144
apparent controversy detailed above
marks the need for better radiological-
pathological correlation studies, applying
more sophisticated MRI and histopatho-
logical techniques.
J Neurol Neurosurg Psychiatry 2006;77:143
144.
doi: 10.1136/jnnp.2005.075101
......................
Authors affiliations
F Barkhof, Department of Radiology, VU
Medical Centre, PO Box 7057, 1007 MB
Amsterdam, The Netherlands
P Scheltens, Department of Neurology, VU
Medical Centre, PO Box 7057, 1007 MB
Amsterdam, The Netherlands
CADASIL
.......................................................................................
Cognitive profile in CADASIL patients
L Caeiro, J M Ferro
...................................................................................
Age is an important predictor of clinical deterioration in CADASIL
patients
C
erebral autosomal dominant arter-
iopathy with subcortical infarcts
and leukoencephalopathy
(CADASIL) often starts with silent
lacunar infarcts or white matter changes
in the third decade of life and cognitive
or other neurological signs become
apparent within the next 10 years. In
the following 20 years, dementia and
psychiatric disturbances become more
and more apparent and death frequently
occurs in the sixth decade of life.13
Age is an important predictor of
clinical deterioration, with an odds ratio
of 1.104 per year starting at the age of
24. Cognitive impairment affects about
60% of CADASIL patients, and psychia-
tric disturbances nearly 30%. Cognitive
impairment initially manifests through
mild executive and visuospatial deficits,
psychomotor slowing, and apathy.5
Working and short term memory
defects also appear insidiously6; later
on, abulia and other executive dysfunc-
tions are the main manifestations of
CADASIL. Two thirds of CADASIL
patients are dependent and have
dementia by the time they die.1
Dementia is more apparent if the patient
has a lower educational level.6
In the paper by Buffon et al in this
issue of the journal (see pages 17580),
the cognitive profile of 42 CADASIL
patients is described. The authors
conclude that executive dysfunction
www.jnnp.com
Correspondence to: Frederik Barkhof,
Department of Radiology, VU Medical Centre,
PO Box 7057, 1007 MB Amsterdam, The
Netherlands; f.barkhof@vumc.nl
Competing interests: none declared
REFERENCES
1 Kertesz A, Black SE, Tokar G, et al. Periventricular
and subcortical hyperintensities on magnetic
resonance imaging. Rims, caps, and
unidentified bright objects. Arch Neurol
1988;45:4048.
2 van den Heuvel DMJ, ten Dam VH, Craen AJM, et
al. Increase in periventricular white matter
hyperintensities parallels decline in mental
processing speed in a non-demented elderly
population. J Neurol Neurosurg Psychiatry
2005;77:14953.
dominates the pattern of cognitive
impairment in CADASIL, followed by
visuo-constructive memory impairment.
With aging, other cognitive dysfunc-
tions become more and more evident,
denoting a diffuse cognitive impair-
ment, except for the relative preserva-
tion of the encoding process in episodic
memory.
This paper replicates the results of
previous studies2 5 6 and confirms that
the cognitive profile of CADASIL is
similar to that presented by patients
with subcortical ischaemic vascular
dementia. In fact, CADASIL can be
considered a pure form of subcortical
ischaemic vascular dementia.
A limitation of the paper by Buffon et
al is the design of the neuropsychologi-
cal evaluation. Inferences concerning
the role of age on cognitive impairment
are drawn from a cross sectional evalua-
tion of CADASIL patients of different
age groups.
Much more robust conclusions would
result from a longitudinal neuropsycho-
logical evaluation of CADASIL patients,
starting in their third decade and
repeated, in parallel with neuroimaging,
for instance, every 5 or 10 years. To
achieve adequate statistical power,
such a longitudinal study would need
to involve many centres and countries,
because of the limited number
of CADASIL patients available in
EDITORIAL COMMENTARY
3 De Groot JC, De Leeuw FE, Oudkerk M, et al.
Periventricular cerebral white matter lesions
predict rate of cognitive decline. Ann Neurol
2002;52:33541.
