Case Reports / Journal of Clinical Neuroscience 21 (2014) 165–167

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4. Hanafy KA, Morgan Stuart R, Fernandez L, et al. Cerebral inflammatory response
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doi:http://dx.doi.org/10.1016/j.jocn.2012.10.043

CADASIL presenting with a behavioural variant frontotemporal dementia
phenotype
S.K. Alexander a,⇑, J.M. Brown a, A. Graham a, P.J. Nestor b
a
b

Department of Clinical Neurosciences, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
German Center for Neurodegenerative diseases (DZNE), Magdeburg, Germany

a r t i c l e

i n f o

Article history:
Received 29 January 2013
Accepted 2 February 2013

Keywords:
bvFTD
CADASIL
Frontotemporal dementia
Notch3

a b s t r a c t
The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with
a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid
white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene.
The second patient presented with progressive memory impairment and marked personality changes
after a transient ischaemic attack. In this second patient, the radiological features were subtle and only
the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these
patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to
distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening
Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate
to investigate this possibility.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction
The behavioural variant of frontotemporal dementia (bvFTD) is
characterised by personality change with a decline in cognition.1
Here, two patients with cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukencephalopathy (CADASIL) – one
with a novel missense mutation C366W in exon 7 of the Notch3
gene – are presented, whose behavioural phenotype closely resembled that of bvFTD.

2. Case report
2.1. Patient 1
This 68-year-old woman presented to general neurological services following concern from her family and neighbours about progressive personality and behavioural change over the past 2 years.
The patient lived alone and was previously independent. Her family’s principal concern related to new problems organising personal
finances, hoarding of rubbish causing her house to be unsanitary,
and increasing reclusiveness. The patient was relatively insightless
as to the extent of her difficulties and extremely resistant to the

⇑ Corresponding author. Tel.: +44 12 2324 5151.
E-mail address: siankathalexander@gmail.com (S.K. Alexander).

idea of outside help for housekeeping or self-care. When the
possibility of a social work referral was mentioned she became
very angry and left the consultation, only persuaded back later
by her family. Her autobiographical memory was relatively
preserved. She could remember recent novels she had read and
discuss their merits, although with a rather fatuous affect. She
was distractible and the consultation was interrupted repeatedly
by trips to the toilet. There was no past medical history or family
history of note, including no history of cerebrovascular disease.
On cognitive examination, the patient’s Mini-Mental State
Examination score was 24/30 and 65/100 on the Addenbrooke’s
Cognitive Examination–Revised version, losing points mostly on
verbal fluency, and also on memory and semantic knowledge
items. MRI demonstrated florid, confluent white matter hyperintensity extending throughout both cerebral hemispheres notably
including the rostral temporal lobes (Fig. 1a). Normal investigations included a routine full blood count and biochemistry,
anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies,
anti-cardiolipin antibodies, very long-chain fatty acids and white
cell enzymes.
Sequencing of Notch3 identified a novel heterozygous missense
mutation (C366R) in exon 7, where an arginine was substituted for
a conserved cysteine residue. This is a novel mutation for CADASIL,
but is in keeping with previously described mutations, which almost invariably involve cysteine mutations in epidermal growth
factor repeats.2,3 These features strongly support the pathogenicity
of this dominant mutation. However, testing for osmophilic

166

Case Reports / Journal of Clinical Neuroscience 21 (2014) 165–167

Fig. 1. Transverse fluid attenuated inversion recovery MRI in (a) Patient 1 showing striking and extensive confluent high signal change affecting the white matter of both
cerebral hemispheres, and (b) Patient 2 showing more subtle changes, with hyperintense foci in the subcortical and periventricular white matter.

granular material on skin biopsy was not pursued due to the
patient’s strong views against this.
2.2. Patient 2
This 49-year-old woman presented with sudden-onset paraesthesia and weakness affecting her right arm and leg, which had resolved by the time she reached hospital. She had a past medical
history of hypertension, rheumatoid arthritis, and osteoarthritis.
She was a non-smoker. Her brother had had a stroke at 49 years
of age and her father had been diagnosed with multiple sclerosis.
She was diagnosed with a transient ischaemic attack (TIA). Her
family reported that she had been developing progressive memory
impairment and marked personality changes, particularly apathy,
selfishness, rigidity, and childish behaviour. She demonstrated
poor planning and judgement when driving. A new and extreme
preference for sweet foods had emerged, with significant weight
gain. The patient was completely insightless into any of these
changes.
On examination, she appeared passive, disinterested, mentally
rigid, and cognitively slow. She walked slowly and was mildly unsteady, but there were no focal neurological signs. Marked distractibility made detailed cognitive testing difficult but she did
complete a Test Your Memory test scoring 35/50 (control mean:
47/50).4
MRI demonstrated only subtle white matter abnormalities
(Fig. 1b) in the form of a few discrete high intensity foci in periventricular, parietal, and frontal white matter. None of these foci
showed restricted diffusion suggestive of recent subcortical
infarction.
Genetic analysis confirmed the patient to be heterozygous for
the missense mutation C144Y in exon 4 of the Notch3 gene, a
mutation that was previously reported as pathogenic for CADASIL.5

