritance is usual but not essential Not everyone presents with all features but the following gives an indication of presentation and chance of occurence, although the figures are based on different[patient.info]
  • Clinical Presentation: Clinical presentation may vary.[ajnr.org]
  • […] two patients with molecularly confirmed CADASIL presenting with a parkinsonian syndrome.[jnnp.bmj.com]
Fatigue
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 31, 2019[patientslikeme.com]
  • […] mini-strokes); This a progressively debilitating disease; The progress, severity and specific symptoms are variable from person to person and can include migraines, headaches, small strokes, strokes, gait problems, mood disorder, anxiety, depression, apathy, fatigue[rarediseaseday.org]
Amyloidosis
  • Amyloid β precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch.). Science 248, 1120–1122 (1990). 13 Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J.[doi.org]
  • Hereditary Transthyretin Amyloidosis Yoshiki Sekijima. Initial Posting: November 5, 2001; Last Update: December 20, 2018. Heritable Pulmonary Arterial Hypertension Eric D Austin, James E Loyd, and John A Phillips, III.[ncbi.nlm.nih.gov]
Vomiting
  • These sorrel formulations may cause nausea or vomiting when taken with the prescription drugs metronidazole (Flagyl ) or disulfiram (Antabuse ). Avoid if pregnant or breastfeeding.[livingnaturally.com]
  • The other individual (PN 3) had visual, sensory, and aphasic aura followed by unilateral headache, photophobia, phonophobia, and vomiting, with attacks clustering in the first 3 years of adolescence.[jamanetwork.com]
  • Common accompanying features were seizures (n 10), fever (n 4), hallucinations (n 13), nausea and/or vomiting (n 9) and meningism (n 2) ( Table 3 ).[journals.plos.org]
  • There was vomiting, pyrexia, confusion and formed, dream-like visual hallucinations. The illness was also associated with odd food preferences (Ruskin, 1909a ). He had to stay in bed for 3 weeks.[doi.org]
Nausea
  • Some of the symptoms can be somewhat pedestrian like numbness or tingling and dizziness or nausea to more serious warnings like severe migraine headaches and even strokes.[theexaminernews.com]
  • Common accompanying features were seizures (n 10), fever (n 4), hallucinations (n 13), nausea and/or vomiting (n 9) and meningism (n 2) ( Table 3 ).[journals.plos.org]
  • These sorrel formulations may cause nausea or vomiting when taken with the prescription drugs metronidazole (Flagyl ) or disulfiram (Antabuse ). Avoid if pregnant or breastfeeding.[livingnaturally.com]
Dysphagia
  • This burden is increased by cognitive deficits and other manifestations, such as dysphagia and incontinence, which are both frequent and a source of further complications.[academic.oup.com]
  • MRI shows basal ganglia and confluent white matter lesions; III: usually after 60 years, with subcortical dementia associated with pseudobulbar signs - dysarthria, dysphagia and emotional lability; and in some cases apathy, mutism and akinesia.[doi.org]
Hypertensive Retinopathy
  • Ruchoux MM, Droy-Lefaix MT, Bakri F, Ruchoux P, Lhuintre Y (1990) Cicletanine and hypertensive retinopathy. Ophthalmic Res 22: 318–329 Google Scholar 37.[doi.org]
Headache
  • Headache Classification Subcommittee of the International Headache Society (2004) The International Headache Classification of Headache Disorders, 2nd edn. Cephalalgia 24(Suppl 1):9–160 Google Scholar 10.[link.springer.com]
  • Symptoms CADASIL is characterized by migranes, headaches, and multiple strokes in adults and young adults, often without cardiovascular risk factors.[cadasil.weebly.com]
  • , since the patient has no history of headaches.[elsevier.es]
  • Abstract A 17-year-old girl presented with migraine with prolonged aura and aura without headache. Neurologic examination was normal. Her mother, who did not have a history of migraine, developed right-face and -arm numbness at the age of 45.[pediatrics.aappublications.org]
Dysarthria
  • Her mother had a similar progressive illness of three years duration with difficulty in walking, dysarthria, cognitive impairment, and incontinence with white matter changes in brain MRI.[neurologyindia.com]
  • […] mechanism.(1) It is noteworthy that risk factors such as hypertension and diabetes mellitus are not common.(1) The age of onset is usually in the 40’s, with most patients presenting with a typical lacunar syndrome (pure motor and/or sensory stroke, dysarthria[eso-stroke.org]
  • His family history disclosed that his brother had a similar episode of dysarthria.[thejournalofheadacheandpain.springeropen.com]
  • Fifty-four per cent of the cases had a history of pathological laughing or crying, mostly in combination with dysarthria.[academic.oup.com]
  • . · Ischemic events are commonly subcortical and sometimes manifest as lacunar syndromes such as pure motor, pure sensory strokes or ataxic hemiparesis, sensory-motor deficit, dysarthria–clumsy hand syndrome (difficulty in speech articulation associated[medium.com]
Aphasia
  • Homonymous Hemianopia (Visual loss in lateral half of both eyes) Kaleidoscopic vision (flashing shapes, patterns, floating specks of light) Sensory Aura: Involving face and arm Motor Aura: Involving arm Aphasic aura Speech Disturbances with expressive aphasia[medium.com]
  • Severe aphasia, apraxia or agnosia are rare in CADASIL. Psychiatric disorders, mainly mood disturbances, appear in 20% of patients, in general as severe depressive episodes.[jneuro.com]
  • However, there is very rarely any severe aphasia (language difficulties), apraxia (difficulties with voluntary behaviour) or agnosia (difficulty with the recognition of objects, people or places with visual difficulties), all features frequently observed[cadasilfoundation.org]
  • Other presentations such as aphasia, hemianopia and other cortical disorders are observed less frequently.[doi.org]
Gait Apraxia
  • However, gait can occasionally be affected without a stroke in a syndrome called gait apraxia. This is where disruption of connections within the white matter in the brain alters the ability to coordinate one’s walking.[cambridgestroke.com]

