NEUROLOGICAL PROGRESS Cerebrovascular Complications of Fabry’s Diseke Panayiotis Mitsias, MD, and Steven R. Levine, MD ~~ Fabry’s disease (FD) is a rare, sex-linked disorder resulting from a-galactosidase deficiency. Cerebrovascular complications have been reported in the literature but have not been systematically analyzed. We report 2 patients and review 51 previously reported cases (descriptive meta-analysis) to clarify the clinical, radiologic, and pathologic features. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygous individuals (n = 43) and 40.3 years of heterozygotes (n = 10). The most frequent symptoms and signs were as follows (in descending order of frequency): hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, and ataxia of gait, in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygote group. The vertebrobasilar circulation was symptomatic in 67% of the hemizygotes and 60% of the heterozygotes. Intracerebral hemorrhage was found in 4 patients (3 hemizygotes and 1 heterozygote). Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. For the hemizygotes, the recurrence rate for cerebrovascular disease was 76% and the death rate was 55%; 86% of the heterozygotes had recurrent cerebrovascular event(s) and 40% died. The cerebrovascular manifestations of FD, in both hemizygotes and heterozygotes, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and portend a poor prognosis. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol 1996;40:8- 17 Fabry’s disease (FD), or angiokeratoma corporis diffusum, is a rare X-linked inherited disorder of glycosphingolipid metabolism [ l]. Deficiency of a lysosomal hydrolase, a-galactosidase A, leads to progressive accumulation of glycosphingolipids, predominantly ceramide trihexoside, in most visceral tissues and body fluids of the affected subjects, primarily in the lysosomes of the vascular endothelium. Progressive endothelial glycophospholipid accumulation results in tissue ischemia and infarction and leads to the major clinical manifestations of the disease [ 11. The glycophospholipids also accumulate in perithelia and smooth muscle cells of the cardiovascular-renal system, and to a lesser extent in reticuloendothelial, myocardial, and connective tissue cells, in epithelial cells of the cornea, kidney, in ganglion and perineural cells of the autonomic nervous system, and in other tissues. Hemizygote males usually have a characteristic skin lesion, and suffer from fever, usually part of the anhidrosis associated with sweat gland failure, acroparesthesias, episodic crises of excruciating pain, corneal and lenticular opacities, and cardiac and renal dysfunction [ 11. Death usually occurs in adult life from renal, cardiac, or cerebral complica- tions of vascular disease [ 11. Heterozygote females are either asymptomatic or exhibit fewer signs and symptoms of the disease, although occasional females have been described with symptoms similar to the males [2]. We report our clinical experience with 1 hemizygote male and 1 heterozygote female with FD suffering cerebrovascular manifestations, and review all previously reported cases in the English literature, to clarify the clinical, radiologic, pathologic, and prognostic features. Our main hypothesis was that there would be different features based on whether individuals were hemizygotes or heterozygotes. From the Center for Stroke Research, Department of Neurology, Henry Ford Hospital and Health Science Center, Detroit, MI. Address correspondence to Dr Mitsias, Center for Stroke Research, Department of Neurology (K-1 l ) , Henry Ford Hospital and Health Science Center, 2739 West Grand Roulevard, Detroit, MI 482022689. Received Apr 19, 1395, and in revised form sep 13, 1395, and Feb 28, 1376. Accepted for publication Mar 8, 1336. Patients and Methods W e reviewed our clinical experience with 2 siblings, 1 male hemizygote and 1 female heterozygote, with cerebrovascular manifestations of FD, and systematically reviewed the literature. Criteria for diagnosis of FD and inclusion into this study included the following: corneal abnormalities, angiokeratoma, positive family history, and decreased a-galactosidase activity on cultured skin fibroblasts or platelets. Literature review cases were identified by using a computerized English language Medline search (key words: Fabry’s disease, Presented in part at the 118th annual meeting of the American Neurological Association, October 1993, Boston, MA. 8 Copyright 0 1996 by the American Neurological Association Fig 1. (A) Unenhanced head computed tomopaphic scan ?om Patient 1 demonstrating basilar artery dilatation and compression of the right side of the anterior pons (arrow). (B) Conventional