4 Fazekas F, Kleinert R, Offenbacher H, et al.
Pathologic correlates of incidental MRI white
matter signal hyperintensities. Neurology
1993;43:16839.
5 Scheltens P, Barkhof F, Leys D, et al. A
semiquantative rating scale for the assessment of
signal hyperintensities on magnetic resonance
imaging. J Neurol Sci 1993;114:712.
6 Schmidt R, Fazekas F, Offenbacher H, et al.
Magnetic resonance imaging white matter lesions
and cognitive impairment in hypertensive
individuals. Arch Neurol 1991;48:41720.
7 DeCarli C, Fletcher E, Ramey V, et al.
Anatomical mapping of white matter
hyperintensities (WMH): exploring the
relationships between periventricular WMH,
deep WMH, and total WMH burden. Stroke
2005;36:505.
individual regions. The harmonisation
of a neuropsychological battery to be
used in different languages is a difficult
but achievable task.7 This longitudinal
study would elucidate the relative role
of lacunes and white matter changes,
their localisation and their influence on
the development of cognitive impair-
ment, mood changes, and movement
performance in CADASIL patients.
As CADASIL is a pure subcortical
ischaemic vascular dementia, it is a
good model for pilot clinical trials for
this type of dementia. Antiplatelets or
statins to prevent progression of the
disease are unlikely to be effective, as
CADASIL is mainly a disease of the
arterial media. Other candidate drugs to
be tested with the aim of improving
cognition are cholinergic agents, mem-
antine, and antidepressants.
J Neurol Neurosurg Psychiatry 2006;77:144
145.
doi: 10.1136/jnnp.2005.074583
......................
Authors affiliations
L Caeiro, J M Ferro, Stroke Unit, Department
of Neurosciences and Mental Health, Servico
de Neurologia, Hospital de Santa Maria,
Faculdade de Medicina de Lisboa, Portugal
Correspondence to: Lara Caeiro, Stroke Unit,
Servico de Neurologia (piso 6), Hospital de
Santa Maria, Av. Professor Egas Moniz, 1649-
035 Lisboa, Portugal; laracaeiro@fm.ul.pt
Competing interests: none declared
REFERENCES
1 Opherk C, Peters N, Herzog J, et al. Long term
prognosis and causes of death in CADASIL: a
retrospective study in 411 patients. Brain
2004;127:25339.
2 OSullivan M, Singhal S, Charlton R, et al.
Diffusion tensor imaging of thalamus correlates
with cognition in CADASIL without dementia.
Neurology 2004;62:7027.
3 Chabriat H, Vahedi K, Iba-Zizen MT, et al.
Clinical spectrum of CADASIL: a study of 7
families. Lancet 1995;346:9349.
EDITORIAL COMMENTARY
4 Peters N, Herzog J, Opherk C, et al. A two-year
clinical follow-up study in 80 CADASIL subjects.
Progression patterns and implications for clinical
trials. Stroke 2004;35:16038.
5 Taillia H, Chabriat H, Kurtz A, et al.
Cognitive alterations in non-demented
Teratogenic effects of antiepileptic drugs
.......................................................................................
Major congenital malformations and
antiepileptic drugs: prospective
observations
M J Brodie
...................................................................................
High dose lamotrigine may be teratogenic
T
he spectre of teratogenesis has been
hanging over young women with
epilepsy ever since the association of
fetal malformations with antiepileptic
drug (AED) exposure was first mooted
by Roy Meadow in a letter to The Lancet
in 1968.1 There followed a flood of
retrospective reports and small prospec-
tive studies suggesting that perhaps all
of the established drugs could be impli-
cated in this problem. The global licen-
sing of nine new antiepileptic drugs over
the past 15 years has added to the
confusion. Those agents that did not
appear to be teratogenic in rodents have
been touted by enthusiasts as possibly
safe in pregnancy. The most confident
claims were made for lamotrigine, and
schedules have been devised to switch
women of childbearing age from carba-
mazepine, phenytoin, or sodium valpro-
ate to this drug. What was (is) clearly
needed was large prospective registries
including only women in whom the
pregnancy outcome was unknown at
recruitment. The UK Epilepsy and
Pregnancy Register was established in
1996 and its findings to the end of
March 2005 are presented by Jim
Morrow and colleagues in this issue of
the journal (see pages 1938).2
CADASIL patients. Cerebrovasc Dis
1998;8:97101.
