(Stroke. 1996;27:143-146.)
© 1996 American Heart Association, Inc.
Articles |
Stroke in Williams Syndrome
Correspondence to Jan B. Wollack, MD, PhD, Department of Pediatrics, University of Maryland School of Medicine, Room N5W51 UMH, 22 S Greene St, Baltimore, MD 21201-1595. E-mail jwollack@umabnet.ab.umd.edu.
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Abstract |
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Background Williams syndrome is a genetic disorder characterized by a high incidence of heart disease, arterial stenosis, and hypertension. Despite these features, cerebrovascular accidents have been described only recently and only in association with stenoses of the cerebral vasculature.
Case Description A 19-year-old girl with Williams syndrome developed an acute-onset hemiparesis. MRI demonstrated an infarct involving the internal capsule and putamen. No stenotic areas were seen on angiography.
Conclusions Stroke should be considered as a possible consequence of Williams syndrome, even in the absence of stenoses of the cerebral vasculature. Comparison of this case with those previously reported in the literature emphasizes the multiplicity of features in Williams syndrome that can contribute to the risk of stroke.
Key Words: cerebral infarction • cerebral ischemia, transient • cerebrovascular disorders • children • genetics
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Introduction |
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Williams syndrome (WS) is a genetic disorder characterized by infantile hypercalcemia, elfinlike facial features, a friendly, outgoing personality, and cardiovascular abnormalities.1 The cardiovascular disorders include hypertension and structural heart disease such as supravalvular aortic or pulmonic stenosis, ventricular septal defects, patent ductus arteriosus, and mitral valve prolapse. There may also be stenoses of peripheral arteries.2 3 4 These features may be related to deletions of the elastin gene, which occur in approximately 90% of cases.5 Numerous other features have been described as well, including stellate iris, dental enamel hypoplasia, renal anomalies, constipation, and musculoskeletal abnormalities.2 Nervous system involvement includes developmental delay, seizures, cerebellar dysfunction, mental retardation, attention deficit disorder, and lower extremity hyperreflexia.2 6 Despite the frequency and severity of the reported cardiovascular features of WS, and the attention given to the neurological aspects, cerebrovascular abnormalities with associated strokes have been described only recently and only in association with stenoses of the cerebral vasculature.7 8 9 10 We describe a 19-year-old adolescent girl with WS who presented with an acute stroke, and we compare the clinical and neuroradiological findings with those of the other five cases in the literature.
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Case Report |
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The patient was born after a normal pregnancy and delivery. She had feeding difficulties as an infant, and her height and weight were at the fifth percentile. At the age of 2 years, she was evaluated for developmental delay and found to have moderate mental retardation, hypercalcemia, hypercholesterolemia, and scoliosis. She was placed on a low-calcium, low–vitamin D diet until age 11 years, when her calcium normalized. At 14 years of age, her serum cholesterol was found to be 5.95 mmol/L, and she was placed on a modified diet. An echocardiogram performed at that time revealed mild mitral valve prolapse. At age 16 years, her blood pressure was found to be 170/105 mm Hg, and a repeated echocardiogram revealed mitral valve prolapse with regurgitation and left-sided atrial and ventricular dilatation. Genetics consultation established the diagnosis of Williams syndrome on the basis of her facial features, "cocktail-party" personality, mental retardation, hoarse voice, short stature, and history of earlier hypercalcemia. Her hypertension was treated with an angiotensin-converting enzyme inhibitor, with a decrease of her blood pressure to between 120/62 and 137/85 mm Hg. Her serum cholesterol was 6.85 mmol/L, and she was begun on an American Heart Association Step 1 diet. Routine examination at age 17 years revealed bilaterally brisk patellar reflexes and a left Babinski sign, which were not investigated further.
At 19 years of age, she awakened with mild right-sided weakness that progressed over the day to right hemiparesis and dysarthria. On arrival at the hospital, she was hypertensive (158/103 mm Hg) with a pulse of 108 beats per minute. Examination revealed prominent ears, stellate pattern of the iris, and prominent lips. Her heart had a regular rhythm with a III/VI blowing systolic murmur and normal peripheral pulses. Neurological examination revealed she had an alert mental status without dysphasia. She spoke in short dysarthric sentences and showed good comprehension. Cranial nerve examination revealed right facial weakness and right tongue deviation. Her motor deficit consisted of a flaccid right hemiparesis affecting the arm more than the face and leg. Sensation was intact. She could not perform the cerebellar examination on the right due to weakness; it was normal on the left. Reflexes were brisk in all extremities, and bilateral Babinski signs were present.
Initial CT of the cranium performed without intravenous
contrast showed a discrete area of hypodensity lateral to the left
internal capsule and adjacent to the left putamen.
T2-weighted MR images of the head revealed a 3x1.5-cm area
of abnormally increased signal intensity in the left internal capsule
and putamen, consistent with infarct (Figure
).
MR angiography suggested a narrowing of the M1 segment of the left
middle cerebral artery, so conventional angiography was performed. No
significant arterial narrowing was found within the cranial
circulation, although injection of the left common carotid artery was
accompanied by severe vasospasm requiring treatment with
intra-arterial nitroglycerin. The renal
circulation was also studied, and cannulation of the renal artery
similarly resulted in local vasospasm. No renal artery stenosis
was found. The following studies were all normal: hemogram, glucose,
electrolyte, blood urea nitrogen, creatinine, liver
function, and protein studies; coagulation profile, including
prothrombin time, partial thromboplastin time, fibrinogen, antithrombin
III, proteins C and S, and anticardiolipin antibody; immunological
profile including antinuclear antibody, rheumatoid factor,
sedimentation rate, cryoglobulin, CH50, C3, and C4; and plasma amino
acids, including homocystine. Neither transthoracic nor
transesophageal echocardiography
revealed a source of embolism.