cerebral angiogram from Patient I . Dolichoectasia of the vertebrobasilar system is evident (S shape) (arrowheads). angiokeratoma corporis diffusum, a-galactosidase) for 1966 through August 1995. References cited within these Medline articles as well as references within textbooks on cerebrovascular disease [3] and on medical genetics [I] were also reviewed for any specific citations or case histories. All cases with adequate data (clinical, radiologic, or pathologic) were included. Statistical Analysis We compared hemizygotes and heterozygotes, for differences in age using the two-sample t test. We accepted p < 0.05 as statistically significant. However, because most of the literature review patients are case reports representing highly biased ascertainment of difficult, unusual, or exceptional cases, we cannot place too much emphasis on the statistical analysis. Patient Reports Patient 1 A 38-year-old woman developed sudden numbness in the right upper extremity up to the level of the elbow. The next morning she experienced numbness of the right leg up to the level of the knee. She was a heterozygote carrier of FD. Her medical history was also significant for hyperlipidemia, moderately severe but treated hypertension, gastric bypass for morbid obesity, and chronic mild anemia. Family history was significant for FD, premature coronary artery disease, and premature strokes. General physical examination revealed pale conjunctivae, an S4 gallop, and no rash. Neurologic examination revealed normal mental status and cranial nerves, right upper extremity drift, and right hemianesthesia. The initial head computed tomographic (CT) scan revealed dilatation of the basilar artery with impression on the right anterior pons (Fig lA), and dilatation of both vertebral and carotid arteries. Conventional cerebral angiography revealed no significant stenosis of any of the cerebral vessels. However, there was marked fusiform aneurysmal dilatation of the basilar artery and the distal most aspects of both vertebral arteries (Fig lB), minimal dilatation of both distal internal carotid arteries, and no sign of focal aneurysm formation or branch occlusions. One month later she reported persistent right-side numbness and weakness especially during manual work. She also had recurrent throbbing, bioccipital headaches, sometimes accompanied by photophobia, sonophobia, nausea, and visual changes, described as flashing lights in the left visual fields. The headaches were present for many years but exacerbated recently. Magnetic resonance imaging (MRI) scan of the head demonstrated marked vascular ectasia of the basilar artery but no evidence of infarction, mass effect, or extracerebral fluid collection. Three months later, the patient reported left frontotemporal headaches associated with photophobia and irritability, preceded by nausea and vomiting and lasting for 4 days. She also had progressive loss of strength of the right arm, handwriting changes, right arm fariguability, a clumsy right leg, and short-term memory loss. Antinuclear antibody titer was 1 :320, on both homogeneous and speckled pattern; VDRL (Venereal Disease Research Laboratory) test, thyroid function tests, serum Biz, and folate levels were normal or negative. Repeat MRI scan of the head revealed a fusiform, dolichoectatic basilar artery and small bright-intensity lesions involving the periventricular white matter of both cerebral hemispheres. MRI scanning of the cervical spine revealed only minimal bulging of the annulus fibrosus at C5-C6, without compression of the spinal cord or the dural sac, that was not felt to be clinically significant. The headaches resolved, while the right hemiparesis persisted, possibly due to compression of the ventral pons by the dilated basilar artery. Formal neuropsychometric evaluation revealed a moderate degree of right hand slowing and mild weakness but otherwise intact neurocognitive abilities. Patient 2 A 36-year-old man, brother of Patient 1, presented with slurred speech and right-sided numbness and weakness that Neurological Progress: Mitsias and Levine: Stroke in Fabry’s Disease 9 B A C Fig 2. (A) Conventional selective right vertebral angiography fiom Patient 2 demonstrating an ectatic, tortuous uertebrobasilar tree (arrows). (B) Conventional cerebral angiograpLy ftom Patient I demonstrating dilatation of the right internal carotid artey (arrows). (C) Unenhanced head magnetic resonance imaging scan from Patient 2 revealing a l e j cerebelhr hemispheric infarct (possible watershed infdrct between the posterior inirioy cerebellar artery and the anterior inferior cerebellar artey) (arrowhead) and ectatic basilar artey (to the side of the cerebelhr