Andr Spenzieri C de Mendona MD Valrio Ribeiro

André Spenzieri C. de Mendonça, MD Valério Ribeiro de Oliveira, MD Flávia Aparecida de Sousa Ribeiro, MD St. Helena Hospital – Goiânia - Goiás CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Purpose CADASIL • Define • To describe three cases of CADASIL in the same family • Discuss the main findings of the MRI image • Pathological features • Evolution and Prognosis • Differential diagnoses • Demonstrate current perspectives of treatment

Definitions CADASIL Hereditary small-vessel disease due to mutations in Notch 3 gene on chromosome 19, which causes stroke in young adults It is also known by the names of hereditary multiinfarct dementia, subcortical vascular dementia and familial encephalophaty

Pathological features CADASIL The histopathology of small arteries and mediumsized leptomeningeal and long perforating arteries of the brain revealed luminal narrowing or even obliteration caused by deposition of electron-dense granular material in the membrane of vascular smooth muscle cells, and loss of smooth muscle cells vessel walls.

Etiology CADASIL Two types of lesions affecting small cerebral arteries compromising cerebral hemodynamics Reduction of the arterial lumen by fibrous thickening of artery walls Destruction of the wall smooth muscle cells of blood vessels can impair the vasodilator response to hypoxia secondary

Epidemiology CADASIL The CADASIL disease has a worldwide distribution, there are few published hundreds of families being referred to this issue as a bibliographic study of 500 Orphanet (www. orpha. net) The disease prevalence of CADASIL is unknown.

Presentation The patient was a previously healthy 23 y female with occasional headache of recent onset diagnosed as migraine without aura, without neuropsychiatric disorders with onset of first symptoms at the age of 22. She had no cognitive impairment, epilepsy, peripheral neuropathy, ocular abnormalities or other neurological disorders. There was no clinical criteria to suggest multiple sclerosis or other demyelinating disease. However, family history showed that the mother of 52 years had onset of seizures and grandmother had debilitating demyelinating disease being defined without a previous diagnosis.

Imaging findings CADASIL The central nervous system lesions have an age of onset and the rate of progression varies widely. Can be identified even in asymptomatic individuals. In most patients, these lesions are located in the subcortical white matter, but can also be found in other locations central nervous system (brain stem and subcortical gray matter)

Imaging findings Initial examination: Conducted study of intracranial arteries by MRI angiography for diagnostic investigation which revealed no vascular changes CADASIL

Imaging findings Intracranial venous phase were normal CADASIL

Imaging findings The FLAIR sequence performed by MRI showed multiple hyperintense lesions affecting the white matter predominantly to the temporal lobe and bilaterally symmetrical CADASIL

Imaging findings MRI axial T 1 sequence after the use of intravenous contrast with gadolinium showed no uptake in the lesions CADASIL

Imaging findings MRI axial T 2 sequence at the level of the midbrain demonstrating hyperintense subcortical white matter bitemporal CADASIL

Imaging findings T 2 * gradient sequence showed no changes CADASIL

Imaging findings Diffusion technique without restriction of water molecules CADASIL

Imaging findings Proton spectroscopy demonstrated increased peak of choline and NAA CADASIL

Imaging findings Studies show that blood flow is reduced in demyelinating lesions compared to normal values in normal white matter due to hypoxicischemic events in vascular occlusion observed in this pathology CADASIL

Imaging findings Intrafamilial comparative study We observed the temporal lobes bilaterally symmetrical and its clinical symptoms reported CADASIL 23 y (daughter) 52 y (mother) 71 y(grandmother) Headaches Seizures Advanced cognitive deficit

Imaging findings The same image looks predominantly at the tips of the temporal lobes in the left picture patient of 23 y, the middle image patient of 52 y and the image on the right patient with 77 y all of the same family and female CADASIL Hyperintense on FLAIR compromising the temporal lobes (white arrows)

Imaging findings FLAIR sequence showing multiple hard hyperintense foci of deep white matter affecting the peri-ventricular level in accordance with the progressive age of the patients still noting brain volume reduction CADASIL 23 y (daughter) 52 y (mother) 71 y(grandmother)

Imaging findings Impairment of deep white matter in the region of high curvature of the semi-oval centers and peri-Rolandic CADASIL 23 y (daughter) 52 y (mother) 71 y(grandmother)

