sions and normal appearing white matter of multiple sclerosis. Brain
2001;124:1743–1753.
27. Creange A, Chazaud B, Plonquet A, et al. IFN-beta decreases adhesion
and transmigration capacities of lymphocytes in Guillain-Barré syndrome. Neurology 2001;57:1704 –1706.
28. Özenci V, Kouwenhoven M, Teleshova N, Pashenkov M, Frederickson
S, Link H. Multiple sclerosis: pro- and anti-inflammatory cytokines and
metalloproteinases are affected differentially by treatment with INF-␤.
J Neuroimmunol 2000;108:236 –243.
29. Galboiz Y, Shapiro S, Lahat N, Rawashdeh H, Miller A. Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype
and response to interferon-beta therapy in relapsing and secondaryprogressive multiple sclerosis patients. Ann Neurol 2001;50:443– 451.

30. Kouwenhoven M, Ozenci V, Gomes A, et al. Multiple sclerosis: elevated
expression of matrix metalloproteinases in blood monocytes. J Autoimmun 2001;16:463– 470.
31. Johnston J, Zhang K, Silva C, et al. HIV-1 tat neurotoxicity is prevented by matrix metalloproteinase inhibitors. Ann Neurol 2001;49:
230 –241.
32. Newman TA, Woolley ST, Hughes PM, Sibson NR, Anthony DC, Perry
VH. T-cell- and macrophage-mediated axon damage in the absence of a
CNS-specific immune response: involvement of metalloproteinases.
Brain 2001;124:2203–2214.
33. Leppert D, Ford J, Stabler G, et al. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases
of multiple sclerosis. Brain 1998;121:2327–2334.

Hereditary infantile hemiparesis, retinal
arteriolar tortuosity, and
leukoencephalopathy
K. Vahedi, MD; P. Massin, MD; J.-P. Guichard, MD; S. Miocque, MD; M. Polivka, MD; F. Goutières, MD;
D. Dress, MD; F. Chapon, MD; M.-M. Ruchoux, MD, PhD; F. Riant, MD; A. Joutel, MD, PhD;
A. Gaudric, MD; M.-G. Bousser, MD; and E. Tournier-Lasserve, MD

Abstract—Background: The main hereditary vascular conditions involving both retinal and cerebral vessels include
cerebroretinal vasculopathy, HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke), and hereditary vascular retinopathy; all are linked to the same locus on chromosome 3p21. Hereditary retinal arteriolar tortuosity is
a distinct, autosomal dominant condition characterized by retinal arteriolar tortuosity and recurrent retinal hemorrhages.
This condition is known to affect only retinal vessels. Methods: Clinical and brain MRI investigations of eight members of
a three-generation family and extensive biological and systemic vascular investigations within one affected family member
were conducted. Results: Six of eight family members were clinically symptomatic; disorders included infantile hemiparesis (2), migraine with aura (3), and retinal hemorrhage (1). Five individuals had retinal arteriolar tortuosities. A diffuse
leukoencephalopathy in association with dilated perivascular spaces was observed in six individuals. Two family members
had silent, deep cerebral infarcts as demonstrated on MRI. Genetic linkage analysis strongly suggests that this disorder is
not linked to the 3p21 hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS locus. Conclusions: The
authors describe a novel hereditary autosomal dominant condition affecting both retinal and cerebral vessels and characterized by infantile hemiparesis, migraine with aura, retinal hemorrhage, retinal arterial tortuosity, and leukoencephalopathy with dilatation of perivascular spaces and microbleeds on brain MRI. Investigation of additional families should
help to map the gene and to better categorize the spectrum of hereditary cerebroretinal small vessel diseases.
NEUROLOGY 2003;60:57–63

Some rare hereditary conditions involving both retinal and cerebral vessels have been reported. Cerebroretinal vasculopathy is an autosomal dominant,
adult-onset condition characterized by early progressive central visual loss, progressive focal neurologic
deficit, cognitive deterioration, seizures, headache,

and contrast-enhancing brain mass lesions.1-3 Within
the retina, the underlying histopathology consists of
bilateral capillary occlusions involving mainly perifoveal vessels leading to multifocal retinal ischemia
and neovascularization.1 Within the brain, there is
an obliterative fibrosis of the walls of arteries and