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The patient was transferred to a rehabilitation facility where she continued to improve, although a moderate hemiparesis persists. In an attempt to lessen the chances of recurrence, ticlopidine therapy was begun, and she was switched to a calcium channel blocker to better control her blood pressure.
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Discussion |
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Many of the cardiovascular abnormalities that can be seen in WS are known or suspected risk factors for stroke, including hypertension, cardiac disease, and arterial stenosis.11 12 Only in the last 2 years, however, have cerebrovascular accidents been reported.7 8 9 10 We describe an additional case of a WS patient with an acute stroke and compare it with the other cases in the literature, reviewing the possible risk factors that were associated with each. These cases not only support the hypothesis that patients with WS are indeed at risk for such events but also suggest that multiple features of the syndrome contribute to the risk of stroke.
The first difference between this case and the others concerns the type
of heart disease that was present
(Table). Our patient had mitral valve
prolapse with regurgitation, a type of defect that is
relatively rare in WS, so much so that Akcoral et al13
have proposed that its presence represents a distinct form of
WS. In general, the contribution of mitral valve prolapse to an
individual's risk of stroke is at most
small.14 15 16 The
defects found in the other patients are much more common in WS, ranging
from 64% of patients having supravalvular aortic
stenosis to 12% having a ventricular septal
defect.2 In four of these patients, the nature of the
defects was such that these defects would be expected to add
significantly to the patients' risk for stroke.15 Another
patient (case 5) had pulmonic stenosis that resolved before his
stroke; given that pulmonic stenosis in WS has a generally good
prognosis,17 it is difficult to speculate on the
contribution that such a defect might make to overall stroke risk in
this disorder.
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Second, the most striking difference between this case and the others
lies in the involvement of the cerebral vasculature. Although
stenoses involving the renal and pulmonary arteries and
the aorta are prominent in WS, stenoses in other
arteries,2 including the carotid,3 4
have
been described less often. The only detailed descriptions of
abnormalities in the cerebral vasculature are those found in the cases
summarized in the Table
. In all but the patient described in
this
report, involvement of two or more vascular distributions was found.
While this finding suggests that stenoses within the cerebral
vasculature might be the major determinant of stroke in these patients,
one must realize that because patients with WS do not commonly undergo
cerebral angiography the incidence of asymptomatic
cerebrovascular stenosis is not known. In reports of three
other patients who underwent this procedure for reasons other than
stroke, no vascular pathology was found.4 18 The
increasing use of noninvasive techniques such as MR angiography should
help to resolve this issue. Nonetheless, the lack of fixed
stenoses in our patient suggests that cerebrovascular
stenoses are not the sole cause of stroke in WS.
Third, hypertension was documented in our patient 3 years before her stroke. Although she was being treated, she was nonetheless significantly hypertensive at presentation. Two of the other patients were also reported to be hypertensive, one chronically (patient 3) and one only at the time of his strokes (patient 2). Since hypertension is a well-documented risk factor for stroke in the non-WS population,12 it may well have contributed to these patients' strokes.
Our patient additionally had hypercholesterolemia. In general, the literature describing WS does not mention serum cholesterol. To our knowledge, the only documentation of a lipid profile in WS was by Narasimhan et al,19 who reported a normal lipid profile in a 5-year-old child with WS. Thus, the incidence of hypercholesterolemia in WS remains to be established. Although hypercholesterolemia is well recognized as a risk factor for cardiac disease, the evidence linking it to stroke is not convincing except in the case of familial hyperlipidemia.12 20 Although the paternal grandmother and aunt of this patient were hypercholesterolemic, her siblings were not, and her serum cholesterol levels remained below those generally reported in patients with familial hypercholesterolemia. Furthermore, angiography in this patient failed to reveal any evidence of atheromatous plaque, making it less likely that this mechanism contributed to her stroke.
During angiography, our patient had two separate episodes of arterial spasm, one involving the renal artery and one the left carotid, the latter requiring the use of intra-arterial nitroglycerin. These events may represent mere coincidence, but the possibility that the patient was predisposed to such events as a consequence of her WS should be considered. It is tempting to speculate that even in the absence of grossly detectable malformations in the vasculature, vessels might exhibit an abnormal reactivity, which in some way may be related to the defect in the elastin gene that is frequently found in patients with WS.5 In the report of Conway et al,3 of three patients with WS who had myocardial infarctions leading to sudden death, in two cases death immediately followed cardiac catheterization. The experience of Conway et al, as well as ours, suggests that caution should be exercised in using angiography in these patients.
Theoretical grounds alone would suggest that patients with WS might have an increased susceptibility to stroke, since several of the features of WS are known risk factors. The six cases reviewed here support this concept. The first five cases, in which all patients had multiple stenoses of the cerebral vasculature, suggest that such stenoses are the predominant cause, even though the incidence of asymptomatic stenoses of these vessels is not clearly known. The lack of such stenoses in the new case reported here suggests that stenoses are not the only factors that can contribute to stroke in these patients and emphasizes the potential contributions of hypertension and congenital heart disease to the overall risk of stroke in WS.
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Acknowledgments |
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Dr Wollack is the recipient of clinician investigator development award NS01514. The authors thank Dr Thomas K. Koch, University of Maryland at Baltimore, for his helpful advice.
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Footnotes |
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From the Departments of Pediatrics (J.B.W., M.K.), Neurology (J.B.W., M.P.L.), and Radiology (M.R.), University of Maryland School of Medicine (Baltimore).
Received August 7, 1995; revision received September 28, 1995; accepted September 28, 1995.
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