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Have test, will screen. Screening people with hereditary haemorrhagic
telangiectasia (HHT) for brain arteriovenous malformations (AVMs) could be
relatively easy – and therefore attractive – but where lies the balance
between risk (both physical and psychological) and benefit?
The ideal screening test should aim to detect a disease that
significantly impacts upon public health, before the disease...
The ideal screening test should aim to detect a disease that
significantly impacts upon public health, before the disease reaches a
critical point (i.e. brain haemorrhage), and detection before this point
should confer a beneficial outcome with intervention (i.e. one or more of
surgical excision, radiotherapy, or endovascular embolisation). The test
itself (MRI and/or catheter angiography) should be sensitive enough to
detect the disease, specific enough to minimise false positives, and it
should be well tolerated with few side effects. Lastly, the population to
be screened should have a high prevalence of the disease, and should be
willing to undergo treatment. If overall there is a fine balance between
benefit and cost (mortality, morbidity, and/or financial), then a
randomised controlled trial (RCT) comparing screening strategies against
each other is called for.
In the case of HHT, it is rare but can cause significant mortality
and morbidity. The exact prevalence of brain AVMs in HHT is uncertain but ³5%.  For brain AVMs in general, high quality information about
prognosis and satisfactory evidence for interventional treatment are
lacking: prospective, population-based studies of prognosis are in their
infancy,[2,3] and there are no randomised controlled trials comparing
different interventions either against each other or conservative
management. Catheter angiography is more sensitive than MRI for brain
AVM detection in HHT, and it carries <_0.1 risk="risk" of="of" permanent="permanent" neurological="neurological" complications.5="complications.5" p="p"/>Easey et al. recently addressed the important dilemma of whether or
not to screen for brain AVMs in HHT by assessing the prevalence of stroke
in the families of individuals with HHT. Their sizeable HHT cohort and
collective experience with the condition are invaluable, but their
conclusion that individuals with HHT should be screened for asymptomatic
brain AVMs is not justified by their data. The design of their study does
not address the question they pose and their findings are not
Easey et al’s study was retrospective and diagnosed HHT on the basis
of clinical diagnostic criteria rather than strictly by mutation analysis
of ALK1 and endoglin genes. This is unfortunate because there is an
increasing body of evidence to suggest that HHT caused by mutations in the
endoglin gene (HHT1) has a distinct and possibly more severe phenotype
than HHT caused by mutations in the ALK1 gene (HHT2).
Of the 98 families studied comprising probands and their relatives in
their generation (n=674), a staggering 200 (30%) were unaffected or
unlikely to have HHT. Strangely, the authors argue against simply studying
the screening group of interest (people with definite HHT) and include
data on strokes in 30% of their cohort who did not, or were unlikely to
have, HHT. Furthermore, all strokes were considered whatever their
aetiology; pulmonary – rather than brain – AVMs may have contributed to
many of these. The total number of people affected by the screening
condition of interest (brain AVMs) is not mentioned, but a brain AVM was
detected on catheter angiography in only 7 of the 35 probable/definite
haemorrhages in the cohort of 674 individuals (table 3). Recurrent events
were not studied. Time-dependent outcome analysis was not used.
The authors then conclude with their finding of a higher relative
risk for stroke by indirect comparison of their heterogeneous cohort with
the Oxford Community Stroke Project. Crucially, they have not directly
established the contribution of the screening condition of interest (brain
AVMs) to this excess risk, nor the effects of treating symptomatic and
incidental brain AVMs.
Our reservations about Easey et al's study are more than pedantic
methodological criticisms; the argument for screening is simply not
persuasive. Their data and the rest of the literature thus far simply do
not justify screening people with HHT for brain AVMs. Screening in this
context does occur in some HHT clinics, but it should not be a practice
standard on the existing evidence.
We are not advocating doing nothing. It may be that screening is
appropriate, but only in certain age groups, or people with particular
mutations. Surely the best solution would be for geneticists, respiratory
physicians, radiologists, radiotherapists, neurosurgeons and neurologists
looking after people with HHT to unite and conduct a properly designed RCT
of screening (and treatment) for brain AVMs?
(1) Fulbright RK, Chaloupka JC, Putman CM, Sze GK, Merriam MM, Lee GK,
Fayad PB, Awad IA, White RI, Jr. MR of hereditary hemorrhagic
telangiectasia: prevalence and spectrum of cerebrovascular malformations.
(2) Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis
of arteriovenous malformations of the brain in adults. Brain 2001;124:1900-26.
(3) Al Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V,
Roberts RC, Sellar RJ, Warlow CP. Scottish Intracranial Vascular
Malformation Study (SIVMS): Evaluation of Methods, ICD-10 Coding, and
Potential Sources of Bias in a Prospective, Population-Based Cohort.
(4) Al-Shahi R, Warlow CP. Interventions for treating arteriovenous
malformations of the brain in adults (Protocol for a Cochrane Review). In:
The Cochrane Library, Issue 2, 2003. Oxford: Update Software 2002.
(5) Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients
with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous
malformation: a meta-analysis. Stroke 1999;30:317-20.
(6) Easey AJ, Wallace GM, Hughes JM, Jackson JE, Taylor WJ, Shovlin CL.
Should asymptomatic patients with hereditary haemorrhagic telangiectasia
(HHT) be screened for cerebral vascular malformations? Data from 22 061
years of HHT patient life. J Neurol Neurosurg Psychiatry 2003;74:743-8.
(7) Berg J, Porteous M, Reinhardt D, Gallione C, Holloway S, Thisanagayam U,
Lux A, McKinnon W, Marchuk D, Guttmacher A. Hereditary haemorrhagic
telangiectasia – a questionnaire base4d study to delineate the different
phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003; in press.