6 Amberla K, Waljas M, Tuominen S,
et al. Insidious cognitive decline in
CADASIL. Stroke 2004;35:
1598602.
Data from a total of 3607 completed
pregnancies have been analysed to date.
The majority of mothers (72%) took a
single AED. Importantly, 239 women
with epilepsy were untreated through-
out pregnancy and the rate of major
congenital malformation (MCM) in
their babies was no different (3.5%)
from that in fetuses exposed to AED
monotherapy (3.7%). The greater risk of
MCM with polypharmacy (6%) and the
likely teratogenic effect of sodium
valproate were confirmed.3 The rate of
MCM in women taking more than
1000 mg valproate daily (9.1%) was
nearly double (5.1%) that in patients
established on a lower dose. The MCM
rate with carbamazepine was only 2.2%,
but it must be remembered that these
drugs may be used to treat different
forms of epilepsy. Rather disappoint-
ingly, no mention is made in the paper
of the effect, protective or otherwise, of
preconception supplementation with
folic acid.
The important new finding from this
study2 was a significant doseresponse
relationship for MCMs with lamotrigine
with a rate of 5.4% reported in babies
born to women taking more than
200 mg lamotrigine daily throughout
145
7 Pantoni L, Basile AM, Pracucci G, et al.
Impact of age-related cerebral white matter
changes on the transition to disability -
the LADIS study: rationale, design and
methodology. Neuroepidemiology
2005;24:5162.
their pregnancy. A recent possibly sup-
portive report from the International
Lamotrigine Pregnancy Registry sug-
gested a higher rate of MCM in babies
exposed to valproate in combination
with lamotrigine (12.5%) compared
with lamotrigine alone (2.9%) or lamo-
trigine combined with other AEDs
(6.6%).4 In the present study, the rate
of MCM for valproate with lamotrigine
was 9.6%.
Data from pregnancy registries are now
coming thick and fast with potentially the
biggest, European Pregnancy Registry
(EURAP), still to report.5 Larger numbers
of pregnancies are required to strengthen
confidence in the power of these observa-
tions. The hope too is that there will be
consistency across the different data sets.
All this activity has the potential to
provide useful guidance for doctors treat-
ing young women with epilepsy. This
story, however, will run and run.
J Neurol Neurosurg Psychiatry 2006;77:145.
doi: 10.1136/jnnp.2005.079376
Correspondence to: M J Brodie, Director,
Epilepsy Unit, Western Infirmary, Glasgow
G11 6NT, Scotland; mjb2k@clinmed.gla.ac.uk
Competing interests: The author is a Member of
Scientific Advisory Board for the European
Pregnancy Registry (EURAP)
REFERENCES
1 Meadow SR. Antiepileptic drugs and congenital
abnormalities. Lancet 1968;2:196.
2 Morrow JI, Russell A, Guthrie E, et al.
Malformation risks of antiepileptic drugs in
pregnancy: a prospective study from the UK
Epilepsy and Pregnancy Register. J Neurol
Neurosurg Psychiatry 2005;77:1938.
3 Penovich P, Gaily E. What can we say to women
of reproductive age with epilepsy? Neurology
2005;64:9389.
4 Cunnington M, Tennis P and International
Lamotrigine Pregnancy Registry Scientific
Advisory Committee. Lamotrigine and the risk of
malformations in pregnancy. Neurology
2005;64:9615.
5 Tomson T, Perucca E, Battino D. Navigating
toward fetal and maternal health: the challenge of
treating epilepsy in pregnancy. Epilepsia
2004;45:11715.
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