The n e w e ng l a n d j o u r na l of
clinical problem-solving
From the Departments of Emergency
Medicine, Children’s Hospital of Boston
(J.S.E.) and Beth Israel Deaconess Medi-
cal Center (J.A.E.) — both in Boston; the
Department of Neurology, University of
California at San Francisco, San Francisco
(S.A.J.); the Department of Emergency
Medicine, Denver Health Medical Cen-
ter, Denver (D.T.V.); and the Department
of Veterans Affairs Health Services Re-
search and Development Center of Excel-
lence and the Department of Internal
Medicine, University of Michigan Medi-
cal School — both in Ann Arbor, MI (S.S.).
Address reprint requests to Dr. Edlow
at Beth Israel Deaconess Medical Center,
1 Deaconess Rd., CC2, Boston, MA 02215,
or at jedlow@bidmc.harvard.edu.
N Engl J Med 2010;362:2114-20.
Copyright © 2010 Massachusetts Medical Society.
2114
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m e dic i n e
All in the Family
Joshua S. Easter, M.D., S. Andrew Josephson, M.D., Deborah T. Vinton, M.D.,
Sanjay Saint, M.D., M.P.H., and Jonathan A. Edlow, M.D.
In this Journal feature, information about a real patient is presented in stages (boldface type)
to an expert clinician, who responds to the information, sharing his or her reasoning with
the reader (regular type). The authors’ commentary follows.
A 34-year-old woman presented to a community hospital with aphasia. Her husband
reported that her condition had been normal until 2 hours earlier, when her arms and
legs suddenly shook for several seconds. Immediately afterward, she was unable to
speak or to move her limbs on the right side. There was no incontinence or tongue
biting.
Although the initial shaking in all four limbs is suggestive of bilateral central ner-
vous system dysfunction, the subsequent focal nature of the deficits, including aphasia
and weakness on the patient’s right side, suggests a unilateral lesion, probably in
the left hemisphere of the brain, affecting the corticospinal tracts and language
centers. In addition, the acute alteration in her ability to speak is more common
with a stroke or a seizure than with a toxic or metabolic cause. If the shaking re-
flected a generalized seizure, the post­ictal dysfunction of the left hemisphere would
suggest an underlying lesion such as a tumor, focal infection, or stroke. The ab-
sence of tongue biting and incontinence and the brevity of the spell make a seizure
less likely but do not reliably rule it out.
The patient had a history of migraines, frequent urinary tract infections, multiple
episodes of epistaxis, depression, and miscarriage. Her medications included venla-
faxine; she was not taking oral contraceptive pills. She was married and had four
children. There was no history of smoking, use of illicit drugs, or alcohol abuse, and
the patient had not traveled recently.
Patients with migraine can present with focal neurologic dysfunction either as part
of their migraine syndrome or as the aura preceding it; these “complicated” mi-
graine spells may be mistaken for stroke or seizure. In this case, migraine should
be viewed as a diagnosis of exclusion.
Two elements of the medical history are suggestive of vascular disorders that
present at an early age. Recurrent episodes of epistaxis suggest a bleeding diathesis
involving platelet dysfunction that could increase the risk of intracerebral hemor-
rhage. Hereditary hemorrhagic telangiectasia can present with recurrent nose-
bleeds as well as with pulmonary, hepatic, and cerebral arteriovenous malforma-
tions. Certain forms of systemic vasculitis, such as Wegener’s granulomatosis, can
lead to vascular events in the brain as well as to epistaxis. Although miscarriages
are relatively common in the general population, they can be a marker of rheuma-
tologic disorders, such as the antiphospholipid-antibody syndrome, which is also
associated with stroke in young persons.
Medications, including over-the-counter preparations, should always be consid-
ered as a possible cause of altered mental status. Venlafaxine, a commonly pre-
n engl j med 362;22  nejm.org  june 3, 2010
 clinical problem-solving

scribed antidepressant, can in rare instances

cause seizures and neurotoxic effects, especially
in cases of overdose, as well as a severe with-
drawal syndrome that can mimic stroke.