See also page 8
From the Service de Neurologie (Drs. Vahedi and Bousser), Service d’Ophtalmologie (Drs. Massin and Gaudric), Service de Neuroradiologie (Dr. Guichard),
Service d’Anatomie et Cytologie Pathologiques (Dr. Polivka), and Laboratoire de Cytogénétique (Dr. Tournier-Lasserve), Assistance Publique–Hôpitaux de
Paris, Hôpital Lariboisière, Paris; Service d’Ophtalmologie (Dr. Miocque) and Service de Neuropathologie (Dr. Chapon), Centre Hospitalier Universitaire de
Caen; Unité de Neuropédiatrie (Dr. Goutières), Assistance Publique–Hôpitaux de Paris, Hôpital des Enfants Malades, Paris; Service de Neurologie (Dr.
Dress), Centre Hospitalier Mémorial de Saint-Lô; Service de Neuropathologie (Dr. Ruchoux), Centre Hospitalier Universitaire de Lille; and INSERM EMI
99-21 (Drs. Riant, Joutel, Bousser, and Tournier-Lasserve), Faculté de Médecine Lariboisière, Paris, France.
The authors have no financial or other relationships that might lead to a conflict of interest.
Received June 11, 2002. Accepted in final form October 15, 2002.
Address correspondence and reprint requests to Dr. Katayoun Vahedi, Service de Neurologie, Assistance Publique–Hôpitaux de Paris, Hôpital Lariboisière, 2
rue A. Paré, 75010 Paris, France; e-mail: katayoun.vahedi@lrb.ap-hop-paris.fr
Copyright © 2003 by AAN Enterprises, Inc.

57

Figure 1. Pedigree of the family. Black ⫽ retinal arteriolar tortuosity or retinal hemorrhage; gray shading ⫽ infantile hemiparesis; white hatched ⫽ possible infantile
hemiparesis; asterisk (*) ⫽ leukoencephalopathy and dilated perivascular spaces; arrow ⫽ proband; ? ⫽
unknown.

veins of medium and small caliber within the white
matter and basal ganglia that is associated with a
variable degree of perivascular inflammation and
multiple foci of parenchymal necrosis.1
HERNS (hereditary endotheliopathy with retinopathy, nephropathy, and stroke) is another autosomal
dominant condition reported in a family with clinical
and pathologic findings very similar to that of cerebroretinal vasculopathy.4 However, renal insufficiency with proteinuria was reported in some
affected family members in addition to early progressive visual loss, focal neurologic deficit, dementia,
and headache. Electron microscopy studies showed

alterations of vascular walls consisting of multilayered basement membrane of capillary and arteriolar
endothelial cells in the brain and other tissues, including the kidney and skin.4
Hereditary vascular retinopathy is another autosomal dominant, occlusive microangiopathy of the
retina starting in and around the posterior pole.5 In
addition to the retinopathy, migraine with and without aura, Raynaud’s phenomenon, mild cognitive decline, and depression, as well as slight MRI brain
white matter abnormalities, have been reported in
hereditary vascular retinopathy. However, no brain
mass lesions such as those in cerebroretinal vasculopathy or HERNS have been reported in this disorder.5,6 Linkage analysis mapped these three
conditions to a common locus on chromosome 3p21.7
Hereditary retinal arteriolar tortuosity is an autosomal dominant condition characterized by spontaneously regressive retinal hemorrhages and retinal
arteriolar tortuosity that may appear or increase
throughout life. More than 13 families and some sporadic cases have been reported since 1958.8-15 Arteriolar tortuosity predominates in the macula.
Capillaries and venules are spared. Arterioles have
normal caliber and there has been no report of retinal ischemic changes. The age at onset of retinal
hemorrhages is variable, from 8 years old to after the
5th decade. Hemorrhages are often recurrent and
usually occur spontaneously, although physical efforts, Valsalva’s maneuvers, or trauma have been
reported as precipitating factors. The disease has a
benign course, as the retinal hemorrhages are usu-

