|1. Department of Neurointerventional Radiology, St Joseph Medical Center, Bloomington, USA
2. Department of Neurosurgery, Advocate Bromenn Medical Center, Bloomington, USA
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral angiopathy. We present a case in which a pattern of diffusion signal change compatible with bihemispheric acute watershed infarcts occurred in a symptomatic patient demonstrating global hypoperfusion. To our knowledge, watershed infarcts in the clinical presentation of CADASIL have not been previously described.
A 48 year old female presented to our emergency department with acute short-term memory loss and word finding difficulty. She had a past medical history significant for CADASIL, diagnosed in 2003 by genetic assessment for NOTCH 3 gene mutation. At the time of initial diagnosis, she presented with aphasia, sleep disturbances, and mood disorder. During the interval from her initial diagnosis to the present, she has experienced numerous episodes of short-term memory loss, word finding difficulties, and mood disturbances. Her mother was diagnosed with CADASIL in 2002. She has a brother and three children ( 22, 20, 15 years of age ) who have not been screened for the NOTCH 3 mutation.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-amyloid type of small vessel arterial disease caused by a mutation of the NOTCH3 gene on chromosome 19q12.The NOTCH3 gene encodes a single pass transmembrane protein that is expressed in vascular smooth muscle and is required for the structural and functional integrity of small arteries by controlling the arterial differentiation and maturation of smooth muscle cells. The missense mutation (more than 150 described) results in a nonfunctional NOTCH3 receptor that leads to accumulation of the pathognomonic granular osmiophilic material deposits within the cells and subsequent degeneration of smooth muscle fibers. This results in fibrosis and loss of vasomotor reactivity of small vessel walls leading to chronic hypoperfusion, dysfunctional arterial autoregulation and ischemic infarcts .
A characteristic MRI imaging feature to CADASIL is the presence of T2 hyperintensity white matter lesions in the anterior temporal poles and external capsules . Associated white matter hyperintense T2 signal is commonly seen in the periventricular and deep white matter. Additional typical features include focal or subcortical white matter increased T2 signal changes in the superior frontal lobes. These lesions are associated with true restricted diffusion in the acute phase with no associated enhancement after gadolinium administration [2,3]. In Binswanger disease, focal increased white matter T2 signal change is identified in the deep grey matter structures, corona radiata and centrum semiovale with identification of true restricted diffusion in the acute phase. Ovoid configuration white matter T2 signal abnormality distributed in a periventricular distribution pattern is typical for MS, with active lesions demonstrating enhancement with or without increased true diffusion signal. In MELAS, multifocal cortical and subcortical T2 signal abnormalities are identified. In the acute phase, swollen gyri are identified on T1 weighted sequences. In the subacute phase cortical lamina necrosis with cortical T1 hyperintensity is noted. This is replaced by cortical atrophy in the chronic phase. Multifocal subcortical and periventricular abnormal white matter T2 signal change is present in FHM with no associated diffusion signal change or enhancement. (Table 2, Fig. 6 ).
Symptoms of CADASIL appear between 30 and 50 years of age and the diagnosis maybe confirmed before the first stroke on the basis of characteristic white matter T2 hyperintensities identified by brain MRI imaging and by the presence of pathognomonic granular osmiophilic material in arterial walls from skin biopsies . Most patients develop cognitive decline before the age of 60 and demonstrate a progressive course leading to severe disability and premature death. Therefore, in a relatively young person with ischemic symptoms and a typical pattern of white matter signal abnormality distribution by MRI imaging, a diagnosis of CADASIL should be considered. MRI findings in CADASIL can be seen prior to the onset of symptoms by 10 to 15 years and lesion volume correlates with the level of disability. MRI findings of increased microbleeds, lacunar infarcts and ventricular volume over time have been associated with progressive cognitive decline in executive function . Increased water diffusion is present within and external to white matter lesions. Quantification of this in time may be an important in monitoring for clinical deterioration .
Only one other clinical CADASIL case report that mimics our findings of bilateral hemispheric acute infarcts has been published . The authors of that paper suggested an embolic source for which none was found. Multifocal acute infarcts in a distribution pattern parallel to the lateral ventricles are typical of watershed infarcts. Watershed infarcts are a well-recognized phenomenon confirmed by autopsy studies and global hypotension as an etiology has been confirmed in animal models . Microcirculatory watershed hypoperfusion as an etiologic factor in CADASIL has been suggested in conjunction with vessel wall hypotonia and hypo-permeability. These pathophysiologic phenomenon occur consequent to the destruction of vascular wall muscle cells and its subsequent failure to secrete vascular permeability factors, rather than luminal stenosis, as has identified in skin biopsies of CADASIL patients . Mouse model studies have supported the theory that cerebrovascular dysfunction and microcirculation failure are key contributors to hypoperfusion and precede white matter damage . It has been shown that patients with CADASIL have lower ambient systemic blood pressure profiles . Multifocal ischemic events may then occur as a result of the concomitant intracranial small vessel hypoperfusion and prolonged phases of systemic hypotension. . Lacunar type infarcts are the predominant ischemic event in CADASIL . MRI imaging in our case showed global hypoperfusion with bihemispheric acute watershed infarcts not previously described.