3. Discussion
Two patients with genetically-confirmed CADASIL with a phenotype strongly suggestive of bvFTD are presented. CADASIL is a
relatively rare disease, usually considered in the context of a young
patient suffering a stroke with a family history of cerebrovascular
disease. Cognitive sequelae are, however, well-recognised in
CADASIL. Previous studies have demonstrated that cognitive decline in CADASIL may precede the first TIA or stroke, although this
may be asymptomatic.6 Early executive dysfunction and inattention are the most frequently described deficits, with a more global
pattern of cognitive impairments in later stages.5–7 In most patients, cognitive decline is slowly progressive with additional stepwise deterioration.3 An estimated 75% of mutation carriers will
eventually develop dementia and in 90% of patients this is associated with impaired mobility.5,7
The presented patients suggest that a dementia dominated by
personality change can occur in CADASIL; in both patients, the
informant history and particularly the behaviour of each patient
in clinic was strikingly reminiscent of that seen in bvFTD. In Patient
1, a diagnosis of bvFTD was initially suspected but MRI made it
immediately apparent that her condition was something other
than frontotemporal lobar degeneration – either a leukodystrophy
or, particularly in view of the temporal lobe white matter changes,
CADASIL. Patient 2, however, highlights that there is a genuine risk
that CADASIL could be misdiagnosed as bvFTD even after imaging.
In her case, an apparent TIA combined with her family history were
the only clues to the diagnosis. The imaging showed negligible
white matter involvement that was not beyond the realm of an
incidental finding, in turn emphasising that the radiological findings in CADASIL may not be obvious.
Patients with a bvFTD phenotype, especially with a family
history of dementia or cerebrovascular disease, warrant

Case Reports / Journal of Clinical Neuroscience 21 (2014) 167–170

consideration, at least, for genetic testing for CADASIL. This may be
particularly important if there is a family history of stroke; given
that stroke is so common, this family history could easily be dismissed as irrelevant in the assessment of suspected bvFTD. Finally,
Patient 2 also suggests that CADASIL might possibly be an underrecognised diagnosis in apparent bvFTD. Screening Notch3 in a
substantial and unselected cohort of FTD patients might be appropriate to investigate this possibility.
Conflict of interest/disclosure
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References

167

2. Joutal A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of
Notch3 mutations in CADASIL patients. Lancet 1997;350:1511–5. http://
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CADASIL: a monogenic condition leading to subcortical ischemic vascular
dementia. Am J Psychiatry 2005;162:2078–85. http://dx.doi.org/10.1176/
appi.ajp.162.11.2078.
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(TYM) for detection of Alzheimer’s disease: cross sectional study. Br Med J
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http://dx.doi.org/10.1161/
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dx.doi.org/10.1093/brain/awh282.

1. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic
criteria for the behavioural variant of frontotemporal dementia. Brain
2011;134:2456–77. http://dx.doi.org/10.1093/brain/awr179.

doi:http://dx.doi.org/10.1016/j.jocn.2013.02.025

Spontaneous vertebral arteriovenous fistula causing cervical myelopathy
and acute ischemic strokes treated by endovascular balloon–assisted
coiling and Onyx embolization
Seby John a,⇑, Neda Jaffari b, Mei Lu b, Muhammad S. Hussain b, Ferdinand Hui b
a
b

Department of Neurology, Cleveland Clinic, 9500 Euclid Avenue, S100-A, Cleveland, OH 44195, USA
Cerebrovascular Center, Cleveland Clinic Foundation, Cleveland, OH, USA

a r t i c l e

i n f o

Article history:
Received 30 October 2012
Accepted 7 January 2013

Keywords:
Cervical myelopathy
Coil-assisted Onyx embolization
Embolic ischemic stroke
Vertebral arteriovenous fistulas

a b s t r a c t
Vertebral arteriovenous fistulas (VAVF) are infrequent lesions characterized by abnormal communication
of the extracranial vertebral artery or one of its branches to the surrounding venous plexuses, without the
presence of any intervening vessels. We describe a rare occurrence of a patient with VAVF presenting
with acute ischemic stroke, encephalomalacia from multiple prior embolic events, and cervical myelopathy, which was successfully treated by coil-assisted Onyx embolization (ev3 Endovascular, Plymouth,
MN, USA) with balloon for flow arrest. Our patient demonstrates that point occlusion with embolization
for VAVF can be a feasible, safe, and effective treatment option for complete obliteration of the fistula,
with subsequent reduction in the volume of the intra-spinal canal venous plexus. Although it is postulated that thromboembolism is less common because of redirection of flow to the venous side of the fistula, our patient also illustrates the potential for to–fro flow in such a fistula to result in embolic injury to
the distal circulation.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction
Vertebral arteriovenous fistulas (VAVF) are rare lesions characterized by abnormal communication of the extracranial vertebral
artery (VA) or one of its branches to the surrounding venous plexuses, without the presence of any intervening vessels or capillaries.1 They can be either spontaneous or traumatic in origin.
Neurological sequellae from vertebral arteriovenous (AV) fistulas
can arise from a number of mechanisms including mechanical
compression or venous hypertension of the spinal cord and
secondary arterial steal. These in turn depend on the pattern of
venous drainage, flow velocity, and chronicity of the AV fistula.

⇑ Corresponding author. Tel.: +1 646 714 5220; fax: +1 216 444 0230.
E-mail address: johns@ccf.org (S. John).

Obliteration of the AV fistula with preservation of the parent artery
is the primary goal of treatment.
We describe a rare occurrence of a patient with VAVF presenting with acute and chronic ischemic strokes and cervical myelopathy which was successfully treated by coil-assisted Onyx
embolization (ev3 Endovascular, Plymouth, MN, USA) with balloon
for flow arrest.

2. Case report
A right-handed hypertensive patient in their 60s presented with
acute onset vertigo. Examination revealed left-appendicular ataxia,
left C5 innervated muscle weakness, decreased left bicep reflex,
and hyperreflexia in both legs. A review of systems was positive
for pain and hyperesthesia in the left arm for 10 years.