Table Clinical and MRI findings of the family

Subject Age,
no.
y

Fundus examination

Neurologic symptoms

Associated diseases

Leukoencephalopathy and
dilated perivascular spaces
on brain MRI

I-1

75 Not done

Subacute frontal dementia

Invasive glioblastoma

⫺

I-2

68 Moderate retinal arterial
Migraine with visual aura
tortuosity in both eyes and
diffuse hypopigmentation

Hypertension
Acoustic schwannoma

⫹

II-1

40 Marked retinal arteriolar
Migraine with visual aura
tortuosity in both eyes and
diffuse hypopigmentation

None

⫹

II-2

37 Marked retinal arteriolar
Migraine with visual and sensory Germinal seminomatous
tortuosity in both eyes and
aura
tumor of the mediastinum
diffuse hypopigmentation
Left pyramidal syndrome and
shortened left leg

⫹

II-3

32 Not done

Retinal hemorrhage
Hematuria

⫹

II-4

28 Moderate retinal arteriolar
Infantile hemiparesis with mild
tortuosity in both eyes and
mental retardation
hypopigmentation of the
Febrile convulsions
inferior part of the fundus

None

⫹

III-1

18 Normal

None

Unknown

III-2

15 Marked retinal arteriolar
Infantile hemiparesis
tortuosity in both eyes and Seizures
hypopigmentation of the
inferior part of the fundus

None

⫹

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January (1 of 2) 2003

None

None

Figure 2. MRI on T2-weighted imaging (top row) and T1-weighted imaging (bottom row) of Case III-2 (A) showing a
right-sided ventricular enlargement and a diffuse right cerebral hemisphere atrophy; Case II-4 (B) showing a symmetrical, predominantly posterior leukoencephalopathy, left ventricular enlargement, and left cerebral hemisphere atrophy; and
Case I-2 (C) showing a diffuse, symmetrical leukoencephalopathy and a nodular hyperintense signal on T2-weighted imaging and hypointense signal on T1-weighted imaging in the left centrum ovale suggestive of a silent deep infarct.

ally limited, responsible for transient visual loss of a
few days’ or weeks’ duration, and the patient may
even be totally asymptomatic. This condition is
known to affect only retinal vessels. Its underlying
physiopathology remains unknown.
Herein we report a detailed clinical and radiologic
description of a three-generation pedigree affected by
a novel, autosomal dominant vasculopathy affecting
both retinal and cerebral vessels and causing infantile hemiparesis, migraine with aura, retinal hemorrhage, retinal arteriolar tortuosity on fundus
examination, and leukoencephalopathy with dilated
perivascular spaces and microbleeds on brain MRI.
Subjects and methods. Subjects. Eight consenting members
over three generations were directly examined. The pedigree is
shown in figure 1. In addition, ophthalmologic examination was
performed in 6 family members (Cases I-2, II-1, II-2, II-4, III-1,

and III-2) and neuroimaging in 7 family members (Cases I-1, I-2,
II-1, II-2, II-3, II-4, and III-2). In addition, extensive systemic
vascular investigations were performed in 1 affected member (II1). These investigations included retinal fluorescein angiography;
cerebral MR angiography (MRA); cervical and transcranial ultrasound examination; transthoracic echocardiography; MRA of the
aorta and its main branches; complete hematologic, clotting, biochemical, and immunologic laboratory investigation; and a skin
biopsy for the study of cutaneous vessels.
MRI investigations. Neuroimaging was performed at 1 to 1.5
T. T1-weighted images (T1WI) were obtained from axial, sagittal,
or both planes and T2-weighted images (T2WI) were obtained
from axial planes. In addition, Patient II-1 had T2*-weighted gradient echo images in both axial and coronal planes and fluidattenuated inversion recovery (FLAIR) in axial planes. A
neuroradiologist (J.P.G.) blinded to the clinical status of patients
reviewed the MRI scans for the presence of any abnormalities.
Genetic studies. Genomic DNA was extracted from peripheral
blood cells of all consenting members (I-2, I-3, II-1, II-2, II-3, II-4,
II-5, and III-2) using standard procedures. Direct sequencing of
exons 3 and 4 of the notch3 gene was performed as described previJanuary (1 of 2) 2003