Quantification and characterization of tissue microcirculation by CBF, CBV and MTT acquired through dynamic bolus chase MR imaging can be performed using deconvolution of the arterial input function and tissue signal change after intravenous gadolinium contrast injection. Decreased CBF and CBV in white matter lesions as well globally within the centrum semiovale in patients with CADASIL, relative to normal patients has been demonstrated . Baseline global CBF in normal subjects in this study was 55.3±27ml/100ml−1/min−1, global CBV 2.69±0.96 ml/100ml−1 and global MTT baseline 3.14±0.61 seconds. The global white matter CBF was reduced to 17.3 ±11.5 ml/100ml−1 and the CBV to 0.8 ±0.39 ml/100ml−1 in patients with CADASIL. There was also a 42% reduction in mean CBF and 50% reduction in CBV relative to normal subjects in typical white matter lesions. Interestingly, perfusion parameters in affected and non-affected white matter regions were identified with normal MTT . Sonographic and other CT perfusion studies have in contradistinction demonstrated an overall increase in cerebral perfusion times. A cerebral perfusion time by sonography was measured at 4.4+/-1.9 seconds in patients with CADASIL and 1.3+/-0.5 in normal subjects . Prolonged MTT was identified in our patient. There are technical limitations in determining perfusion parameters of the cortex and assessment controversy remains with some studies showing a global decrease and some just in the cortical regions of the occipital lobe [3,11]. The exact relationship between CBF and CBV in CADASIL is unknown. Importantly, correlation between white matter signal abnormality CBV and clinical symptoms may allow for using this singular parameter for monitoring treatment protocols and or asses individual progression .
Basal perfusion and hemodynamic reserve are diminished in regions of white matter signal change and these correspond to clinical severity . More severe reduction in CBF and CBV are identified in white matter lesions of demented CADASIL patients . Diminished global white matter CBV reflects diffuse small artery disease with maximal vasodilatation and not infarction, despite having commensurate decreased CBF. Acetazolamide has been shown to increase CBF and CBV in the cortex and white matter as well as more significantly within white matter lesions of affected patients and treatment with this drug has demonstrated clinical benefit [11,14].
Dysfunctional cerebrovascular autoregulation is a significant factor in the pathogenesis of CADASIL and has been demonstrated as the precursor to ischemic insults in animal models. . To our knowledge, imaging findings compatible with bihemispheric acute watershed infarcts in the context of global hypoperfusion in a patient with acute symptomatic CADASIL has not been described. Prospective observational study of watershed infarcts in a significant number of CADASIL patients is required and the findings may have important implications in the diagnosis and management of this condition.
The most characteristic MRI imaging feature to CADASIL is the presence of T2 hyperintensity white matter lesions in the anterior temporal poles and external capsules. These white matter signal abnormalities have diminished CBV that correlate with clinical outcomes. Microcirculatory hypoperfusion related watershed infarction in the context of global hypoperfusion may be a causative factor in symptomatic CADASIL.
Figure 1: Magnetic Resonance Imaging (Open in original size)
48 year old female with acute symptomatic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Select axial FLAIR sequences demonstrating confluent near symmetric bihemispheric subcortical increased white matter T2 hyperintense signal in the temporal lobes (arrows in A), extreme capsules (arrows in B) and the subcortical white matter (arrows in C), typical for CADASIL (1.5 Tesla magnet, TR 8.000, TE 127.30, NEX 1.5, Flip 160.15, slice thickness 5mm)
Figure 2: Magnetic Resonance Imaging (Open in original size)
48 year old female with acute symptomatic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Select axial diffusion sequences demonstrating bihemispheric multiple foci of increased signal, distributed in a typical peri-ventricular pattern compatible with acute watershed infarcts (arrows). The anterior arrow in "A" additionally identifies acute punctate infarction in the superficial perforator territory. (1.5 Tesla magnet, TR 8,600, TE 74.50, NEX 1.0, Flip 90, slice thickness 5mm)
Figure 3: Magnetic Resonance Imaging (Open in original size)
48 year old female with acute symptomatic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Select axial ADC mapped sequences demonstrating multiple foci of true restricted diffusion decreased signal distributed in a typical peri-ventricular pattern compatible with acute watershed infarcts (arrows), corresponding to the abnormalities identified by diffusion weighted imaging. The anterior arrow in "A" additionally identifies acute punctate signal loss related to punctuate infarction in the superficial perforator territory. (1.5 Tesla magnet, TR 8,600, TE 74.50, NEX 1.0, Flip 90, slice thickness 5mm)
Figure 4: Magnetic Resonance Imaging (Open in original size)
48 year old female with acute symptomatic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Qualitative assessment of perfusion MRI imaging demonstrates bihemispheric decreased cerebral blood flow (A) increased mean transit time (B) and decreased cerebral blood volume (C), as shown by long white arrows along the expected range. Normal range delineated by white bar. ( 1.5 Tesla magnet, Echo Planar Imaging, TR 2000, TE 13.20, NEX1, Flip 60, Slice thickness 5 mm, Dynamic imaging performed before, during and after a single 0.2mmol/kg dose Multihance (Gadobenate dimeglumine, Bracco Diagnostics, Princeton, NJ) power injection at a rate of 4 cc/s. The arterial input function to calculate perfusion parameters determined from the middle cerebral artery. Calculation of relative CBF, CBV and MTT from multiple regions of interest placed within the cerebral hemispheres bilaterally as shown by short white arrows).
Figure 5: Table (Open in original size)
Summary table for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Figure 6: Table (Open in original size)
Differential diagnoses table for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
CADASIL = Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Staff at St Joseph Medical Center and Advocate Bromenn Hospital.
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