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clinical problem-solving

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.
From the Departments of Emergency
Medicine, Childrens Hospital of Boston
(J.S.E.) and Beth Israel Deaconess Medical 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 Center, Denver (D.T.V.); and the Department
of Veterans Affairs Health Services Research and Development Center of Excellence and the Department of Internal
Medicine, University of Michigan Medical 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.

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 nervous system dysfunction, the subsequent focal nature of the deficits, including aphasia
and weakness on the patients 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 reflected a generalized seizure, the postictal dysfunction of the left hemisphere would
suggest an underlying lesion such as a tumor, focal infection, or stroke. The absence 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 venlafaxine; 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 migraine 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 hemorrhage. Hereditary hemorrhagic telangiectasia can present with recurrent nosebleeds as well as with pulmonary, hepatic, and cerebral arteriovenous malformations. Certain forms of systemic vasculitis, such as Wegeners 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 rheumatologic 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 considered as a possible cause of altered mental status. Venlafaxine, a commonly pre-

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clinical problem-solving

scribed antidepressant, can in rare instances

cause seizures and neurotoxic effects, especially
in cases of overdose, as well as a severe withdrawal 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 saturation of 97% while breathing ambient air. Her
gaze deviated to the left. She was mute and followed spoken commands intermittently. Her neck
was supple and without bruits. Cardiovascular examination 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 normal 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 indicates a lesion in the left hemisphere that involves
the corticospinal tract, cortical eye fields, and
optic tracts. As described, the aphasia is more expressive 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 involvement is also possible. The pattern of weakness 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 controls 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 serum sodium level of 142 mmol per liter, a serum
creatinine level of 0.7 mg per deciliter (62 mol per

Figure 1. CT Scan of the Brain Obtained in the Emergency

Department.
A CT scan of the brain obtained without the administration of contrast material shows a hyperdense left middle
cerebral artery (arrow).

liter), and a serum calcium level of 8.7 mg per deciliter (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 partialthromboplastin time 34.5 seconds. Approximately
3 hours after the onset of symptoms, a computed
tomographic (CT) scan of the head obtained without the administration of contrast material revealed 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 common cause of stroke, in this young woman with
no known risk factors for atherosclerotic disease,
a dissection or other vasculopathy is a more likely cause of carotid emboli. Cardiac causes should
also be considered, including arrhythmias, valvular disease, and a right-to-left cardiac shunt. Hypercoagulable states, either genetic or acquired,
are also potential contributors in young patients
with stroke, especially in the absence of traditional vascular risk factors.
The more pressing issue is the need for acute

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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. Intravenous recombinant tissue plasminogen activator (rt-PA) is currently approved by the Food and
Drug Administration for the treatment of is
chemic stroke within 3 hours after onset; however, 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 intravenous rt-PA therapy on the basis of the time
elapsed since the onset of symptoms, she would
still be eligible for several intermediate endovascular interventions, including mechanical embo
lectomy and intraarterial thrombolysis, although
the effects of such procedures on morbidity have
not been well established. The patients condition should be considered a treatable neurologic emergency warranting immediate evaluation 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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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 intubated to protect the airway. The emergency physician 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 endovascular mechanical retrieval of the clot. After the procedure, blood flow through the middle cerebral
artery was restored, but the patients 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 identify other potential causes of stroke, such as
carotid-artery dissection and disease of the aortic
arch. Either magnetic resonance imaging or CTbased angiography is useful, although CT is used
more often because it is widely available in emergency departments and can be completed more
rapidly.
In this case, recanalization of the culprit artery was successfully achieved through endovas-

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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 definitive therapy, although this measure has not
been shown to improve the outcome.
The right middle-lobe infiltrate may simply
reflect aspiration pneumonia, a common complication 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 endocarditis 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 hypercoagulable state, or both. In this case, the lung findings,
embolic stroke, and history of epistaxis could all
be manifestations of hereditary hemorrhagic tel
angiectasia, if the presumed infiltrate is in fact
a pulmonary arteriovenous malformation, with a
paradoxical cerebral embolus through a right-toleft pulmonary shunt.
An evaluation for hypercoagulability was negative
for factor V Leiden, prothrombin 20210 mutation,
and deficiencies in antithrombin, protein C, and
protein S. Venous ultrasonography of the patients
legs showed no evidence of a clot. A repeat CT angiogram of her neck revealed no evidence of a dissection. Her cardiac echocardiogram, including a
bubble study, showed a blood-flow pattern that
was consistent with an atrial septal defect.
Between 20 and 30% of the general population is
found on echocardiography to have an intracardiac shunt, most commonly through a patent foramen ovale; given this high prevalence, caution
should be used before attributing a stroke to a
paradoxical embolism through an atrial septal
defect. However, in a young patient with no vascular risk factors or other explanation for stroke,
the possibility of paradoxical embolism through
a shunt must be considered.