infarct) (arrow). started in the early morning and resolved within 1 hour. There were no other symptoms. His medical history was significant for FD, diagnosed 12 years prior to this event by skin biopsy and corneal whorls, renal failure (on peritoneal dialysis), cholecystectomy, appendectomy, foot surgery, and inguinal herniorrhaphy. His general medical examination revealed sinus tachycardia and a blood pressure of 176188 mm Hg. Angiofibromas were seen over the buttocks and genitalia. The neurological examination demonstrated a mild, generalized weakness but was otherwise normal. Head CT scan on admission was normal. Conventional cerebral angiography revealed an ectatic, tortuous basilar artery (Fig 2A) and carotid arteries (Fig 2B). Twelve-lead electrocardiogram (EKG) revealed a prolonged QT interval or T U fusion. Holter cardiac monitoring for 24 hours was normal. The patient was treated with aspirin and left the hospital against medical advice. Twenty months later the patient underwent cadaveric renal transplant. Six months after the transplant he developed unilateral or bilateral temporal headaches, sharp, occasionally throbbing, not increasing with coughing or sneezing, with no time preference, lasting for 1 to 2 hours, without any other associated symptoms. MRI scan of the head revealed a left cerebellar hemispheric infarct (possible watershed infarct between the posterior and anterior inferior cerebellar arteries), an ectatic basilar artery (Fig 2C), and a few nonspecific foci of hyperintensity in the cerebral white matter on T2weighted imaging. Results In addition to our 2 patients, we systematically analyzed data fiom 42 other reported hemizygotes and 9 heterozygotes with FD who had symptoms or signs of cerebral vascular involvement [2, 4-40]. The clinical, radiologic, pathologic, and outcome data are summa- 10 Annals of Neurology Vol 40 No 1 July 1996 rized in Table 1. Detailed information on the clinical, radiologic, and pathologic features of these 53 patients (hemizygotes n = 43, heterozygotes n = 10) is presented in rwo tables registered with the National Auxiliary Publications Service. For information on how to order, see note at end of article. Clinical Features In the hemizygote group, the mean age at onset of symptomatic cerebrovascular disease was 33.8 years (2 13.8 years, range = 16-70 years). Twenty-nine hemizygotes (67.4%)had at least one cerebrovascular event consistent with posterior circulation territory ischemia, 5 (1 1.6%) had anterior circulation ischemia, whereas in I0 patients (23%) the territory could not be determined from the available information. One patient had involvement of both the anterior and the posterior circulation, and 1 involvement of the posterior and indeterminate circulation. Three patients had intracerebral hemorrhage either at the initial o r a subsequent event. Hemiparesis (63%), vertigo/dizziness (39%), diplopia (37%), dysarthria (30%), nystagmus (26%), nausea/ vomiting (24%), head pain (24%), hemiataxia (2 I%), and ataxia of gait (18%) were the most common symptoms and signs. In 5 patients no information on clinical picture, but only the diagnosis, was provided. In the heterozygote group, the average age at onset of symptomatic cerebrovascular disease was 40.3 years (? 15.8 years, range = 20-57 years) (p = 0.172, for comparison with hemizygotes). In 5 patients (50%), the clinical presentation was consistent with involvement within the vertebrobasilar territory. One patient Table I . Summary of Cerebrovascular Features of Fabry j Disease Clinical featuresa Age at presentation Age range Most common symptoms Hemiparesis Vertigo I dizziness Diplopia Dysarthria Nystagmus Memory loss Hemizygotes Heterozygotes 33.8 ? 13.8 yr 16-70 yr 40.3 -C 15.8 y~ 20-57 yr 63% 39% 37% 30% 26% 40Yo 50% - 21% Ataxia - Depressed level of consciousness Radiologic features (brain imaging) Normal VB infarcts Multiple small infarcts t_ PVWML” Ectatic basal vessels Intraparenchymal hemorrhage Ventricular dilatation Vascular pathology‘ Thickened basal vessels Atheromatous basal vessels Intracellular arterial and arteriolar deposits Dolichoectatic VB vessels Outcomed Recurrent cerebrovascular disease Recurrent VB events Indeterminate location Multiple events Intraparenchymal hemorrhage Subdural hematoma Death 4/16 (25%) 6/16 (37%) 7/16 (44%) 3/16 (19%) 1/16 (6%) 1/16 (6%) 215 (40%) 115 (20%) 315 (60%) 4 (33%) 2 (17%) 2 (17%) 1 (8%) 0 (0%) 1 (33%) 0 (0%) 3 (100%) 22 (76%) 16 (73%) 14 (48%) 5 (23%) 2 (7%) 1 (3%) 16 (55%) 6 (60%) 6 (60%) 2 (20%) 215 (40%) 015 (0%) 215 (40%) 0 (0%) 0 (0%) 0 (0%) 4 (40%) ’Data based o n 43 hemizygotes and 10 heterozygotes (details in Tables A and B of NAPS document # 05315). ”Data based on