CASE REPORTS

Presumptive Subdural Empyema in a Dog Taemi Horikawa, DVM, Edward MacKillop, DVM, DACVIM (Neurology), Anne Bahr, MS, DVM, DACVR

ABSTRACT A 13 mo old mixed-breed dog was referred for acute lateralized forebrain signs. MRI of the brain demonstrated abnormalities consistent with severe meningitis and subdural empyema secondary to a retrobulbar abscess. The dog’s clinical signs improved with antibiotic therapy, and repeat imaging showed resolution of subdural fluid accumulation presumed to be empyema with mild residual meningeal enhancement. Subdural empyema is an infrequent cause of encephalopathy in small animals and usually develops through direct extension of a pericranial infection. This report presents a case of presumptive subdural empyema in a dog that was successfully treated without surgical intervention. MRI is the preferred imaging modality for diagnosis of subdural empyema, and the characteristic imaging features are described. (J Am Anim Hosp Assoc 2014; 50:291– 295. DOI 10.5326/JAAHA-MS-6030)

Introduction

The purpose of this report is to describe a case of subdural

Subdural empyema is a focal collection of purulent material be-

empyema that was successfully treated with antibiotics after a pre-

tween the dura mater and the arachnoid mater. While spinal

sumptive diagnosis was made based on the clinical presentation and

empyema is usually epidural, intracranial empyema is most

characteristic imaging features.

commonly subdural due to the limited epidural space in the cranial cavity.1–9 Subdural empyema has been infrequently reported in

Case Report

small animals (six reports in cats and one report in a dog), with

A 13 mo old castrated male golden retriever/standard poodle

an extremely high mortality rate.7–9 Of the veterinary reports re-

mixed-breed dog was referred for progressive encephalopathy. The

garding subdural empyema, only one cat was successfully treated

dog had been treated with a 7 day course of amoxicillin trihydrate/

and was doing well at the time of follow-up 4 yr later.9 In that

clavulanate potassium (16.7 mg/kg per os [PO] q 12 hr) and

case, the diagnosis was made via MRI and decompressive cra-

meloxicam (0.1 mg/kg PO q 24 hr) for a possible tooth root

niectomy followed by cytology and culture.9 In all other veter-

abscess approximately 6 wk earlier. Clinical signs of oral pain

inary reports, the diagnosis had been confirmed via postmortem

improved but recurred 3 wk after finishing antibiotics. Thus,

examination.7–9

a longer course (2 wk) of antibiotics was prescribed. Despite

Although uncommon in people, subdural empyema has been

antibiotics, the clinical signs continued to progress. The dog de-

extensively described in the human medical literature. Subdural

veloped a fever (40.6 C), left-sided facial swelling, exophthalmos,

empyema is a progressive, fatal disease in humans if left untreated;

and mucopurulent to serosanguinous discharge from the left eye.

however, the mortality rate has significantly decreased with the

The patient was given IV fluids and subcutaneous buprenorphine

10

introduction of antibiotics. MRI is the preferred modality for the

and enrofloxacin at another hospital before being referred for

diagnosis of subdural empyema in people.10,11 Decompressive sur-

additional diagnostics. The dog was previously healthy with no

gery and culture are considered the gold standard in management

significant medical history and was up-to-date on vaccines and

of either intracranial or spinal subdural empyema in human cases.10

flea and heartworm preventative medications.

From the Animal Eye Center, Rocklin, CA (T.H.); Pittsburgh Veterinary Specialty and Emergency Center, Pittsburgh, PA (E.M.); and PetRays Veterinary Radiology Consultants, The Woodlands, TX (A.B.).

CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; FLAIR, fluidattenuated inversion recovery; PO, per os; T1W, T1-weighted; T2W, T2-weighted; T2*W, T2*-weighted gradient echo

Correspondence: [email protected] (T.H.)