Figure 4. CT Scan of the Torso Obtained 1 Week

after Admission.
The coronal-planeformatted CT scan shows an arterio
venous malformation in the lung (arrow).

tion, chest radiographs, urine cultures, and blood

cultures showed no evidence of focal infection.
Chest and abdominal CT scans were obtained to
detect any occult infection; a contrast-enhanced
CT scan of the torso revealed a pulmonary arteriovenous malformation as well as a hemangioma in
her liver (Fig. 4). These CT scan results led to a reevaluation of the chest radiograph initially obtained in the emergency department, and the malformation that was previously thought to be an
infiltrate was correctly identified (Fig. 5).

The cause of this patients stroke is probably a

paradoxical embolism through the intrapulmonary shunt created by the pulmonary arteriovenous malformation. This finding prompts reconsideration of the echocardiographic findings.
The reportedly positive bubble study may indicate
a right-to-left shunt through a pulmonary arteriovenous malformation rather than through an
atrial septal defect or a patent foramen ovale (see
Video). Typically, with an intracardiac shunt, as
One week into her hospital course, the patient be- with a patent foramen ovale, the bubbles are seen
gan to have a persistent fever. Physical examina- on the left side of the heart within three beats of
n engl j med 362;22 nejm.org june 3, 2010

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A video of an
echocardiogram
showing bubbles
suggestive of an
intrapulmonary
shunt is available
at NEJM.org

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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 angiography and chest radiography confirmed the occlusion of the vessels leading to the malformation.
Subsequent discussions with the family disclosed that the patients uncle had also had an
arteriovenous malformation. Thus, she met the
criteria for a clinical diagnosis of hereditary hemorrhagic telangiectasia: epistaxis, a visceral arteriovenous malformation, and a family history.
Genetic testing confirmed the diagnosis of hereditary hemorrhagic telangiectasia type 2 on the basis of a missense mutation produced by a base-pair
Figure 5. Chest Radiograph Showing the Pulmonary
substitution in the gene encoding activin-recepArteriovenous Malformation.
torlike kinase 1 (ALK1). Testing of the patients
After a review of the CT scan of the torso, the chest
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 minireading 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- patients children, should be screened for cerecations include hypoxemia, hemoptysis, and hemo brovascular malformations is a matter of controthorax.
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 telangiC 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 paformations. The clinical diagnosis of hereditary tients 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-conspontaneous epistaxis; mucocutaneous telangi- trolled trial1 and a meta-analysis,2 as well as unectasias; 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 encases be confirmed through genetic testing.
dorsed this new time window.4 In addition, various 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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When an ischemic stroke occurs in a young

patient without the traditional vascular risk factors, alternative causes must be considered. In
retrospect, several clues could have expedited the
correct diagnosis of this patients 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 patients chest radiograph. Whereas aspiration pneumonia is common in patients with stroke, both
the shape and the location of the lesion were, in
retrospect, not typical of this diagnosis. Consideration of an alternative cause of the radiographic abnormality might have prompted earlier use of chest CT, which ultimately revealed
the arteriovenous malformation. Findings on the
echocardiographic bubble study, initially interpreted as consistent with an atrial septal defect
or a patent foramen ovale, were only later recognized 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 malformation is present in 30 to 75% of patients with
hereditary hemorrhagic telangiectasia, depending 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 established, 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 approximately 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 arteriovenous 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 malformations may have neurologic sequelae. Complications of paradoxical emboli include cerebral