On physical examination, the patient was afebrile

and had a regular pulse, at 106 beats per minute, a
blood pressure of 116/71 mm Hg, a respiratory
rate of 23 breaths per minute, and an oxygen satu-
ration of 97% while breathing ambient air. Her
gaze deviated to the left. She was mute and fol-
lowed spoken commands intermittently. Her neck
was supple and without bruits. Cardiovascular ex-
amination revealed a regular but tachycardic
rhythm, with normal S1 and S2 and no murmurs
or rubs. The lungs were clear on auscultation.
On neurologic examination, the patient was
aphasic and had right homonymous hemianopia.
She had a facial droop on the right side, complete
paralysis of the right arm, and partial paralysis of
the right leg. Strength was normal on the left side.
Her reflexes were absent on the right side and nor-
mal on the left. Plantar responses were extensor
on the right side and flexor on the left. Sensation
appeared to be normal throughout her body.
Involvement of the visual pathway in the form of
a right homonymous hemianopia, as well as the
aphasia, definitively localizes the lesion to the
supratentorial area of the brain. The combination
of motor loss on the right side of the body, gaze
deviation to the left, and visual-field loss indi-
cates a lesion in the left hemisphere that involves
the corticospinal tract, cortical eye fields, and
optic tracts. As described, the aphasia is more ex-
pressive than receptive in nature, since the patient
is mute, with partially preserved comprehension;
this finding localizes the lesion to the inferior
frontal lobe, although partial temporal-lobe in-
volvement is also possible. The pattern of weak-
ness involving the face and arm more than the
leg indicates a process that is affecting the lateral
part of the left hemisphere, partially sparing the
corticospinal tract in the medial cortex that con-
trols the lower limb. Infarctions involving the
superior division of the middle cerebral artery
would produce this pattern.
Laboratory analysis showed a serum glucose level
of 106 mg per deciliter (5.9 mmol per liter), a se-
rum sodium level of 142 mmol per liter, a serum
creatinine level of 0.7 mg per deciliter (62 μmol per
Figure 1. CT Scan of the Brain Obtained in the Emergency
Department.
A CT scan of the brain obtained without the administra-
tion of contrast material shows a hyperdense left middle
cerebral artery (arrow).
liter), and a serum calcium level of 8.7 mg per deci-
liter (2.2 mmol per liter). The white-cell count was
11,900 per cubic millimeter, the hematocrit 40.3%,
the platelet count 258,000 per cubic millimeter, the
prothrombin time 12.9 seconds, and the partial-
thromboplastin time 34.5 seconds. Approximately
3½ hours after the onset of symptoms, a computed
tomographic (CT) scan of the head obtained with-
out the administration of contrast material re-
vealed a hyperdense left middle cerebral artery
(Fig. 1).
Given the thrombosis seen on CT, the evaluation
should focus on potential sources of emboli to
the brain, including the aortic arch and the heart.
Although carotid-artery atherosclerosis is a com-
mon cause of stroke, in this young woman with
no known risk factors for atherosclerotic disease,
a dissection or other vasculopathy is a more like-
ly cause of carotid emboli. Cardiac causes should
also be considered, including arrhythmias, valvu-
lar disease, and a right-to-left cardiac shunt. Hy-
percoagulable states, either genetic or acquired,
are also potential contributors in young patients
with stroke, especially in the absence of tradi-
tional vascular risk factors.
The more pressing issue is the need for acute