ª 2014 by American Animal Hospital Association

JAAHA.ORG

291

At the time of referral, body temperature was slightly elevated (39.1 4C); the dog was painful on oral examination, but no abnormalities were noted; both globes retropulsed normally; and the dog was alert but mentally inappropriate and intermittently head pressed. Gait was considered normal; however, there was a compulsive tendency to circle to the left. Postural reactions were significantly delayed in the right thoracic and pelvic limbs with equivocal deficits on the left side. Neuroanatomic localization was the left prosencephalon. The differential diagnoses for neurologic signs included meningoencephalitis, neoplasia (primary brain tumor or round cell tumor), and either intracranial or brain malformation. Retrobulbar abscess (secondary to direct penetrating injury, tooth root abscess, or hematogenous spread), orbital cellulitis, and orbital tumor were considered for the etiology of ocular signs.

FIGURE 1

Transverse MRIs through the forebrain of a dog with

clinical signs of progressive encephalopathy, fever, left-sided facial

Diagnostics Initial Diagnostics Complete blood count, serum biochemical profile, and thoracic

swelling, and left ocular discharge. A: T2W image (repetition time [TR], 5617 msec; echo time [TE], 102 msec) shows a hyperintense accumulation in the left subdural space (white arrowheads), which

radiographs were unremarkable. Schirmer tear test revealed de-

is incompletely suppressed with mild heterogeneity on (B) FLAIR-

creased tear production bilaterally.

weighted image (TR, 8802 msec; TE, 133 msec). Contrast-enhancing

Advanced Imaging MRI of the brain was performed using a 1.0 T magneta. The study

rim surrounding the accumulation (white arrowheads) is seen on T1W images both (C) pre-IV contrast medium administration (TR, 400 msec; TE, 14 msec) and (D) post-IV contrast medium administration

was comprised of transverse T1-weighted (T1W), transverse and

(TR, 400 msec; TE 14 msec). Falcine shift (black arrowheads) due to

sagittal T2-weighted (T2W), transverse T2*-weighted (T2*W), and

the mass effect of the subdural fluid is apparent on all images.

transverse fluid-attenuated inversion recovery (FLAIR) images of the head. T1W images were obtained in the transverse, sagittal, and dorsal plane following IV contrast administration (gadopentetate

a similar accumulation of fluid between the olfactory bulbs with

dimeglumine) . There was a large collection of T2 hyperintense

equally intense enhancement of the meninges (Figure 2A). An ill-

signal (maximally 3 mm) along the surface of the entire left cere-

defined mass that was hyperintense on T2W images and hypointense

brum (Figure 1A), causing compression of the ipsilateral ventricle,

on T1W images was noted in the retrobulbar space adjacent to the

falcine shift to the right, and transtentorial brain herniation; the

calvaria. The periphery of the mass enhanced following contrast

majority of the signal did not suppress on FLAIR images (Figure

administration (ring enhancement) with confluent enhancement of

1B). The fluid accumulation was slightly hyperintense to ventricular

the orbital bone and meninges, suggesting a retrobulbar abscess with

cerebrospinal fluid (CSF) and hypointense compared to white or

intracranial extension (Figure 2A). A small amount of gravity-

gray matter on T1W images (Figure 1C). On T2W and FLAIR

dependent fluid was present within the left frontal sinus. Post-

images, there was an increase in conspicuity of sulci along the left

contrast, there was a slight enhancement of the lining of the sinus

cerebrum potentially due to sulcal widening or meningeal hyper-

indicating sinusitis. The MRI findings indicated a marked left-sided

intensity. No abnormal signal void was noted on T2*W images.

subdural fluid accumulation along the cerebrum and between the

Following contrast medium administration, there was marked en-

olfactory bulbs, pronounced meningitis around the subdural fluid

hancement of the meninges adjacent to the left cerebrum and be-

accumulation, sinusitis, and retrobulbar fluid accumulation with

tween the hemispheres. Within the meninges over the left

secondary exophthalmos. The presumptive diagnosis was subdural

cerebrum, there was an isointense region on T1W images that did

empyema secondary to a retrobulbar abscess.

b

not enhance with contrast, suggesting an intrameningeal collection of cell/protein-rich fluid (Figure 1D). The fluid was considered

CSF Analysis

subdural in location based on its appearance as a crescent con-

Following the MRI, mannitolc (0.5 g/kg) was administered IV

forming to the surface of the entire left cerebrum. There was

and CSF was collected from the cerebellomedullary cistern.