Workup

  • Genetic testing for pathogenic mutations in the NOTCH3 gene is available for use in the diagnostic workup of individuals with a clinical history and symptoms suspicious for CADASIL syndrome.[unicare.com]

Treatment

  • Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring mean flow velocity (MFV) in the middle cerebral artery was performed at baseline and the end of the treatment period.[ncbi.nlm.nih.gov]
  • Management and treatment There is no cure for CADASIL. Antiplatelet therapy is often used but it has not yet been proven as an effective treatment.[orpha.net]
  • There is no cure or effective treatment for CADASIL yet.[rarediseases.info.nih.gov]
  • “However, we found a significant treatment effect on several measures of executive function,” he said.[doi.org]
  • Treatment - CADASIL There is currently no treatment for CADASIL that is proven to be effective. While antiplatelet treatment is often used, it is also not proven to be useful.[checkorphan.org]

Prognosis

  • Prognosis The prognosis is poor with most patients eventually becoming bed-ridden and dement and requiring constant nursing care. The median age at death is 68 years. Expert reviewer(s): Dr S.A.J. [Saskia] LESNIK OBERSTEIN - Dr G.M.[orpha.net]
  • The phenotypic variability in families carrying the same molecular defect as presented here makes the prediction of prognosis inconceivable.[ncbi.nlm.nih.gov]
  • Prognosis Prognosis is progressive and the earliest forms of CADASIL are the most severe. Prolonged periods of stability or even transient mild improvements lasting years are common.[cadasil.weebly.com]
  • Talk to your doctor and entire medical team about the diagnosis of CADASIL and individual prognosis. Dichgans M. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. UpToDate Inc. website.[thinkgenetic.com]
  • Prognosis - CADASIL Symptoms usually progress slowly. By age 65, the majority of persons with CADASIL have severe cognitive problems and dementia. Some people lose the ability to walk and most become completely dependent due to multiple strokes.[checkorphan.org]

Etiology

  • Etiology CADASIL is caused by mutations in the NOTCH3 gene ( 95% of cases), located to 19p13.2-p13.1, which encodes transmembrane receptor NOTCH3, mainly expressed in vascular smooth muscle cells.[orpha.net]
  • Insights gained from the study of CADASIL should help us better understand its etiology, as well as the options for treatment of the more common forms of microvascular disease seen in the elderly.[ncbi.nlm.nih.gov]
  • The original reference is provided for historical interest, and review articles are included to show recent advances in etiology and treatment.[books.google.de]
  • We propose to characterize the etiology and natural history of CADASIL subjects through comprehensive clinical and molecular characterizations.[clinicaltrials.gov]
  • This case highlights the evolving process of affective disorder diagnosis and underlying organic etiologies.[dovepress.com]

Epidemiology

  • Summary Epidemiology In Europe, the prevalence of CADASIL has been estimated to range between 1/50 000- 1/25 000.[orpha.net]
  • Synonyms: C erebral A utosomal D ominant A rteriopathy with S ubcortical I nfarcts and L eucoencephalopathy (CADASIL), familial vascular leukoencephalopathy Epidemiology This is a rare familial form of multi-infarct dementia and other neurological problems[patient.info]
  • Carrier prevalence was found to be 4.14/100000[3].An epidemiological study in Northeast England found a similar prevalence of 1.32/100000 for the disease [4].[medium.com]
  • Epidemiology • Unknown prevalence – 400 families world-wide – 2/100,000 – Largely undiagnosed • Gender effect – women less severely impaired cf. to men after adjusting for age and education after 50 years of age • Presents in mid-20s to age 45 • Shortened[de.slideshare.net]
Sex distribution
Age distribution

Pathophysiology

  • Mutations described here cause an odd number of cysteines in the N-terminal of the EGF domain of Notch3 protein, which seems to have an important functional effect in the pathophysiology of CADASIL.[ncbi.nlm.nih.gov]
  • . * A comprehensive source that thoroughly examines the neurological manifestations of stroke * A guide to highly studied topics, including stroke complications, syndromes, and stroke related psychiatric disorders * A better understanding of the pathophysiological[books.google.de]
  • Ongoing research intends to find out the exact pathophysiology of the disease using animal models so that specific therapeutics can be developed.[medium.com]
  • The pathophysiology of CADASIL is poorly understood, and there is no proven effective therapy. Patients require genetic counseling and close follow-up.[pediatrics.aappublications.org]

Prevention

  • By that time, the two main clinical trials on aspirin in primary stroke prevention—the US and British studies, published in the late 1980s—recruited only male participants.[cadasilfoundation.org]
  • Migraine should be treated both symptomatically and prophylactically (with preventative methods), depending on the frequency of symptoms.[checkorphan.org]
  • Treatment is usually focused on the prevention of complications. For example, anti-platelet agents such as aspirin, are given to prevent occurrence of stroke.[brighthub.com]
  • Asprin is used in patients who have other risk factors for stroke such as diabetes and heart disease as a prophylactic (preventative) medication.[ulf.org]

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