nine head CTs and seven MRIs for hemizygotes and three head CTs and two MRIs for heterozygotes ‘Data based on 12 hemizygotes and three heterozygotes. dAvailable outcome data based on 29 of 43 (67%) hemizygotes and 10 of 10 (100%) heterozygotes. VB = verrebrobasilar; PVWML = periventricular white-matter hyperintensities; NAPS = National Auxiliary Publications Service; CT = computed tomographic scan; MRI = magnetic resonance imaging scan. (10%) initially had definite carotid territory, and subsequently posterior circulation and ischemia, and in 3 patients (30%) the vascular territory was indeterminate. In 2 of the latter, the clinical picture was more suggestive of a progressive hydrocephalus, rather than pure ischemia. O n e patient (10%) had a pontine hemorrhage. Memory loss (50%), vertigo (50%), ataxia (40%), hemiparesis (do%), depressed level of consciousness (40%), hemisensory symptoms (30%), and sphincter incontinence (30%) were the predominant symptoms and signs. Headache was present in 2 patients (20%). Radiologic Features In the hemizygote group, head CT scan results were reported in 9 patients. T h e findings were as follows: normal (n = 3), large occipital infarct (n = 2), multi- ple small, deep infarcts (n = 2 ) , pontine infarct (n = I), large cerebellar infarct (n = I), infarct/location not reported (n = I), prominent basilar artery (n = I), and intracerebral hemorrhage (n = 1). Cranial MRI results in 7 patients included the following: multiple small, deep infarcts (n = 4 ) , periventricular whitematter hyperintensities (n = j ) , cerebellar infarcts (n = 2 ) , prominent, ectatic basal vessels (n = a), venrricular dilatation (n = I), and normal findings (n = 1). In the heterozygote group, head CT scan results were reported in 3 patients. The findings included the following: normal (n = 2), prominent basilar artery (n = l), and ventricular dilatation (n = 1). MRI data in 2 patients were as follows: periventricular white-matter hyperintensities (n = 2), pontine infarct (n = I), multiple small infarcts (n = l), basilar and vertebral artery dilatation (n = I), and ventricular dilatation (n = 1). Neurological Progress: Mitsias and Levine: Stroke in Fabry’s Disease 11 Cerebral angiography results were reported in 10 hemizygotes and 2 heterozygotes. In the hemizygotes, it was normal (n = 7), or demonstrated the following: dolichoectatic basilar artery (n = 2), vertebral arteries (n = I), internal carotid artery (n = I), or diffuse vascular sclerosis (n = I ) . In the heterozygotes, dolichoectatic basilar artery (n = 2 ) , internal carotid arteries (n = 2), and vertebral arteries (n = 1) were seen. Pathologic Findings Neuropathologic autopsy results were available in 12 hemizygotes and 3 heterozygotes. In the hemizygote group, the distribution of cerebral infarcts was as follows: large superficial cerebral hemispheric (n = 7), multiple small and deep (n = 6), large cerebellar hemispheric (n = I), multiple small cerebellar (n = 6), and brainstem (n = 4). Intracerebral hemorrhage (n = 2), subdural hematoma (n = l), ventricular dilatation (n = I), and cerebral hemispheric edema (n = 1) occurred. Thickened vessels of the circle of Willis with narrowing of the lumina (n = 4), moderate atheroma of the major cerebral vessels (n = I ) , intracellular deposits in arteries and arterioles (n = 2), and massive dilatation of the basilar (n = 1) and vertebral arteries (n = 1) were the vascular findings. Dolichoectasia of the basilar artery (n = 3), vertebral arteries (n = 2), internal carotid arteries (n = 2), atheroma of the cerebral vessels (n = I), and pontine hemorrhage (n = I ) were found in the heterozygotes. Outcome Information on subsequent presentations was available for 29 of 43 (67%) hemizygote patients. Twenty-two (76%) developed recurrent cerebrovascular events; of these, 14 (48%) had multiple events. In 16 (73%) the recurrence was in the vertebrobasilar territory, while in 5 (23%) the territory was undetermined. Three patients developed subsequent intracranial hemorrhage, 2 intracerebral and I subdural. With information on the timing of recurrence available in 14 patients, the mean interval between the first cerebrovascular event and the first recurrence was 6.4 years (? 6.1 years, range = 0-19 years). Sixteen patients (55%) died. With information on timing available for 14 patients, the mean interval to death was 8.2 years (? 