NEUROLOGY 60

59

Figure 3. Red free fundus photography and fluorescein angiogram of the right
eye of case II-1. (a, b, c) Red-free photographs of the posterior pole (a) and of the
nasal (b) and the inferior parts (c) of the fundus. Marked tortuosity of medium
and small arterioles is present. No changes are apparent in the veins. Note the
diffuse hypopigmentation of the fundus with increased visibility of the choroidal
vessels (b, c), contrasting with her dark hair (not shown). (d, e) Red-free photograph (d) and arteriovenous phase of the angiogram (e) in the macular area.
Arteriolar tortuosity is particularly visible. No capillary abnormalities, microaneurysms, or telangiectasia are observed.

ously.16 In addition, we performed genetic linkage analysis with three
markers spanning the cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL)/
NOTCH3 locus on 19p13, including an intragenic marker (D19S841)
and two perigenic markers (D19S226 and D19S199).17 Genetic linkage to the hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS locus on chromosome 3p21 was tested using seven
microsatellite markers (D3S3685, D3S3564, D3S3582, D3S1581,
D3S1578, D3S1289, and D3S3616) spanning this locus and selected
from published data.7
Results. Case reports. Case III-2. The proband is a 15-yearold boy who has an infantile hemiparesis associated with seizures
(table). Detailed pregnancy and birth history obtained from the
mother indicated no remarkable event in the neonatal period. The
first symptoms were noticed at age 4 months and consisted of a
left-sided weakness with pyramidal tract signs. Seizures developed at age 10. It consisted of two episodes of partial seizures with
elementary symptomatology (brief scintillating scotomas and head
and neck rotation to the left) and secondary generalization. MRI
performed at age 10 showed a right-sided ventricular enlargement
and right cerebral hemisphere atrophy with midline shift to the
right and a large paraventricular area of T1 hypointensity (figure
2). On T2WI there were a few small, well-delineated, and round
T2 hyperintensities in the putamen and one in the left centrum
ovale, with slight symmetrical white matter pallor in the parietal
regions. When examined at age 15, he had left-sided hemiatrophy
and pyramidal signs but no mental retardation. He did not report
having headaches. Blood pressure was 110/70 mm Hg. There
was no history of retinal hemorrhages. Visual acuity was normal
in both eyes. Fundus examination disclosed marked retinal
arteriolar tortuosity in both eyes, without retinal hemorrhages
60

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January (1 of 2) 2003

and with normal veins. Hypopigmentation of the inferior part
of the fundus was noted.
Case II-1. This 40-year-old woman is the mother of the proband (see the table). At age 30, she had a first episode of bilateral
scintillating scotomas of abrupt onset accompanied by a diffuse
headache of 1 week’s duration. Since age 35, she complained once
a year of episodes of blurred vision lasting for 30 minutes and
accompanied by a right-sided hemicrania with phono- and photophobia. She has no other notable medical history. She did not
report other types of headache. She had no history of retinal
hemorrhages. Her neurologic examination was normal. Blood
pressure was 110/60 mm Hg. Visual acuity was normal in both
eyes with a ⫹0.75-diopter (D) correction. Fundus examination
showed marked retinal arteriolar tortuosity in both eyes without any
retinal hemorrhage or exudate (figure 3). A diffuse hypopigmentation
of the fundus was noted. Fluorescein angiography showed no other
abnormality; arteriolar caliber was normal and there was no leakage
of fluorescein or capillary dropout (see figure 3). The brain MRI
showed three types of abnormalities (figure 4). First, there were
widespread, symmetrical, predominantly posterior white matter hyperintensities on T2WI and FLAIR. Second, within the putamen and
the adjacent white matter, there were multiple, bilateral, welldelineated areas of increased signal of various sizes on T2WI and
decreased signal of various sizes on T1WI and FLAIR suggestive of
dilated perivascular spaces, with the largest measuring 14 mm.
There was also one such area in the deep cerebellum. Third, there
were multiple, deep, small, hypointense foci on T2*-weighted gradient echo images suggestive of past microbleeds. They were located in
the deep cerebellum, periventricular white matter, and the caudate
nucleus. Other investigations including transthoracic echocardiography, aortic and intracranial MRA, cervical and transcranial ultrasound examinations, anticardiolipin antibodies, lupus anticoagulant,

