Journal of the Neurological Sciences 163 (1999) 163–167 White matter dementia in CADASIL a,b,e , *, Laetitia L. Thompson a,b , Chun-I Sze c , Jack A. Simon a,d , Christopher M. Filley James F. Paskavitz a , Bette K. Kleinschmidt-DeMasters a,c a Behavioral Neurology Section, Department of Neurology, UCHSC B-183, 4200 East Ninth Avenue, Denver, CO 80262, USA b Department of Psychiatry, UCHSC B-183, 4200 East Ninth Avenue, Denver, CO 80262, USA c Department of Pathology, UCHSC B-183, 4200 East Ninth Avenue, Denver, CO 80262, USA d Department of Radiology, UCHSC B-183, 4200 East Ninth Avenue, Denver, CO 80262, USA e Denver Veterans Affairs Medical Center, Denver, CO, 80262, USA Received 5 October 1998; received in revised form 15 January 1999; accepted 18 January 1999 Abstract Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. Neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. Magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This case illustrates that CADASIL can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with CADASIL closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.  1999 Elsevier Science B.V. All rights reserved. Keywords: White matter dementia; CADASIL; Leukoencephalopathy; Dementia 1. Introduction Disorders of cerebral white matter have not been traditionally regarded as exerting a major effect on neurobehavioral function. The role of white matter in cognitive and emotional behavior has recently received more attention, however, and a wide variety of neurobehavioral syndromes may occur with white matter disorders [1]. In patients with prominent involvement of the cerebral white matter, the syndrome of white matter dementia commonly develops [1,2]. Cerebral autosomal dominant arteriopathy *Corresponding author. Tel.: 11-303-315-6461; fax: 11-303-3155867. with subcortical infarcts and leukoencephalopathy (CADASIL) is a newly described disease characterized by progressive dementia as well as recurrent vascular events, migraine, and mood disorder [3]. Leukoencephalopathy is present on neuroimaging studies in all affected individuals [3]. The mapping of the CADASIL gene to chromosome 19q12 led to the recognition that a vascular white matter disorder similar to Binswanger9s Disease may have a genetic basis, and CADASIL can now be regarded as a genetic cause of vascular dementia [3]. We present a case of CADASIL in which neurobehavioral dysfunction dominated the clinical course. This report demonstrates that white matter dementia can be the phenotypic expression of this disease, and highlights the neurobehavioral importance of cerebral white matter disorders. 0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00038-6 164 C.M. Filley et al. / Journal of the Neurological Sciences 163 (1999) 163 – 167 2. Case report This 62-year-old right-handed man was evaluated at age 58 for a three-year history of progressive neurobehavioral decline characterized by apathy, confusion, and poor self care. The illness began, however, in his mid-30s, when he was noted to undergo a gradual personality change marked by progressive irritability, social withdrawal, and estrangement from his family. He was divorced at age 49 because of the delusional belief that his employer was having an affair with his wife, and that this individual was the father of his two sons. At age 54, he threatened to blow up the facility where he was employed. By age 55, he was no longer able to work because of his behavioral disturbances. Two years later he was treated with nortriptyline for anxiety and depression, and in the following year a psychiatrist diagnosed an ‘unspecified mental disorder.’ In the following year, he became unable to live by himself, and on admission to another hospital he had ‘confusion’ and was diagnosed with ‘organic affective disorder.’ Past medical history was notable for the absence of hypertension. He had suffered a myocardial infarction at age 38. Family history was remarkable for multiple strokes in his father and diabetes mellitus in his mother. The patient had completed high school and taken some college courses before becoming an operating engineer. Neurologic examination revealed no elemental findings other than slow gait and a snout reflex. Mental status testing showed him to be alert and fully oriented. Digit span was six forward and four in reverse. Months of the year in reverse order were recited slowly but correctly. He recalled none of four complex stimuli after 5 min, but remembered all four with semantic cueing. He had no aphasia, apraxia, or agnosia. Visuospatial skills as assessed by drawing tasks were mildly impaired. Simple calculations were performed normally, but proverb interpretation was concrete. He was apathetic and unmotivated, but showed no signs of depression or psychosis. His score on the Mini-Mental State Examination [4] was 26 out of 30. Cranial MRI revealed extensive, diffuse, symmetric, and confluent white matter changes that were most evident on T2-weighted images (Fig. 1). There was relative sparing of the subcortical U fibers and the corpus callosum. Small infarcts were evident in the centrum semiovale and the left thalamus. The white matter changes were equally conspicuous