7.4 years, range = 0-20 years). In 10 patients, death was directly linked to the cerebrovascular event, 4 died of renal failure, and 1 of intestinal volvulus; there was no information as to the cause of death in 1 patient. In the heterozygote group, 3 patients (30%) died as a direct consequence of the initial cerebrovascular event, and 1 patient (1O0/o) died from a subsequent event. The causes of death were progressively deepening coma in 3 patients and pontine hemorrhage in 1. The mean interval from initial presentation to death was 0.8 years (2 1.5 years, range = 0-3 years). Six 12 Annals of Neurology Vol 40 No 1 July 1796 of 7 survivors (86%) developed recurrence of cerebral ischemia; 2 (28%) had multiple events. The recurrences were always in the posterior circulation; the mean interval to recurrence was 2.2 years (t 1.3 years, range = 1-4 years). Discussion The neurologic complications of FD include peripheral neuropathy, autonomic neuropathy, and cerebrovascular disease [ 11. Heterozygotes usually present either with no symptoms [I] or with milder manifestations of FD compared with hemizygotes [ 2 ] ,although cerebrovascular manifestations are common in both the hemizygote and the symptomatic heterozygote groups. We thus postulated that there would be differences in the clinical features of cerebrovascular involvement between hemizygotes and heterozygotes with FD. However, the rarity of FD does not allow estimation of the overall incidence of cerebrovascular complications in this condition, or their frequency in relation to other neurologic or medical complications. The onset of cerebrovascular disease was at a relatively young age for stroke for both hemizygotes and heterozygotes. Hemizygotes presented with cerebrovascular disease almost 7 years earlier than heterozygotes, strongly suggesting that the degree of enzyme deficiency may be directly related to, and determine in part, the rate of development of the vascular changes. The difference in age of presentation between the two groups was not statistically significant. However, we cannot place too much emphasis on the statistical analysis, because most of the previous articles are case reports representing highly biased ascertainment of difficult, unusual, or exceptional cases. Ischemic Cerebrovascular Disease The majority of patients both in the hemizygote and the heterozygote groups presented with symptoms and signs related to vertebrobasilar ischemia. Ischemic symptoms due to anterior circulation involvement were relatively uncommon. Given the greater occurrence, in general, of anterior circulation versus posterior circulation symptoms of cerebrovascular disease [41, 421, our data suggest that there may be a general predilection for involvement of the arteries of the posterior circulation in FD. The reasons for this are not clear, as it is reasonable to presume that the enzymopathy would affect the cerebral arteries in a uniform manner. The limited neuroradiologic and neuropathologic data may provide some insight into this selective involvement. In a number of patients [14, 17, 18, 26, 271, the medium- and small-sized arteries were markedly thickened and their lumina were narrowed, and the large intracranial arteries, especially those of the posterior circulation, were dolichoectatic [ l l , 15, 18, 30, 36, our 2 cases]. It is conceivable that vertebral or basilar artery Table 2. Nonischemic Complications o f Dolichoectatic Intracranial Arteries in Fabry i Disease 1. Hydrocephalus 2. Optic atrophy 3. Oculomotor paralysis 4. Trigeminal neuralgia 5. Eighth nerve dysfunction 6. Hypoglossal nerve palsy 7. Hypertension (?) dolichoectasia may cause reduction of blood flow and, more important, stretching, distortion, and obstruction of the already stenotic basilar tributaries, thus resulting in brainstem or cerebellar ischemia [43].Complete or partial thrombosis resulting in unilateral restricted pontine infarct in the territory of a penetrating artery (presumably related to distortion and obstruction of paramedian or circumferential basilar artery branches, or reduced flow from atherosclerosis) have occurred. Large bilateral pontine infarcts from basilar artery occlusion [44],cerebellar infarct [45],or embolic infarction of the occipital lobe [46]or the thalamus [47]have been documented in patients with dolichoectatic basilar artery, and have been observed in several of the patients in our series (see NAPS document ## 05315). In the anterior circulation, large superficial ischemic infarcts were seen in 5 patients in the hemizygote group. These could also be the result of artery-to-artery embolism from dolichoectatic intracranial internal carotid arteries. In general, focal cerebral ischemia frequently complicates dolichoectatic internal carotid arteries. Yu and colleagues [48] reported that 61% of patients with carotid dolichoectasia of any etiology had signs or symptoms in the ipsilateral territory. Rautenberg and co-workers (491 reported that of 45 patients with dilative intracranial