Figure 4. MRI of Patient II-1 (A, B) and Patient II-3 (C). Note the small, deep hypointensities in the cerebellum and the
caudate nucleus on T2*-weighted imaging suggestive of past microbleeds (A); the large, well-delineated hypointensity in
the basal ganglia on fluid-attenuated inversion recovery (FLAIR) and T1-weighted imaging suggestive of dilated perivascular spaces (B, top; and C, top); and the diffuse, symmetrical, predominantly posterior white-matter abnormalities on
FLAIR (B, bottom) and T2-weighted imaging (C, bottom).

antinuclear factor, and creatinine clearance were normal. There was
no microalbuminuria. Light microscopic study of a skin biopsy including several arterioles, capillaries, and venules did not disclose
vessel-wall lesions; there were no abnormal deposits on PAS and
Congo red stains or on antiubiquitin immunohistochemistry. Biopsy
for ultrastructural study included only capillaries and some very
small venules with no detectable abnormality.
Case II-2. This 37-year-old man is the brother of Case II-1
(see the table). Since age 20, he had episodes of bilateral blurred
vision lasting for 5 to 10 minutes. These episodes were followed by
paresthesia that, within a few minutes, successively involved his
fingers on one side, and then a severe, initially unilateral then
diffuse headache with phono- and photophobia and vomiting. Frequency was one attack per week during the first year, then they
stopped for a period of 15 years. He recently had a short period of
repeated identical attacks. He did not report other types of headache and had no other remarkable medical history except depression at age 33. Neurologic examination disclosed a left pyramidal
syndrome with a left Babinski’s sign and a 2-cm shortening of the
left leg. Blood pressure was 120/80 mm Hg. Fundus examination
showed marked bilateral retinal arteriolar tortuosity with diffuse
hypopigmentation of the fundus. T2WI of the brain showed a
nodular right paraventricular hyperintensity with a slight adjacent ventricular enlargement suggestive of an old deep infarct and
symmetrical micronodular areas of increased signal located in the
basal ganglia suggestive of dilated perivascular spaces, with the
largest measuring 3 mm. On follow-up, the patient had a germinal
seminomatous tumor of the mediastinum with carcinomatous
lymphangitis.

Case II-3. This 32-year-old farmer is the brother of Cases II-1
and II-2 (see the table). At age 2 he had a severe craniofacial
trauma with coma but fully recovered. At age 22 he had an
abrupt-onset central scotoma of the right eye reported to be due to
a retinal hemorrhage, which completely recovered after 2 months.
During investigation of this retinal hemorrhage a microscopic hematuria was found. No medical chart was available. When examined at age 32, his neurologic examination and blood pressure
(120/80 mm Hg) were normal. He did not report headache. Brain
MRI showed a diffuse, periventricular, predominantly posterior
leukoencephalopathy and multiple, bilateral, and well-delineated
areas of increased signal on T2- and decreased signal on T1WI in
the putamen and the pallidum suggestive of dilated perivascular
spaces of various sizes (see figure 4). The largest was in the
putamen and measured 10 mm. The patient died 1 year later at
age 33, following a major head injury with diffuse pneumoencephalitis, left frontal extradural hematoma, and subarachnoid hemorrhage complicated by multiple, bilateral, large cortical infarctions
due to intracranial arterial spasm.
Case II-4. This 28-year-old man is the brother of Cases II-1,
II-2, and II-3 (see the table). He has an infantile hemiparesis
associated with a mild mental retardation. No fetal distress was
reported despite a post-term pregnancy. The first symptoms were
noticed at age 7 months and consisted of a right-sided weakness
with pyramidal tract signs. He had 1 episode of febrile seizures at
age 4. He was taking phenobarbital and then sodium valproate for
8 years with no further seizures. He has no other remarkable
medical history and does not report headache. On examination he
had a right hemiparesis with spasticity and Babinski’s sign and a
January (1 of 2) 2003