292

JAAHA |

50:4 Jul/Aug 2014

Presumptive Subdural Empyema in a Dog

with mild hyperostosis of the calvaria adjacent to the prior abscess (Figure 2B). CSF analysis with cytology was normal. Based on the imaging findings, clindamycin was continued for 6 additional wk (4 mo total). The dog was reexamined at 6 and 9 mo and was doing well with no signs of recurrence or sequelae.

Discussion Previous reports of subdural empyema in the veterinary literature are very limited, with six reports in cats and one report in a dog.7–9 MRI findings have been described in three of those cats but not in a dog.8,9 In one cat, the diagnosis of subdural empyema based on FIGURE 2

Dorsal plane T2W MRIs (A) before (TR, 417 msec;

MRI characteristics was confirmed by decompressive craniectomy

TE, 14 msec) and (B) 10 wk after (TR, 367 msec; TE, 10 msec)

followed by cytology and culture.9 All other cases were euthanized

initiating medical treatment of presumptive subdural empyema. A:

due to progressive neurologic dysfunction, and diagnosis was

This MRI shows subdural accumulation with intense meningeal

established by postmortem examination.7–9 Foramen magnum

enhancement adjacent to the left cerebrum and between the left

brain herniation was identified on MRI in one cat and necropsy in

olfactory bulb and the falx (white arrowheads). A focal region of

three other cases.7–9

mass effect outlined by hyperintensity (white arrows) in the left

On MRI, subdural fluid collections are usually found spread

retrobulbar tissue with a mild exophthalmos on the left is also seen.

widely over the convexities and interhemispherically.9,10,12 In gen-

B: Ten weeks later, the majority of the subdural fluid accumulation is

eral, epidural fluid accumulations tend to be either biconvex or

resolved with only a mild residual contrast enhancement (white

lentiform, whereas subdural fluid tends to be crescent-shaped.13,14

arrow) of the left retrobulbar tissue. Resolution of the left exoph-

Unlike epidural fluid accumulation, subdural fluid can cross suture

thalmos is also apparent.

lines due to lack of dural tethering by the cranial sutures.12–14 The intracranial subdural space is lined by a single layer of endothe-

Cerebrospinal fluid analysis showed a normal number of WBCs

lial cells where it is bounded by the dura mater externally and the

(4/mm3; reference range, , 5/mm3) with a marginal increase in

arachnoid internally, with no septations other than where the

protein (28.8 mg/dL; reference range, , 25 mg/dL) and an increased

arachnoid granules are imbedded in the dura.15 Because the sub-

percentage of neutrophils (42%).

dural potential space is not restricted by the cranial sutures, subdural fluid accumulations may extend over an entire cerebral