arteriopathy, one-third presented with transient or permanent ischemia of the cerebral hemispheres. Nonischemic complications of dolichoectatic intracranial arteries may also complicate FD (Table 2). One hemizygote [18] and three heterozygotes [ 1 1 , 36, 371 had presentations consistent with hydrocephalus, and findings of triventricular hydrocephalus and dolichoectatic basilar arteries. A dolichoectatic basilar artery can cause hydrocephalus by impinging on the third ventricle or the cerebral aqueduct [50, 511. Other presentations, such as in 1 patient with third nerve palsy [ 121, 1 with trigeminal neuralgia [32],4 with isolated eighth nerve dysfunction [11-13], and 1 with dysfunction of the hypoglossal nerve [37] could also be attributed to compression of the individual nerves by the dolichoectatic basilar or vetebral arteries, as previously described in patients with similar neurovascular compression syn- dromes, although of different etiologies [43, 52-54]. Optic atrophy was observed in 3 patients [ I 1 , 13, 151 and could also be attributed to compression of the optic nerve by a dolichoectatic supraclinoid segment of the internal carotid artery [55]. Deep small cerebral infarcts, usually multiple, were found in 10 patients. Most likely, the underlying mechanism was progressive occlusion of the small intracranial arteries or arterioles, secondary to deposition of the glycosphingolipid in the vessel wall, as shown pathologically in several patients [14, 17, 23, 261. Hypertension is a known strong risk factor for the development of small cerebral artery occlusive disease (561. It is possible that hypertension was a strong contributing factor for the development of the previously described small cerebral vessel changes, especially given that patients with FD usually develop chronic, progressive renal impairment, and consequently hypertension. Unfortunately, this is only speculative at this point, as specific information on hypertension, as well as other possible risk factors (diabetes mellitus, cigarette smoking, hyperlipidemia, and ischemic heart disease) for the development of arterioral lipohyalinosis and, as a result, of small deep infarcts, was unfortunately lacking in the majority of the reported patients. In FD, deposition of the glycosphingolipid occurs in all areas of the body but predominantly in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels [ I ] , thus resulting in extensive vascular smooth-muscle involvement, presumably leading to the development of the intracranial cerebral artery dolichoectasia. Arterial strength and elasticity are provided by the extracellular matrix, which is composed of collagen, elastin, glycosaminoglycans, and proteoglycans [ 571. Smooth-muscle cells increase their synthesis of these macromolecules in response to increases or redistribution of tension in the arterial wall [58, 591. If glycosphingolipid deposition in vascular smooth muscle interfered with matrix production or organization, the result could be a loss of structural integrity of the arterial wall, leading to gradual dilatation and aneurysm formation. It is recognized that the proportions of extracellular matrix components vary between different arteries. Intracranial arteries have little elastin in the medial layer [GO] and have walls that are proportionately thinner than the walls of extracranial arteries of comparable caliber [61].Such differences may be relevant in understanding why dolichoectasia in FD patients developed only in intracranial arteries, despite rather extensive glycolipid storage in other cells. Overall, these findings are consistent with the observations of HegedGs [62] who observed defects in the internal elastic lamina and reticular fiber deficiency in the muscular layer of patients with ectatic basilar arteries and suggested that insufficiency of smooth-muscle Neurological Progress: Mitsias and Levine: Stroke in Fabry’s Disease 13 cells along with aging and hypertension may cause insufficient repair of vessel wall lesions. This has been accepted as a major operational parameter for the development of atherosclerotic aneurysms, and it likely plays a role in the development of intracranial arterial dolichoectasia in patients with FD. Dolichoectasia of the intracranial arteries is considered to be rare [63, 641. Depending on the criteria of definition, the incidence varies between 0.06% [48] and 5.8% [52]. The vertebrobasilar system is commonly involved. The pathogenesis has not yet been elaborated, but atherosclerosis or hypertensive vasculopathy seems to play a major role, as at least 75% of patients with dilative arteriopathy have chronic hypertension. The exact role of hypertension has not been