NEUROLOGY 60

61

Figure 5. Genetic linkage analysis with chromosome 19 and chromosome 3 markers spanning respectively the CADASIL
and the hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS loci. The various alleles of D19S226,
D19S841, and D19S199 for CADASIL (A) and D3S3685, D3S3564, D3S3582, D3S1581, D3S1578, D3S1289, and
D3S3616 for hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS locus (B) carried by each subject are
indicated. The haplotype inherited from the affected parent is represented on the left side. For each microsatellite tested,
there are at least two affected individuals who do not share any allele with their affected relatives, strongly suggesting
that neither of these loci is linked to the disease.

right-sided hemiatrophy with a shortened right leg. Blood pressure was 130/80 mm Hg. Brain MRI at age 28 showed a diffuse
left ventricular enlargement extending into the basal ganglia; a
left cerebral hemisphere atrophy; a symmetrical, predominantly
posterior leukoencephalopathy (see figure 2); and few welldelineated and round areas of increased signal on T2WI and decreased signal on T1WI in the right putamen suggestive of dilated
perivascular spaces. Fundus examination disclosed moderate retinal arteriolar tortuosity in both eyes, with hypopigmentation of
the inferior part of the fundus.
Case I-2. This 68-year-old man is the father of Cases II-1,
II-2, II-3, and II-4. He has a 10-year history of hypertension (see
the table). He underwent surgery for a right-sided acoustic
schwannoma at age 67. At age 45 he had repeated episodes of
bilateral, scintillating scotomas of abrupt onset and of brief duration immediately followed by a severe headache of 30 minutes’
duration during a 2-month period. His neurologic examination
was normal and his blood pressure was 140/80 mm Hg. Fundus
examination showed moderate retinal arteriolar tortuosity in both
eyes, with diffuse hypopigmentation of the fundus. Brain
MRI showed an old, deep infarct in the left centrum ovale, a
symmetrical periventricular leukoencephalopathy on T2WI, a predominantly parieto-occipital atrophy, and a few bilateral, micronodular, round, and well-delineated areas of increased signal
on T2WI and decreased signal on T1WI in the putamen suggestive
of dilated perivascular spaces.
Case I-1. This 75-year-old woman is the sister of Case I-2 (see
the table). She has no remarkable medical history. At age 75, she
rapidly developed memory disturbances, psychiatric symptoms
with frontal signs, and urinary incontinence. Brain MRI showed a
large, gadolinium-enhancing mass involving the corpus callosum
and the frontal lobes and extending to the diencephalon. The
patient slightly improved with corticosteroids but died after 4
months. Brain autopsy showed an invasive glioblastoma but no
brain white matter or vascular wall abnormalities.
Case III-1. This 18-year-old woman is the sister of the proband (see the table). She had no remarkable medical history. Her
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January (1 of 2) 2003

neurologic and fundus examinations were normal. Brain MRI was
not performed.
Genetic studies. Genomic DNA direct sequencing of exons 3
and 4 of the notch3 was performed for Case III-2 and did not
detect any CADASIL type mutation. Genetic linkage analysis with
chromosome 19 markers showed that for each of the 3 markers
tested, 2 affected individuals did not share the haplotype transmitted by the affected founder, I-2, to the other affected members,
which strongly suggests that this disorder is not linked to the
CADASIL locus (figure 5).
Genetic linkage with chromosome 3 markers showed that for
each of the 7 markers tested, which were fully informative, there
were at least 2 affected individuals who did not inherit the allele
transmitted by the affected founder (I-2) to the other affected
offspring (see figure 5). These data strongly suggest that this
disorder is not linked to the 3p21 hereditary vascular retinopathy/
cerebroretinal vasculopathy/HERNS locus.