Treatment and Outcome

hemisphere. They are, however, limited by the falx cerebri and d

The patient was started on IV antibiotics (45 mg/kg cefotaxime IV

tentorium cerebelli and do not cross the midline because of the

q 8 hr) and an anti-inflammatory dose of dexamethasonee (0.25

meningeal reflections.12–15 Empyema appears slightly hyperintense

mg/kg IV q 24 hr). Artificial tear ointmentf oculus uterque q 8 hr

to CSF and hypointense relative to brain parenchyma on T1W

was used to address decreased tear production. There was a sig-

images and either iso- or hyperintense relative to CSF on T2W

nificant improvement in mentation and postural reactions after

images.9–12,16 In contrast, sterile subdural effusion is isointense to

48 hr. The dog was subsequently switched to oral antibiotics (14.5

CSF on both T1W and T2W images, and chronic subdural he-

g

h

mg/kg clindamycin PO q 12 hr and 8.8 mg/kg enrofloxacin PO q

matoma is isointense to brain parenchyma in T2W images.17 The

i

MRI findings in the current case were consistent with what is seen

(1 mg/kg/day PO for 1 day, 0.67 mg/kg/day for 2 days, and 0.33

in humans; however, some areas of fluid accumulation on T2W

mg/kg/day for 2 days). During examination (approximately 2 wk

images were hypointense relative to CSF rather than iso- or hy-

after discharge from the hospital), neurologic deficits had re-

perintense. That may be due to heterogeneity of the purulent

solved. Enrofloxacin was discontinued after 1 mo, and clinda-

material with variability in the protein and cellular constituents of

mycin was continued as the sole treatment. MRI of the brain was

the fluid. The fluid in subdural empyema is typically surrounded by

repeated 10 wk after the initial study to help direct long-term

a contrast-enhancing rim, which is due to formation of a mem-

antibiotic therapy. There was complete resolution of subdural

brane of granulomatous tissue on the leptomeninges and inflam-

fluid accumulation and only a very mild residual enhancement of

mation in the adjacent cerebral cortex.9,10,12 A chronic subdural

the meninges and the retrobulbar tissue was noted on the left side,

hematoma in a dog with ceroid lipofuscinosis was also found to

24 hr) in combination with a 5 day tapering course of prednisone

JAAHA.ORG

293

have marked enhancement of the meninges; however, subdural

cephalosporin along with a more limited capacity for penetra-

hematoma is readily distinguished from empyema by the presence

tion into the central nervous system and was, therefore, not

15

Diffusion-weighted imaging

considered adequate for treatment of an intracranial infection.22 A

(DWI) may be valuable in evaluating a subdural fluid collection.

combination of clindamycin and enrofloxacin was chosen for oral

Similar to brain abscess, empyema has high signal on DWI, most

therapy because both drugs cross the blood-brain barrier and,

likely because the high viscosity of the purulent fluid restricts

when administered together, provide excellent broad-spectrum

of signal void on T2*W images.

12,16,17

proton mobility.

The apparent diffusion coefficient map

antimicrobial activity. Enrofloxacin was discontinued after 1 mo

usually shows decreased diffusion, seen as low signal intensity,

because an aerobic gram-negative bacterial infection was consid-

within empyemata.11,16 Subdural hematoma may also appear as an

ered less likely based on previous veterinary case reports.7–9 Clin-

area of high signal on DWI, although signal void on T2*W images is

damycin was chosen for long-term antibiotic therapy due to its

12,16,17

seen in hematomas but not empyemata.

Sterile subdural ef-

affordability and activity against gram-positive bacteria and an-

fusion tends to have low signal on DWI similar to that of CSF.12,16,17

aerobes. Subdural fluid presumed to be empyema had resolved on

In the current case, presumptive diagnosis of subdural empyema

MRI after 10 wk of antibiotic therapy; however, there was mild

was based on characteristic MRI features and supported by positive

meningeal enhancement and hyperostosis of the calvaria. It was

clinical response to antibiotic therapy and resolution on subsequent

unclear if those changes represented either mild osteomyelitis/

imaging. A very mild neutrophilic pleocytosis was consistent with

meningitis or were reactive to prior infection; therefore, clinda-

localization of infection primarily outside of the subarachnoid space.

mycin was continued for an additional 6 wk. The total length of

Decompressive craniectomy for meningeal culture and lavage was

treatment was 4 mo, which is comparable to treatment times re-

considered because that is the treatment of choice in humans;

ported in human cases of subdural empyema that were successfully

however, the owner of the dog had reservations about the cost and

treated with medical therapy alone.23 The length of therapy was also

risks associated with cranial surgery. In veterinary cases, surgical

comparable to the minimum recommended treatment time for

treatment may not be pursued due to client concern regarding

other forms of bacterial osteomyelitis (e.g., vertebral osteomyelitis,

the invasiveness of the procedure and associated risks, unavailability

diskospondylitis).23,24 MRI was not repeated after discontinuation

of appropriate equipment, and cost. In this case, decompressive

of clindamycin because of the cost of reimaging.

craniectomy was recommended because surgery tends to provide

Subdural empyema in humans typically develops as direct

a more predictable and favorable outcome in humans with sub-

extension of paranasal sinusitis or otitis media/interna, but other

dural empyema. Pending the client’s decision regarding surgery,

possible causes include hematogenous spread from distant sites,

the dog subsequently made a profound clinical response to anti-

cranial surgery, trauma, retrograde septic thrombophlebitis, or

biotics and craniectomy was, therefore, deemed unnecessary.

secondary infection of subdural effusion or hematoma.10,12

The most common bacteria associated with meningitis or

Common sources of infection in either meningitis or meningo-

meningoencephalitis in dogs and cats are Staphylococcus spp.,

encephalitis are similar to those implicated in subdural empyema

Pasteurella multocida, Nocardia spp., and Actinomyces spp., and

and include otitis interna, tooth root abscesses, retrobulbar ab-

18–20

various anaerobic species.