clarified, and there are actually reports [65, 661 suggesting that hypertension is the result of neurovascular compression a t the ventrolateral medulla by likely ectatic cerebral arteries. Further, the disease has also been observed in older patients in the absence of atherosclerosis [67]. In young children with a-glucosidase deficiency leading to extensive glycogen deposition in the vascular smooth muscle [45], fatal subarachnoid hemorrhage and cerebellar infarction has been reported. Several other factors can also be considered in the etiology of cerebral ischemia in patients with FD. Cardiac abnormalities are frequently encountered and they can potentially lead to cardiogenic cerebral embolism. Coronary artery disease, caused by deposition of the glycosphingolipid [68], can result in premature myocardial infarction [ I 1, 22, 271 with secondary wallmotion abnormalities, mural thrombus formation, and subsequent cardiogenic embolism. Valvular heart disease, especially of the mitral valve, is frequently encountered. In one series [69] mitral valve prolapse was found in 54% of the hemizygotes and 58% of the heterozygotes, and there was no correlation between its presence and clinical disease severity, age, or other echocardiographic variables. Sakuraba and associates [70] found mitral valve prolapse in 56% of hemizygotes and 39% of heterozygotes, disruption of chordae tendineae attached to the mitral valve in 1 hemizygote and fluttering of the aortic valve in 1 heterozygote, even before definite clinical symptoms were detected. The pathologic findings of Becker and colleagues [ 191, of diffuse thickening of the leaflets of the mitral valve with prominent ballooning toward the left atrium of both the anterior leaflet and each of the scallops of the posterior cusp, and the presence of glycolipid deposits in all the structures of the heart, offers some explanation for the increased incidence of mitral valve prolapse in FD. Mitral valve prolapse may have a role in cerebral ischemia, at least in younger patients [711. Hypertrophic cardiomyopathy can complicate FD [72, 731. In one series [70] concentric hypertrophy of 14 Annals of Neurology Vol 40 No 1 July 1996 the left ventricle and/or ventricular septum were found in 1 of 10 hemizygotes and 7 of 13 heterozygotes. Goldman and colleagues [69] demonstrated that although hemizygote males had greater aortic root diameter, thicker interventricular septum, and greater ventricular mass than heterozygous females, older heterozygote females had more severe evidence of cardiac disease than did younger male patients. Colucci and co-workers [74] reported 1 male hemizygote with infiltrative cardiomyopathy, indistinguishable from hypertrophic obstructive cardiomyopathy. More recently, an atypical variant of FD in hemizygotes with residual, rather than absent, enzyme activity has also been described [ 1, 351. These “cardiac variants” typically have left ventricular and interventricular septum hypertrophy [ l , 351, abnormalities known to be associated with increased risk for stroke [75], mostly when accompanied by atrial fibrillation 176, 771. Impaired autonomic function in male [25] and female [38] patients with FD, presumably related to glycolipid deposition in the autonomic nervous system and vascular beds, has been reported. Resulting severe orthostatic hypotension may lead to transient or permanent cerebral ischemia, especially in the presence of cerebral vessel occlusive disease [78]. Widespread endothelial abnormalities have been reported in FD [l], related to tissue deposits of glucophospholipids, predominantly ceramide trihexoside, and to a lesser extent ceramide digalactoside and the tissue blood type B substance. These endotheliopathies can potentially lead to platelet activation. Igarashi and colleagues [79] found markedly increased platelet aggregation in the presence of ADP, collagen, and epinephrine as well as increased plasma P-thromboglobulin in both hemizygotes and heterozygotes without prior histories of thrombotic episodes. The majority of these subjects also had mitral valve prolapse, also known to be associated with platelet hyperactivity [SO] even in the absence of thromboembolic complications. As the majority of ischemic events in patients with FD were in the posterior circulation, the previously mentioned factors (which tend to involve the carotid circulation) may play a relatively less important role for cerebral ischemia, compared with the cerebrovascular changes induced by the enzymopathy. Table 3 summarizes the potential mechanisms of cerebral ischemia in patients with FD. Hemorrhagic Cerebrovascular Disease Intracerebral hemorrhage was seen in 3 hemizygotes [7, 11, 351 and 1 