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 The n e w e ng l a n d j o u r na l
Figure 2. Chest Radiograph Obtained in the Emergency
Department.
A chest radiograph obtained with portable equipment
shows adequate placement of the endotracheal tube.
A possible right middle-lobe infiltrate was also seen.
therapy in this young woman with an ischemic
stroke affecting the dominant hemisphere. Intra-
venous recombinant tissue plasminogen activa-
tor (rt-PA) is currently approved by the Food and
Drug Administration for the treatment of is­
chemic stroke within 3 hours after onset; how-
ever, a recent study has shown that rt-PA therapy
can be effective when administered up to 4.5 hours
after the onset of symptoms. Thus, some stroke
centers would now consider this patient eligible
to undergo intravenous thrombolysis. Even if local
protocols excluded her as a candidate for intra-
venous rt-PA therapy on the basis of the time
elapsed since the onset of symptoms, she would
still be eligible for several intermediate endovas-
cular interventions, including mechanical embo­
lectomy and intraarterial thrombolysis, although
the effects of such procedures on morbidity have
not been well established. The patient’s condi-
tion should be considered a treatable neuro-
logic emergency warranting immediate evalua-
tion and therapy.
The patient was not given thrombolytic therapy;
instead, treatment with intravenous heparin was
started, and the patient was transferred to the
emergency department of a tertiary care hospital.
On arrival, 5 hours after the onset of symptoms,
she still could not follow commands and remained
nonverbal and unable to move her right side. She
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of m e dic i n e
Figure 3. CT Angiogram of the Brain Obtained
on the Day of Admission.
Vascular reconstructions of the CT angiogram show
a filling defect suggestive of a clot in the left middle
cerebral artery (arrow).
could not control her oral secretions and was intu-
bated to protect the airway. The emergency physi-
cian interpreted a postintubation chest radiograph
as normal (Fig. 2). A CT angiogram of the head
and neck revealed a filling defect suggestive of a
clot in the left middle cerebral artery (Fig. 3).
Angiography was performed and intraarterial
rt-PA was administered, followed by endovascu-
lar mechanical retrieval of the clot. After the pro-
cedure, blood flow through the middle cerebral
artery was restored, but the patient’s hemiparesis
persisted. The radiologist interpreted the chest
radiograph that had been obtained earlier in the
emergency department as showing a possible
pneumonia affecting the right middle lobe (Fig. 2).
The patient was given intravenous levofloxacin
and was admitted to the intensive care unit.
Vascular imaging in patients with suspected is­
chemic stroke allows visualization of occluded
large vessels of the brain. It can also rapidly iden-
tify other potential causes of stroke, such as
carotid-artery dissection and disease of the aortic
arch. Either magnetic resonance imaging or CT-
based angiography is useful, although CT is used
more often because it is widely available in emer-
gency departments and can be completed more
rapidly.
In this case, recanalization of the culprit ar-
tery was successfully achieved through endovas-
 clinical problem-solving

cular means. The practice of transferring patients

who are not eligible for intravenous thrombo­
lysis to tertiary care centers for endovascular
therapies has become increasingly common.
Treatment with intravenous heparin is sometimes
started at the initial facility as a bridge to de-
finitive therapy, although this measure has not
been shown to improve the outcome.
The right middle-lobe infiltrate may simply
reflect aspiration pneumonia, a common com-
plication in patients with stroke, especially after
emergency intubation. In the case of this young
woman, however, the infiltrate may provide a clue
to the cause of the ischemic stroke and merits
further investigation. Septic emboli due to endo-
carditis could lead to pneumonia and stroke.
Another possibility is that the finding on the
chest radiograph is not pneumonia. Patients with
the antiphospholipid-antibody syndrome may have
pulmonary infiltrates along with embolic strokes
from noninfective endocarditis, a hypercoagula-
ble state, or both. In this case, the lung findings,
embolic stroke, and history of epistaxis could all Figure 4. CT Scan of the Torso Obtained 1 Week
be manifestations of hereditary hemorrhagic tel­ after Admission.
angiectasia, if the presumed infiltrate is in fact The coronal-plane–formatted CT scan shows an arterio­
a pulmonary arteriovenous malformation, with a venous malformation in the lung (arrow).
paradoxical cerebral embolus through a right-to-
left pulmonary shunt.
tion, chest radiographs, urine cultures, and blood
An evaluation for hypercoagulability was negative cultures showed no evidence of focal infection.
for factor V Leiden, prothrombin 20210 mutation, Chest and abdominal CT scans were obtained to
and deficiencies in antithrombin, protein C, and detect any occult infection; a contrast-enhanced
protein S. Venous ultrasonography of the patient’s CT scan of the torso revealed a pulmonary arterio-
legs showed no evidence of a clot. A repeat CT an- venous malformation as well as a hemangioma in
giogram of her neck revealed no evidence of a dis- her liver (Fig. 4). These CT scan results led to a re-
section. Her cardiac echocardiogram, including a evaluation of the chest radiograph initially ob-
bubble study, showed a blood-flow pattern that tained in the emergency department, and the mal-
was consistent with an atrial septal defect. formation that was previously thought to be an
infiltrate was correctly identified (Fig. 5).
Between 20 and 30% of the general population is
found on echocardiography to have an intracar- The cause of this patient’s stroke is probably a
diac shunt, most commonly through a patent fo- paradoxical embolism through the intrapulmo-
ramen ovale; given this high prevalence, caution nary shunt created by the pulmonary arterio-
should be used before attributing a stroke to a venous malformation. This finding prompts re-
paradoxical embolism through an atrial septal consideration of the echocardiographic findings.
defect. However, in a young patient with no vas- The reportedly positive bubble study may indicate
cular risk factors or other explanation for stroke,a right-to-left shunt through a pulmonary arterio- A video of an
the possibility of paradoxical embolism through venous malformation rather than through an echocardiogram
a shunt must be considered. atrial septal defect or a patent foramen ovale (see showing bubbles
suggestive of an
Video). Typically, with an intracardiac shunt, as intrapulmonary
One week into her hospital course, the patient be- with a patent foramen ovale, the bubbles are seen shunt is available
gan to have a persistent fever. Physical examina- on the left side of the heart within three beats of at NEJM.org