on computerized tomography (CT), which was performed during his subsequent hospitalization. The cerebral cortex was spared on both MRI and CT. Laboratory evaluation showed a normal chemistry survey, complete blood count, erythrocyte sedimentation rate, thyroid function tests, vitamin B12, folate, and urinalysis. Rapid protein reagin and human immunodeficiency virus testing were negative. Cerebrospinal fluid analysis was unremarkable. An electroencephalogram showed a 9 Hz dominant alpha rhythm and diffuse intermixed theta and delta activity. A right frontal brain biopsy disclosed normal neocortex, with no evidence of recent or remote ischemic damage or Fig. 1. MRI scan showing severe leukoencephalopathy as revealed by diffuse white matter hyperintensity on T2-weighted images (TR 2100, TE 30). Scattered small infarcts are also apparent. C.M. Filley et al. / Journal of the Neurological Sciences 163 (1999) 163 – 167 165 Fig. 2. Punch skin biopsy demonstrating granular osmiophilic material (GOM) deposits on, and embedded in, the membranous infoldings of the vascular smooth muscle cells (curved arrows). Some GOM are scattered in the extracellular interstitial tissue of the small cutaneous arteriolar wall (straight arrows). A capillary with endothelial cells and erythrocytes is seen in the left upper corner (ultrathin section,316 750). neuritic plaques. The white matter showed vascular hyalinization causing arteriolar narrowing but no occlusion. A suggestion of ill-defined white matter pallor was present, but active demyelination was not seen. No macrophage or microglial influx or astrocytosis was observed, and axons were preserved. Congo red stain for amyloid was negative. The patient recovered uneventfully after the surgery, and was then admitted to a nursing home, where he remained clinically stable. At age 62, he underwent left pretibial skin biopsy that revealed granular osmiophilic material, pathognomonic for CADASIL, adjacent to vascular smooth muscle cells (Fig. 2). Genetic analysis showed an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region of chromosome 19q12, a mutation specifically associated with the disease. 3. Neuropsychological evaluation Standardized neuropsychological testing was performed when the patient was 58 years old. Table 1 lists neuropsychological test results. Overall performance on the Dementia Rating Scale [5] was normal, but many other results were abnormal. He was severely impaired on the time component of the Numerical Attention Test [6]. Similarly, he showed significant slowing of information processing on the Trail Making Test [6]. His learning of new information was slow and inefficient, although delayed recall of information previously learned was generally normal. On the California Verbal Learning Test [7], he recalled none of the items presented on the second 16word list, but his recognition performance was normal. On a nonverbal learning task [6], he became increasingly confused as he was shown the same figure several times and his performance actually declined over repeated trials. He had normal language as demonstrated by intact auditory comprehension [8], naming ability [9], and vocabulary [10]. Visuospatial tests [10,11] were performed normally, but he had trouble finding his way around the building (e.g. to and from the bathroom). On a task designed to assess the ability to manage a checkbook, he wrote a sample check correctly, but could not determine where to enter deposit or check amounts into a ledger. He was severely perseverative on the Wisconsin Card Sorting Test [12]. His verbal fluency on both phonemic and semantic tasks [13] was impaired. He did not report significant depressive symptoms on the Beck Depression Inventory [14]. The neuropsychological results were therefore characterized by a deficit in sustained attention, slowed information processing, impaired learning with intact recognition, a mild visuospatial deficit, and frontal lobe dysfunction as demonstrated by severe perseveration, poor reasoning, and C.M. Filley et al. / Journal of the Neurological Sciences 163 (1999) 163 – 167 166 Table 1 Neuropsychological test results Test Raw score Clinical significance Mattis Dementia Rating Scale Attention Initiation / Perseveration Construction Conceptualization Memory Numerical Attention Test (Cancellation) Time Errors Trail Making Test (Time) Part A Part B California Verbal Learning Test Total Trials 1–5, List A List B Short Free / Short Cued Recall Long Free / Long Cued Recall Recognition Story Learning Recall Figure Learning Recall Copy BDAE Complex Material a Boston Naming Test WAIS-Rb Vocabulary Block Design Digit Symbol Wisconsin Card Sorting Test Perseverative Responses Phonemic Fluency (FAS) Animal Naming Beck Depression Inventory 136 / 144 36 / 37 32 / 37 6/6 38 / 39 24 / 25 Normal Normal Mild Normal Normal Normal .300 2 Severe Normal 131 260 Moderate to severe Moderate 34 0 6/6 6/6 16 1 trial 67% 3 trials, not to criterion 100% 15 11 58 Mild to moderate Severe Mild, moderate Mild, moderate Normal Normal Normal Severe Normal Normal Normal Normal 10 6 3 Normal Normal Mild to moderate 119 11 8 7 Severe Moderate Moderate Normal a b BDAE – Boston Diagnostic Aphasia Examination. WAIS-R – Wechsler Adult Intelligence Scale-Revised. impaired verbal initiation. Language was preserved, and no depression was detected. 