heterozygote [ 151. Most likely, the hemorrhage was a consequence of uncontrolled hypertension secondary to uremia. However, the relatively young age of the patients suggests that the underlying degeneration of the cerebral vessels, secondary to the Table 3. Mechunisms of Cerebral Ischemia in Patients with Fably > Diseuse 1. Intracranial arterial dolichoectasia Related to: a. Glycosphingolipid deposition in vascular smooth muscle b. Hypertension Resulting in: a. Complete or partial thrombosis of main arterial trunk b. Stretching, distortion, and obstruction of tributary vessels c. Artery-to-artery embolism 2. Progressive occlusion of small arteries or arterioles secondary to deposition of glucosphingolipid in the vessel wall 3. Cardiogenic embolism secondary to: a. Wall-motion abnormalities secondary to ischemic heart disease b. Valvular heart disease, especially mitral valve prolapse c. Hypertrophic cardiornyopathy 4. Impaired autonomic function 5. Platelet activation deposition of glycosphingolipid in the vessel wall, could be a strong contributing factor. In addition, the finding of a clot in the occipital lobe of 1 patient [7] can raise the suspicion of occipital infarct and subsequent reperfusion hemorrhage in the posterior circulation. Other factors, such as coagulopathy, or cerebral vascular malformations, are potential explanations, but further clinical information was unfortunately lacking. Subarachnoid hemorrhage from rupture of a dolichoectatic basilar artery has also been reported [45] but was not mentioned in any of the patients with FD. Management Treatment is far from satisfactory as no specific therapy for the cerebrovascular complications of FD is available. Administration of antiplatelet agents may help to prevent the atherosclerotic and thromboembolic effects of damage to the vascular endothelium, but experience with this approach is limited. In one study, administration of ticlopidine significantly modified platelet aggregation in patients with FD [81], but whether this is of significance in a clinical setting remains to be shown. Management of underlying cardiac problems, and use of oral anticoagulant agents, if there are conditions predisposing to cardiogenic embolism, should also be considered. In addition to correcting renal function, renal transplantation may also prevent the further development of vascular lesions, thus preventing cerebrovascular manifestations, by providing a source of normal enzyme for release in the circulation. A report of progressive cardiac involvement despite successful renal allotransplantation [82], however, as well as the yet undiscovered long-term effects of fetal liver transplantation or substrate (globotriaosylceramide) depletion by plasmapheresis, emphasizes the importance of long-term follow-up studies. Genetic counseling, and prenatal diagnosis based on enzyme assay in amniocytes and chorionic villi [83], should be offered. In conclusion, FD is frequently associated with cerebrovascular complications. Cerebral ischemia occurs at a relatively young age. Hemizygotes tend to develop cerebral ischemia at a younger age than heterozygotes. Multiple mechanisms may be involved, the most predominant being a noninflammatory dilative vasculopathy induced by the enzymopathy. There is a general predilection for involvement of the posterior circulation. Vertebrobasilar dolichoectasia, resulting in stretching and occluding the ostia of the already stenotic brainstem perforators, is the most common underlying process. FD disease should be considered in the differential diagnosis of ischemic stroke in the young, especially if there are accompanying radiologic findings of dolichoectatic intracranial vessels. These patients should be evaluated further with an examination for characteristic skin lesions, slit-lamp examination for corneal dystrophy, and measurement of leukocyte agalactosidase activity. Note Readers can obtain 14 pages of supplementary material from the National Auxiliary Publications Service, c/o Microfiche Publications, PO Box 35 13, Grand Central Station, New York, NY 10163-3513. Request document no. 05315. Remit with your order (not under separate cover), in US funds only, $7.75 for photocopies or $4.00 for microfiche. Outside the United States and Canada, add postage of $4.50 for the first 20 pages and $1.00 for each 10 pages of material thereafter, or $1.75 for the first microfiche and $.50 for each fiche thereafter. There is a $15.00 invoicing charge on all orders filled before payment. Supported in part by N I H grant NS23393 and a grant-in-aid from the American Heart Association, Michigan Affiliate. W e thank Dr. K. M. A. 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