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 The n e w e ng l a n d j o u r na l of m e dic i n e

the abnormal blood-flow pattern was attributed

to the pulmonary arteriovenous malformation
rather than to an atrial septal defect. The patient
underwent successful transcatheter embolotherapy
of the malformation, and subsequent CT angiog-
raphy and chest radiography confirmed the occlu-
sion of the vessels leading to the malformation.
Subsequent discussions with the family dis-
closed that the patient’s uncle had also had an
arteriovenous malformation. Thus, she met the
criteria for a clinical diagnosis of hereditary hem-
orrhagic telangiectasia: epistaxis, a visceral arte-
riovenous malformation, and a family history.
Genetic testing confirmed the diagnosis of hered-
itary hemorrhagic telangiectasia type 2 on the ba-
Figure 5. Chest Radiograph Showing the Pulmonary sis of a missense mutation produced by a base-pair
­Arteriovenous Malformation. substitution in the gene encoding activin-recep-
After a review of the CT scan of the torso, the chest tor–like kinase 1 (ALK1). Testing of the patient’s
­radiograph that had been obtained in the emergency four children showed that three of them also had
department was reassessed, revealing the pulmonary this mutation.
arteriovenous malformation (arrow) that on the earlier
At the time of discharge, the patient had mini-
reading had been misinterpreted as an infiltrate.
mal neurologic improvement. By 6 months, her
speech had improved substantially, but some
their arrival on the right side. In this case, how- weakness persisted in her right arm and hand.
ever, their delay by several cardiac cycles suggests Although she could walk unaided, she required a
an intrapulmonary shunt due to a pulmonary arte- foot brace.
riovenous malformation. Patients with untreated
pulmonary arteriovenous malformations have an Whether people with hereditary hemorrhagic
increased risk of cerebral complications, includ- telangiectasia who are asymptomatic, such as this
ing stroke and brain abscess. Pulmonary compli- patient’s children, should be screened for cere-
cations include hypoxemia, hemoptysis, and hemo­ brovascular malformations is a matter of contro-
thorax. versy. It is not clear whether treating unruptured
The finding of a pulmonary arteriovenous malformations will improve outcomes and hence
malformation, the liver findings on CT, and the whether such screening would be appropriate.
history of recurrent epistaxis make it likely that
this patient has hereditary hemorrhagic telangi- C om men ta r y
ectasia, a systemic disorder with an autosomal
dominant pattern of inheritance, which is charac- The abrupt onset of a focal neurologic deficit is a
terized by telangiectasias and arteriovenous mal- true emergency. In this case, by the time the pa-
formations. The clinical diagnosis of hereditary tient’s CT scan was interpreted, the standard
hemorrhagic telangiectasia is established if at 3-hour window for rt-PA administration had
least three of four criteria are met: recurrent, passed. Data from a randomized, placebo-con-
spontaneous epistaxis; mucocutaneous telangi- trolled trial1 and a meta-analysis,2 as well as un-
ectasias; a visceral arteriovenous malformation; controlled, observational registry data,3 suggest
and a first-degree relative with hereditary hemor- that rt-PA can be effective when given within 4.5
rhagic telangiectasia. Clinical diagnosis of he- hours after the onset of symptoms. A recent
reditary hemorrhagic telangiectasia may in some American Heart Association guideline has en-
cases be confirmed through genetic testing. dorsed this new time window.4 In addition, vari-
ous endovascular therapies may be beneficial
Given the arteriovenous malformation noted on when instituted within 8 hours after the onset of
chest CT, the echocardiogram was reassessed, and manifestations of ischemic stroke.