Discussion. We report a French Caucasian kindred affected over three generations by a retinal and
CNS disease consistent with an autosomal dominant
pattern of transmission. Six of eight family members
were clinically symptomatic: infantile hemiparesis
occurred in two patients, migraine with aura in
three and retinal hemorrhage in one. Several arguments suggest that this disorder is due to a vasculopathy affecting both retinal and brain vessels.
Retinal arteriolar tortuosity was found on fundus
examination in five individuals and it was highly
suspected in a sixth one who experienced retinal
hemorrhage. With regard to cerebral involvement,
several clinical and neuroimaging findings suggest a

vascular disease: the occurrence of an infantile hemiparesis in two patients and possibly in a third (Patient II-2); the presence of a silent, old, deep infarct
on brain MRI in two other individuals; and the detection of multiple, small foci of decreased signal on
T2*-weighted gradient echo images suggestive of microbleeds in Patient II-1, the sole individual in whom
this sequence was performed. Interestingly, in addition to these neuroimaging findings, multiple,
rounded, and well-delineated areas of hypointense
signal on T1WI and hyperintense signal on T2WI
located within the basal ganglia and the white matter were also observed in several patients. These images are consistent with dilated perivascular spaces,
although it is quite difficult to conclude formally on
the nature of the underlying lesions in the absence of
neuropathologic data.18,19
Several hereditary conditions have been reported
to affect cerebral and retinal vessels, but they can be
excluded in the current family based on clinical or genetic linkage analysis. CADASIL, an autosomal dominant small-artery disease of the brain, is characterized
by the association of subcortical ischemic strokes, dementia, migraine with aura, and leukoencephalopathy.20 Pathologic analysis showed that CADASIL is
underlain by a systemic arteriopathy affecting mainly
cerebral vessels but also other small vessels such as
retinal vessels.21 However, the disorder reported is
clearly distinguishable from CADASIL, as infantile
hemiparesis, retinal hemorrhage, and arteriolar tortuosity have not been reported in CADASIL.20,22 Furthermore, the disease affecting the current family is not
linked to CADASIL/NOTCH3 locus on 19p13.17
This disorder is also clearly distinguishable from
the three cerebroretinal hereditary conditions recently linked to 3p21. Indeed, retinal vascular lesions in those conditions include capillary occlusion,
telangiectasia, and microaneurysms, which are absent in our family. In addition, genetic linkage analysis with chromosome 3p21 markers spanning the
hereditary vascular retinopathy/cerebroretinal vasculopathy/HERNS locus showed that this disorder is
not linked to 3p21.
The retinal vascular lesions observed in our family
are identical to those observed in another autosomal
dominant condition designated as hereditary retinal
arteriolar tortuosity with retinal hemorrhages.8-15 The
two conditions share marked tortuosity of the medium
and small retinal arterioles and the absence of capillary abnormalities, venules tortuosity, retinal ischemic
changes, or visual loss. However, hereditary retinal arteriolar tortuosity is known to affect only retinal vessels, except in one case of a migrainous patient with
hereditary arteriolar tortuosity and multiple small areas of ischemia in the midbrain on brain MRI.15 Unfortunately, there was no MRI illustration provided in
this report and there are no other neuroimaging data
reported in patients with hereditary retinal arteriolar
tortuosity.8-14

Ophthalmologic investigation of patients with unexplained perinatal ischemic stroke or young individuals with dilated perivascular spaces or brain white
matter abnormalities may help to better define the
relationship between retinal arteriolar tortuosity
and cerebral vessel abnormalities. Gene identification of this novel hereditary cerebral and retinal vasculopathy should help to expand the spectrum of
hereditary small vessel diseases of the brain.
Acknowledgment
The authors thank all of the family members who participated in
this study.

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January (1 of 2) 2003

NEUROLOGY 60

63

Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy
K. Vahedi, P. Massin, J.-P. Guichard, et al.
Neurology 2003;60;57-63
DOI 10.1212/WNL.60.1.57
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