Imaging findings Bilateral and symmetric temporal lobe is an important feature in the imaging findings. The brain atrophy is a sign of disease progression and often found to be related to cognitive impairment and functional CADASIL 23 y (daughter) 52 y (mother) 71 y(grandmother)

Imaging findings Sagittal FLAIR sequence shows extensive involvement of the corpus callosum (blue arrows) in older patientswith clinical lush cognitive impairment, difficulty walking, psychiatric disorders CADASIL

Imaging findings Corpus Callosum preserved in patients 23 y and 52 y (left and center) compared with the diffuse involvement of the corpus callosum in the oldest patient (right) CADASIL

Imaging findings T 2 sequence at the basal ganglia of older patients showing disease progression observed here in the latest scan on the right with important involvement of white matter cortical / subcortical sparing the subcortical fiber in "U" 1985 2009

Imaging findings First examination in 1985 Control held in 2009 Worsening mental statu First diagnosed as Multiple Sclerosis on this MRI performed in 1985 Difficulty in walking Cognitive deficit Incontinence sphincter

Pathological features CADASIL Geneva Foundation for Medical Education and Research Reduction of the arterial lumen by fibrous thickening of artery walls Destruction of the wall smooth muscle cells of blood vessels can impair the vasodilator response to hypoxia

Natural History & Prognosis CADASIL The CADASIL disease has a progressive course and a final very debilitating and disabling. There is great variability within and between families. There is the description of individuals who remained asymptomatic until the seventh decade of life. In the final phase of the disease, most patients have dementia with pseudobulbar palsy and sphincter incontinence

DIFFERENTIAL DIAGNOSIS • Sporadic subcortical atherosclerotic encephalopathy • MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes • Primary CNS angiitis • Binswanger's disease • Hypercoagulable state

DIFFERENTIAL DIAGNOSIS Images obtained in patients with biopsy-proven CADASIL (top row) and sporadic subcortical atherosclerotic encephalopathy (bottom row) showing the different involvement of white matter and frontal temporo-polar with marked symmetry of lesions Auer D P et al. Radiology 2001; 218: 443 -451

DIFFERENTIAL DIAGNOSIS Volume display color-coded pixels with significantly increased signal intensity in CADASIL compared with sporadic subcortical atherosclerotic encephalopathy Auer D P et al. Radiology 2001; 218: 443 -451 © 2001 by Radiological Society of North America

DIFFERENTIAL DIAGNOSIS Comparison of statistical parametric mapping group of patients with CADASIL and sporadic subcortical atherosclerotic encephalopat hy without (A, C) and (B, D) correction of the group threshold Auer D P et al. Radiology 2001; 218: 443 -451 © 2001 by Radiological Society of North America

DIFFERENTIAL DIAGNOSIS Comparison between CADASIL patient in 71 y with an extension of the lesions to the subcortical region and MELAS in a patient of 35 y (Literature File) CADASIL Millar, W. S. et al. Am. J. Roentgenol. 2004; 182: 1537 -1541

TREATMENT GUIDELINES CADASIL There is no effective therapy. These patients are usually monitored in child neurology, but with the progression of the disease need to have a multidisciplinary team, where the psychological support of patients and their families should not be forgotten. Thus, treatment is provided only symptomatic relief. Migraine headaches are treated with analgesia. The efficacy and safety of triptans are uncertain. The frequent and disabling attacks may require prophylactic drug therapy in the long term. Depression and mood disorders are treated with conventional antidepressants. The crises of emotional lability benefit from the administration of serotonin reuptake inhibitors

References 1. Sourander, P. and J. Walinder, Hereditary multi-infarct dementia. Lancet, 1977. 1(8019): p. 1015 2. Auer, D. P. , et al. , Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology, 2001. 218(2): p. 443 -451 3. O'Sullivan, M. , et al. , MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology, 2001. 56(5): p. 628 -634 4. Davous, P. , CADASIL: a review with proposed diagnostic criteria. Eur J Neurol, 1998. 5(3): p. 219 -233 5. Jouvent, E. , et al. , Brain atrophy is related to lacunar lesions and tissue microstructural changes in CADASIL. Stroke, 2007. 38(6): p. 1786 -1790. 6. Oberstein L et al: Incipient CADASIL. Arch Neurol 60: 707 -712, 2003