In contrast, cultures from subdural

scesses, and sinusitis; however, hematogenous spread from ex-

empyemata in prior veterinary case reports most commonly found

tracranial source such as endocarditis, pneumonia, and prostatitis

polymicrobial infection with at least one anaerobic bacteria

has also been reported.7–9,19,20 In cases of subdural empyema

7–9

(Fusobacterium spp., Bacterioides spp., and Actinomyces spp.).

secondary to sinusitis, the infection spreads intracranially through

Culture of CSF is rarely useful in identifying the causative agent for

thrombophlebitis of the emissary veins, which drain the external

bacterial meningoencephalomyelitis in dogs and cats.18 In this case,

skull into the dural sinuses.12 Direct extension of the infection

CSF culture was not submitted because of the marginal changes on

may also occur through the Haversian canals within bones of the

CSF analysis and the subdural location of infection.

skull. In small animals, subdural empyema developed secondary

Cefotaxime, a third-generation IV cephalosporin, was initially

to direct inoculation from a puncture wound in one cat and from

chosen because of its broad-spectrum activity against gram-

local extension from otitis media/interna in another cat.8,9 The

positive and gram-negative bacteria, including resistant bacterial

underlying etiology was undetermined in the remaining cases.7–9

21

In the current case, a retrobulbar abscess with intracranial

Cefpodoxime is the only third-generation cephalosporin with an

extension was considered the most likely source of intracranial in-

oral formulation available for use in small animals. Cefpodoxime

fection. Retrobulbar abscess can result from a penetrating injury,

has a spectrum of activity that resembles a first-generation

tooth root abscess, infections in sinuses or zygomatic glands, or

isolates, along with its capacity to cross the blood-brain barrier.

294

JAAHA |

50:4 Jul/Aug 2014

Presumptive Subdural Empyema in a Dog

hematogenous spread.25 There is limited literature on orbital infection with intracranial extension in animals. In a recent study of four dogs with evidence of orbital inflammation with intracranial extension on MRI, retrobulbar abscess was found in three of the four dogs, and thickened periorbital tissue with contrast enhancement was found in close anatomic relationship to cavernous sinus in two of the dogs.26 Intracranial extension of retrobulbar blastomycosis has also been reported in a dog in which infection followed the optic canal and orbital fissure into the ventral aspect of diencephalon.27 In humans, intracranial extension of orbital inflammation is most commonly established via the orbital fissure subsequently entering the middle cranial fossa and cavernous sinus.28,29 Sinusitis, which is the most common cause of subdural empyema in children, was noted in the current case, although the degree of sinusitis was very mild.10–12 Retrobulbar abscess with intracranial extension was considered more likely based on the confluence of enhancement between the retrobulbar space and meninges.

Conclusion This report describes the clinical presentation and MRI findings of presumptive subdural empyema in a dog with resolution following antibiotic therapy. FOOTNOTES a General Electric 1.0T Signa; GE Healthcare, Milwaukee, WI b Magnevist; Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ c ManniJect 20%; Nova-Tech Inc., Grand Island, NE d Cefotaxime; West-Ward Phamaceutical Corp., Eatontown, NJ e DexaJect; Bimeda-MTC Animal Health Inc., Cambridge, ON, Canada f Artificial tears ointment; Rugby Laboratories Inc., Duluth, GA g Clindamycin HCl; Lannett Company Inc., Philadephia, PA h Baytril; Bayer HealthCare LLC, Shawnee Mission, KS i Prednisone; West-Ward Phamaceutical Corp., Eatontown, NJ REFERENCES 1. Dewey CW, Kortz GD, Bailey CS. Spinal epidural empyema in two dogs. J Am Anim Hosp Assoc 1998;34(4):305–8. 2. De Stefani A, Garosi LS, McConnell FJ, et al. Magnetic resonance imaging features of spinal epidural empyema in five dogs. Vet Radiol Ultrasound 2008;49(2):135–40. 3. Lavely JA, Vernau KM, Vernau W, et al. Spinal epidural empyema in seven dogs. Vet Surg 2006;35(2):176–85. 4. Nykamp SG, Steffey MA, Scrivani PV, et al. Computed tomographic appearance of epidural empyema in a dog. Can Vet J 2003;44(9):729–31. 5. Granger N, Hidalgo A, Leperlier D, et al. Successful treatment of cervical spinal epidural empyema secondary to grass awn migration in a cat. J Feline Med Surg 2007;9(4):340–5. 6. Sutton A, May C, Coughlan A. Spinal osteomyelitis and epidural empyema in a dog due to migrating conifer material. Vet Rec 2010; 166(22):693–4.