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 clinical problem-solving
When an ischemic stroke occurs in a young
patient without the traditional vascular risk fac-
tors, alternative causes must be considered. In
retrospect, several clues could have expedited the
correct diagnosis of this patient’s condition. One
such clue was the recurrent epistaxis, and earlier
recognition of its relevance might have altered
the evaluation. Another clue was the potential
significance of the abnormality noted on the pa-
tient’s chest radiograph. Whereas aspiration pneu-
monia is common in patients with stroke, both
the shape and the location of the lesion were, in
retrospect, not typical of this diagnosis. Con-
sideration of an alternative cause of the radio-
graphic abnormality might have prompted ear-
lier use of chest CT, which ultimately revealed
the arteriovenous malformation. Findings on the
echocardiographic bubble study, initially inter-
preted as consistent with an atrial septal defect
or a patent foramen ovale, were only later recog-
nized to be more consistent with a pulmonary
arteriovenous malformation. With the first two
conditions, the bubbles characteristically appear
in the left atrium sooner than they do with a
pulmonary arteriovenous malformation.5,6
Whereas a pulmonary arteriovenous malfor-
mation is present in 30 to 75% of patients with
hereditary hemorrhagic telangiectasia, depend-
ing on the genotype, 80 to 90% of all pulmonary
arteriovenous malformations occur in patients
with hereditary hemorrhagic telangiectasia.7-9
Thus, in this case, the diagnosis of hereditary
hemorrhagic telangiectasia was quickly estab-
lished, once the finding on the chest CT scan
had been correctly identified as a pulmonary
arteriovenous malformation.10 Hereditary hemor­
rhagic telangiectasia, which occurs in approxi-
mately 1 in 7500 persons, is also associated with
vascular malformations in other organs.11 Tel­
angiectasias in the gastrointestinal tract can
lead to bleeding from the stomach.
Hereditary hemorrhagic telangiectasia can
also lead to more severe complications. Owing
to their vascular fragility, pulmonary arterio-
venous malformations can cause hemothorax
and hemoptysis.10,11 In the absence of a normal
capillary bed to filter particulate matter as it
traverses the lung, pulmonary arteriovenous mal-
formations may have neurologic sequelae. Com-
plications of paradoxical emboli include cerebral
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ischemia (annual risk, 0.92%) and brain abscess
(annual risk, 0.32%).8,12 Given these potential
consequences, most pulmonary arteriovenous
malformations are corrected by means of percu-
taneous embolization. In 4 to 23% of patients
with hereditary hemorrhagic telangiectasia, arte-
riovenous malformations are also present in the
brain, where they have the potential to rup-
ture.12,13 Approximately 10% of patients with
hereditary hemorrhagic telangiectasia die pre-
maturely or have major disability because of
these complications.14
Whereas screening for cranial arteriovenous
malformations is controversial owing to the high
morbidity associated with intervention for iden-
tified cranial abnormalities, consensus guide-
lines from the Hereditary Hemorrhagic Telangi-
ectasia Foundation International recommend
screening for pulmonary arteriovenous malfor-
mations in all patients with hereditary hemor-
rhagic telangiectasia, since these lesions can be
treated.7,9 The optimal screening test is contro-
versial. Chest radiographs and blood oxygen
measurements are insensitive. Contrast echocar-
diography may detect small lesions that do not
require treatment, but it is the standard form of
testing in North America.6 Chest CT is an excel-
lent test but requires ionizing radiation.
Patients who present with signs and symp-
toms suggestive of hereditary hemorrhagic tel­
angiectasia, as well as family members of pa-
tients in whom the disorder is diagnosed, should
undergo genetic screening. Heterozygous muta-
tions in five different genes that encode compo-
nents of the transforming growth factor β signal-
ing pathway involved in blood-vessel development
have been associated with hereditary hemor-
rhagic telangiectasia.9 However, genetic testing
has false negative results in 75 to 92% of pa-
tients who have whole-exon deletions and inser-
tions or mutations in regulatory regions or in
unknown genes.15 Patients who have positive
test results or whose clinical presentation sug-
gests hereditary hemorrhagic telangiectasia should
be referred to a specialist for coordination of
care and family testing.
No potential conflict of interest relevant to this article was
reported.
We thank Drs. Robert White, Jr., and Katherine Henderson for
reviewing an earlier draft of this article.
2119
 clinical problem-solving

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Copyright © 2010 Massachusetts Medical Society.

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