4. Discussion In the few years since its discovery, CADASIL has attracted considerable attention as a genetic leukoencephalopathy associated with stroke, migraine, mood disorders, and dementia. Although dementia has been recognized to be a predominant feature of some affected individuals [15], details of the syndrome have not been fully described. Moreover, other neurobehavioral manifestations of CADASIL have received little attention. Our patient had a 25-year history of a slowly progressive neurobehavioral disorder that included personality change, psychosis, mood disorder, and eventually dementia. Severe leukoencephalopathy was detected by neuroimaging studies, but the prominence of psychiatric features, the absence of hypertension, and the paucity of motor signs hindered accurate diagnosis. Skin biopsy and genetic analyses were ultimately required to establish the diagnosis of CADASIL with certainty. The clinical features of our patient bear close resemblance to those associated with other disorders of cerebral white matter, and this case represents an instructive example of white matter dementia. The syndrome of white matter dementia provides a useful framework for considering the neurobehavioral phenotype of CADASIL. This category of dementia has recently been proposed to call attention to dementia in patients with disorders of cerebral white matter [2], and a characteristic clinical profile has been suggested [1]. Our patient with CADASIL fits this pattern quite closely. Detailed neurobehavioral and neuropsychological testing revealed deficits in sustained attention, memory retrieval, visuospatial skills, frontal lobe function, and psychiatric status, with preservation of language and extrapyramidal function; procedural (skill) memory, also thought to be spared in white matter dementia, could not be evaluated. The long period of neuropsychiatric syndromes before the onset of dementia is remarkable. Over the extended C.M. Filley et al. / Journal of the Neurological Sciences 163 (1999) 163 – 167 course of his disease, our patient first manifested an insidious change in personality that began in his mid-30s and slowly progressed. Next, while in his 40s, he became frankly delusional about what he erroneously believed was his wife9s infidelity, a problem that led to marital separation and divorce. Then, in his early 50s, he became so threatening and aggressive at work that he was unable to retain employment, and diagnoses of anxiety, depression, and affective disorder were made. Only after these periods in his life was cognitive impairment suspected, and because of preserved language and motor function, uncertainty remained about the nature and severity of his disease. This pattern of neuropsychiatric syndromes preceding dementia has been observed in other cerebral white matter disorders, possibly reflecting a progression from early frontal and temporal white matter involvement when the disease is less advanced to more extensive leukoencephalopathy that results in dementia [16]. An important issue in white matter disorders is whether both white and gray matter involvement is necessary for the development of neurobehavioral dysfunction, or if white matter disease alone is sufficient. This distinction is not trivial; because many subcortical diseases affect both white and gray matter, the specific contribution of pathology in the white matter is difficult to assess. In a recent clinical-pathological study of CADASIL, two of the four demented patients presented had only leukoencephalopathy [15], suggesting that dementia may result either from involvement of both white and gray matter, or white matter alone. Our patient had severe leukoencephalopathy in comparison to subcortical gray matter involvement. The course of the disease was progressive over 25 years, and we interpret this case as an example of white matter dementia in CADASIL resulting from the gradual progression of leukoencephalopathy specifically disrupting higher cerebral functions. In summary, this case demonstrates that CADASIL may selectively and profoundly affect neurobehavioral function, and produce the syndrome of white matter dementia. More generally, our patient exemplifies the capacity of cerebral white matter disorders to disturb cognition and emotion by interfering with the operations of multiple neural networks in the brain subserving higher function [1]. Further study of clinical-pathological correlations in CADASIL and other leukoencephalopathies promises to extend our understanding of the pathogenesis of neurobehavioral dysfunction in these disorders. 167 Acknowledgements We are grateful to Dr Elisabeth Tournier-Lasserve for the genetic analysis of our patient. References [1] Filley CM. The behavioral neurology of cerebral white matter. Neurology 1998;50:1535–40. [2] Filley CM, Franklin GM, Heaton RK, Rosenberg NL. White matter dementia. Clinical disorders and implications. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:239–54. 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