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 percutaneous embolization. In 4 to 23% of patients
with hereditary hemorrhagic telangiectasia, arteriovenous malformations are also present in the
brain, where they have the potential to rupture.12,13 Approximately 10% of patients with
hereditary hemorrhagic telangiectasia die prematurely 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 identified cranial abnormalities, consensus guidelines from the Hereditary Hemorrhagic Telangiectasia Foundation International recommend
screening for pulmonary arteriovenous malformations in all patients with hereditary hemorrhagic telangiectasia, since these lesions can be
treated.7,9 The optimal screening test is controversial. Chest radiographs and blood oxygen
measurements are insensitive. Contrast echocardiography 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 excellent test but requires ionizing radiation.
Patients who present with signs and symptoms suggestive of hereditary hemorrhagic tel
angiectasia, as well as family members of patients in whom the disorder is diagnosed, should
undergo genetic screening. Heterozygous mutations in five different genes that encode components of the transforming growth factor signaling pathway involved in blood-vessel development
have been associated with hereditary hemorrhagic telangiectasia.9 However, genetic testing
has false negative results in 75 to 92% of patients who have whole-exon deletions and insertions or mutations in regulatory regions or in
unknown genes.15 Patients who have positive
test results or whose clinical presentation suggests 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.

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References
1. Hacke W, Kaste M, Bluhmki E, et al.

Thrombolysis with alteplase 3 to 4.5 hours

after acute ischemic stroke. N Engl J Med
2008;359:1317-29.
2. Hacke W, Donnan G, Fieschi C, et al.
Association of outcome with early stroke
treatment: pooled analysis of ATLANTIS,
ECASS, and NINDS rt-PA stroke trials.
Lancet 2004;363:768-74.
3. Wahlgren N, Ahmed N, Dvalos A,
et al. Thrombolysis with alteplase 3-4.5 h
after acute ischaemic stroke (SITS-ISTR):
an observational study. Lancet 2008;372:
1303-9.
4. del Zoppo GJ, Saver JL, Jauch EC, Adams
HP Jr. Expansion of the time window for
treatment of acute ischemic stroke with
intravenous tissue plasminogen activator:
a science advisory from the American
Heart Association/American Stroke Association. Stroke 2009;40:2945-8.
5. Nanthakumar K, Graham AT, Robinson TI, et al. Contrast echocardiography for
detection of pulmonary arteriovenous malformations. Am Heart J 2001;141:243-6.

6. Zukotynski K, Chan RP, Chow CM,

Cohen JH, Faughnan ME. Contrast echo

cardiography grading predicts pulmonary
arteriovenous malformations on CT. Chest
2007;132:18-23.
7. Guttmacher AE, Marchuk DA, White
RI. Hereditary hemorrhagic telangiectasia.
N Engl J Med 1995;333:918-24.
8. Cottin V, Dupuis-Girod S, Lesca G,
Cordier JF. Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler disease). Respiration
2007;74:361-78.
9. Bayrak-Toydemir P, McDonald J,
Markewitz B, et al. Genotype-phenotype
correlation in hereditary hemorrhagic
tela ngiectasia: mutations and manifestations. Am J Med Genet A 2006;140:46370.
10. Saluja S, Henderson KJ, White RI Jr.
Embolotherapy in the bronchial and pulmonary circulations. Radiol Clin North
Am 2000;38:425-48.
11. Shovlin CL, Letarte M. Hereditary
haemorrhagic telangiectasia and pulmo-

nary arteriovenous malformations: issues

in clinical management and review of
pathogenic mechanisms. Thorax 1999;54:
714-29.
12. Maher CO, Piepgras DG, Brown RD Jr,
Friedman JA, Pollock BE. Cerebrovascular
manifestations in 321 cases of hereditary
hemorrhagic telangiectasia. Stroke 2001;
32:877-82.
13. Fulbright RK, Chaloupka JC, Putman
CM, et al. MR of hereditary hemorrhagic
telangiectasia: prevalence and spectrum
of cerebrovascular malformations. AJNR
Am J Neuroradiol 1998;19:477-84.
14. Brady AP, Murphy MM, OConnor TM.
Hereditary haemorrhagic telangiectasia:
a cause of preventable morbidity and mortality. Ir J Med Sci 2009;178:135-46.
15. Lenato GM, Lastella P, Di Giacomo
MC, et al. DHPLC-based mutation analysis
of ENG and ALK-1 genes in HHT Italian
population. Hum Mutat 2006;27:213-4.
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clinical problem-solving series

The Journal welcomes submissions of manuscripts for the Clinical Problem-Solving

series. This regular feature considers the step-by-step process of clinical decision
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