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| Journal of the New Zealand Medical Association,
23-June-2006, Vol 119 No 1236
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An unusual cause of stroke
Rebecca Ratcliffe, Lim Jones, Nicole McGrath, Michael
Reardon
Stroke is common in New Zealand, and cerebrovascular disease
is by far the most common aetiology. However sometimes a patient who presents
with a stroke without cerebrovascular risk factors makes one realise that there
are other causes of stroke, sometimes with some serious familial
implications.
Case reportA 58-year-old New Zealand European man presented with a
history of sudden onset of left hemiplegia. On arrival at hospital he was
conscious and had a Glasgow Coma Score (GCS) of 15. He had a complete flaccid
left-sided hemiplegia with no visual field loss, speech abnormality, or parietal
sensory signs. Prior to this presentation he had been fit and well. He was
normotensive, a non-smoker, and had a random cholesterol of 4.5 mmol/L. His
father had died suddenly at the age of 50 years and according to the family he
had memory problems prior to his death. Our patient worked as an operator in an
oil refinery.
A computed tomography (CT) brain scan (Figure1) showed
diffuse white-matter changes, and a subsequent magnetic resonance imaging (MRI)
scan of his brain showed extensive bilateral white-matter changes in the
subcortical brain tissue of primarily frontal, parietal, and brain stem areas
(Figure 2). He also had a 2.6-cm hyperintense lesion in the right thalamus
consistent with his recent infarct.
An inpatient carotid Doppler ultrasound was normal. A lumbar
puncture was normal except for an elevated protein of 0.98 g/L with no
oligoclonal bands. Because of his MRI scan abnormalities and a lack of vascular
risk factors, a diagnosis of
cerebral autosomal dominant arteriopathy
with subcortical infarcts and leucoencephalopathy (CADASIL) was
considered.
A mutation analysis of the NOTCH3 gene was carried out and
this showed an Arg141Cys mutation detected in exon 4, confirming the diagnosis
of CADASIL.
He was transferred to our rehabilitation ward and after a
month he had gained limited function of his left leg and was able to mobilise
with a walking stick independently. He was discharged home with no obvious
cognitive decline or behavioural abnormality. His inpatient mini mental state
examination was 30 out of 30. His two daughters have been referred to genetic
counselling. The patient’s two sisters have also expressed a wish to have
genetic counselling carried out.
Figure 1. CT brain scan showing diffuse and extensive
white-matter changes in the subcortical areas of the brain
 Figure 2. Extensive periventricular and deep
white-matter abnormalities in this T2 flair MRI sequence. There is also an
infarct in the right internal capsule area (dark arrow)
 DiscussionCADASIL is a hereditary microangiopathy caused by a mutation
in the NOTCH 3 gene on chromosome 19. While the total number of reported
families with CADASIL is greater than 400 worldwide,1 it is assumed that the
incidence of the disease is much greater. It is characterised by a history of
migraine headaches (30–40% of individuals), and mid-adult (30–60
years) onset of cerebrovascular disease progressing to dementia.
Amberla et al2 observed a deterioration of working memory
and executive function in individuals with NOTCH3 mutations in the prestroke
phase. In symptomatic patients, white-matter hyperdensities are symmetrically
distributed and located in the periventricular and deep white matter.3 The
frontal lobe is the site with the highest lesion load.
A NOTCH 3 gene mutation is detected in more than 90% of
CADASIL patients. NOTCH3 is a 2,321 aminoacid type 1 transmembrane protein that
is believed to be involved in the specification of cell fate during
development.4 Almost all mutations in CADASIL to date involve the loss or gain
of a single cysteine residue in the NOTCH3 gene. Indeed, in our case he had a
cysteine replacing an arginine residue in exon 4 of the NOTCH3 gene.
The pathogenesis of arterial disease in CADASIL is still not
entirely clear. However NOTCH3 protein is uniquely present in vascular
smooth-muscle cells. The abnormal protein may make the vascular smooth-muscle
cells degenerate to produce the typical granular osmiophilic depositions (GOM),
which can be seen in skin biopsies under an electron microscopy. However these
are difficult to find and not always present in patients with CADASIL.
The loss of vascular smooth-muscle cells and related
vascular-wall changes may be responsible for affecting the tone, elasticity, and
reactivity of the affected cerebral arteries.5 The arteries most severely
affected in CADASIL are the medullary arteries, which supply the deep white
matter and basal ganglia. They are end-arteries with very few collaterals.
Damage of these vessels leads to ischaemic insults producing stroke-like
episodes and ultimately to cognitive decline and death. The mean age of death
has been observed to be between 54 and 64 years6 and men tend to die earlier
than women.7 At the time of death, 77% of patients in one study were demented.8.
Acute encephalopathy,9 psychiatric disorders, epilepsy,7 and
early myocardial infarction have been described with CADASIL.
CADASIL is inherited as an autosomal dominant disease and in
our index case he had no obvious family history. However his father had died
suddenly at the age of 50 years and the cause for this is not clear.
De novo mutations have been reported
with the condition.10 Penetrance of the disease is probably 100% but expression
varies in age of onset, severity of the clinical symptoms, and the progression
of the disease. Our index case has two daughters who have no children yet and
they have expressed a wish to seek testing and counselling regarding the
disease.
There are few treatment options for patients with CADASIL.
Most physicians prescribe aspirin to prevent strokes, however there is no
evidence for its use in CADASIL. Indeed some CADASIL patients have been shown on
MRI scan to have cerebral microbleeds,11 and angiography and anticoagulants are
contraindicated in this condition. Most physicians control cerebrovascular risk
factors such as hypertension and hypercholesterolaemia. Acetazolamide has been
shown to increase cerebral blood flow in haemodynamic studies of CADASIL
patients,12 and has been mentioned as a potential drug treatment.
A diagnosis of CADASIL should
be considered in patients who present with subcortical strokes, especially in
those with a history of migraine. It should also be considered in patients
whenever an MRI scan reveals significant white-matter changes in the subcortex
and basal ganglia.
Author information:
Rebecca Ratcliffe, House Officer; Lim Jones, House Officer; Nicole McGrath,
Consultant Physician; Michael Reardon, Consultant Physician; Department of
Medicine, Whangarei Hospital, Whangarei, Northland
Acknowledgements: We
thank all the staff, including nurses and therapists of Ward 15, in Whangarei
Hospital. Special thanks also go to Dr Tus
Fernando.
Correspondence: Dr
Michael Reardon, Department of Medicine, Whangarei Hospital, PO Box 742;
Whangarei. Fax (09) 430 4117; email: michaelreardon1@eircom.net
References:
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