7. Dow SW, LeCouteur RA, Henik RA, et al. Central nervous system infection associated with anaerobic bacteria in two dogs and two cats. J Vet Intern Med 1988;2(4):171–6. 8. Klopp LS, Hathcock JT, Sorjonen DC. Magnetic resonance imaging features of brain stem abscessation in two cats. Vet Radiol Ultrasound 2000;41(4):300–7. 9. Barrs VR, Nicoll RG, Churcher RK, et al. Intracranial empyema: literature review and two novel cases in cats. J Small Anim Pract 2007;48(8):449–54. 10. Agrawal A, Timothy J, Pandit L, et al. A review of subdural empyema and its management. Infect Dis Clin Pract 2007;15:149–53. 11. Kastrup O, Wanke I, Maschke M. Neuroimaging of infections. NeuroRx 2005;2(2):324–32. 12. Atlas SW, ed. Magnetic resonance imaging of the brain and spine. 4th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2009:978–80. 13. Weingarten K, Zimmerman RD, Becker RD, et al. Subdural and epidural empyemas: MR imaging. AJR Am J Roentgenol 1989;152(3): 615–21. 14. Parizel PM, Makkat S, Van Miert E, et al. Intracranial hemorrhage: principles of CT and MRI interpretation. Eur Radiol 2001;11(9):1770–83. 15. Dill SR, Cobbs CG, McDonald CK. Subdural empyema: analysis of 32 cases and review. Clin Infect Dis 1995;20(2):372–86. 16. Tsuchiya K, Osawa A, Katase S, et al. Diffusion-weighted MRI of subdural and epidural empyemas. Neuroradiology 2003;45(4):220–3. 17. Asakawa MG, MacKillop E, Olby NJ, et al. Imaging diagnosis— Neuronal ceroid lipofuscinosis with a chronic subdural hematoma. Vet Radiol Ultrasound 2010;51(2):155–8. 18. Radaelli ST, Platt SR. Bacterial meningoencephalomyelitis in dogs: a retrospective study of 23 cases (1990–1999). J Vet Intern Med 2002; 16(2):159–63. 19. Meric SM. Canine meningitis. A changing emphasis. J Vet Intern Med 1988;2(1):26–35. 20. Muñana KR. Encephalitis and meningitis. Vet Clin N Am Small Anim Pract 1996;26(4):857–74. 21. Nau R, Sörgel F, Eiffert H. Penetration of drugs through the bloodcerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010;23(4):858–83. 22. Abdel-Rahman SM, Maxson S, Teo C, et al. Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets. J Clin Pharmacol 2000;40(3):290–5. 23. Leys D, Destee A, Petit H, et al. Management of subdural intracranial empyemas should not always require surgery. J Neurol Neurosurg Psychiatry 1986;49(6):635–9. 24. Greene CE, ed. Infectious diseases of the dog and cat. 3rd ed. Philadelphia (PA): Saunders; 2006:828–33. 25. Gelatt KN. Veterinary ophthalmology. 4th ed. Ames (IA): Blackwell Publishing; 2007:542–3. 26. Kneissl S, Konar M, Fuchs-Baumgartinger A, et al. Magnetic resonance imaging features of orbital inflammation with intracranial extension in four dogs. Vet Radiol Ultrasound 2007;48(5):403–8. 27. Baron ML, Hecht S, Westermeyer HD, et al. Intracranial extension of retrobulbar blastomycosis (Blastomyces dermatitidis) in a dog. Vet Ophthalmol 2011;14(2):137–41. 28. de Jesús O, Inserni JA, Gonzalez A, et al. Idiopathic orbital inflammation with intracranial extension. Case report. J Neurosurg 1996;85(3):510–3. 29. Jain A, Rubin PA. Orbital cellulitis in children. Int Ophthalmol Clin 2001;41(4):71–86.

JAAHA.ORG

295