“Economy Class”
`stroke syndrome?
`
`Brief Communications
`
`Abstract—The authors report three cases of ischemic stroke in young adults
`that occurred during or after an airplane flight. Workup was negative for any
`cause of stroke other than the presence of a patent foramen ovale (PFO).
`There is an increasing awareness of deep vein thrombosis and pulmonary
`embolism occurring in relation to long flights. Individuals with a PFO under
`these circumstances may be vulnerable to stroke from paradoxic embolism.
`“Economy class” stroke syndrome may be underdiagnosed and is an emi-
`nently preventable cause of stroke.
`NEUROLOGY 2002;58:960–961
`
`Y. Isayev, MD; R.K.T. Chan, MBBS, MRCP(UK); and P.M. Pullicino, MD, PhD
`
`An association between air travel and thromboembo-
`lism was first recognized in 1988 and was named the
`“economy class syndrome.”1 Multiple subsequent re-
`ports have confirmed the link between long flights
`and deep vein thrombosis (DVT) and pulmonary embo-
`lism (PE). We are aware of only one report of embolic
`stroke related to an air flight in a patient with a patent
`foramen ovale (PFO).2 In the last 2 years, we have seen
`3 patients younger than 50 years of age in whom ische-
`mic stroke occurred in relation to air travel and all had
`a PFO.
`Case report. Case 1. Four hours into a 12-hour
`flight from Tokyo, a healthy 46-year-old right-handed
`man developed sudden right visual loss while straining
`in the bathroom. Neurologic examination showed a right
`homonymous hemianopia. An MR scan of the brain
`showed infarction in the territory of the left posterior
`cerebral artery. An MR angiogram was normal. A trans-
`esophageal echocardiogram revealed a PFO with a right-
`to-left shunt detected on Valsalva maneuver. The results
`of lower limb venous Doppler performed 7 days after the
`event were negative. The patient was administered warfa-
`rin sodium. Twelve months after the stroke the patient
`still has a right homonymous hemianopia.
`Case 2. An athletic 46-year-old man developed sudden
`shortness of breath and left-sided weakness as he reached
`for his luggage in the overhead compartment at the end of
`a 14-hour flight. He had not gotten up from his seat during
`the flight. On examination he had a right gaze preference,
`left visual hemineglect, and a left hemiplegia. He received
`IV tissue plasminogen activator. A brain MR scan revealed
`a large infarct involving the territory of the inferior divi-
`sion of the middle cerebral artery. The results of MR angio-
`gram and a conventional cerebral angiogram were normal.
`A transesophageal echocardiogram revealed a small PFO
`
`From the Department of Neurology (Drs. Isayev and Chan), State Univer-
`sity of New York at Buffalo; and Department of Neurosciences (Dr. Pul-
`licino), New Jersey Medical School, Newark.
`Received June 29, 2001. Accepted in final form December 6, 2001.
`Address correspondence and reprint requests to Dr. Patrick M. Pullicino,
`Department of Neurosciences, New Jersey Medical School, Medical Science
`Building, 185 S. Orange Avenue, MSB-H506, Newark, NJ 07103-2714.
`
`960 Copyright © 2002 by AAN Enterprises, Inc.
`
`with a right-to-left shunt detected during the Valsalva ma-
`neuver. A venous Doppler of the low extremities performed
`7 days after the stroke was normal. The patient improved
`greatly with almost complete resolution of his deficits. He
`continues to be treated with long-term anticoagulation.
`Case 3. A healthy 41-year-old white woman developed
`sudden left-sided hearing loss, transient vertigo, and left-
`sided facial numbness 12 hours after a flight. She was a
`passenger on 2 flights of approximately 90 minutes each
`separated by 6 hours of sitting in a transit lounge. The
`second flight was in a cramped and poorly pressurized
`propeller aircraft. On examination she had complete left-
`sided hearing loss confirmed by an audiogram. She had
`slight sensory loss to pinprick around her mouth on the
`left. The rest of the neurologic examination was normal.
`Cerebral MRI revealed a small acute infarct in the left
`caudolateral pons in the region of the vestibulocochlear
`nucleus. Magnetic resonance angiography showed a rele-
`vant vascular occlusion. TEE revealed a large PFO. She
`was administered warfarin but had persisting deafness on
`the left side.
`All patients were healthy, nonsmoking, nonobese indi-
`viduals with no vascular risk factors and no significant
`medical history. Results of laboratory workup including
`protein C, protein S, factor V mutation, anti-thrombin III,
`lupus anticoagulant, anti-cardiolipin antibody, homocys-
`teine level, antinuclear antibodies, and sedimentation rate
`were normal in all three patients. The third patient also
`had normal factors VIII, IX, and XI.
`The first two patients were optimally anticoagulated
`with IV heparin at the time of lower limb venous Doppler
`study.
`
`Discussion. Paradoxic embolism through a PFO
`appears the most plausible cause of stroke in our
`patients. The history and MRI findings were highly
`suggestive of cerebral embolism, and investigation
`did not detect any other potential cause for stroke,
`other than PFO. Two of the three patients performed
`physical activity likely to produce a Valsalva maneu-
`ver just before the onset of stroke symptoms. The
`failure to demonstrate a DVT does not necessarily
`diminish the likelihood of paradoxic embolism.3 It
`has been suggested that the presence of PFO alone is
`
`MYLAN - EXHIBIT 1011
`
`

`

`sufficient to implicate paradoxic embolism as the
`cause of stroke among young patients with crypto-
`genic stroke because of the high frequency of PFO in
`this group of patients.4 This is particularly true if the
`intra-atrial defect is large5 or if a Valsalva maneuver
`occurred before or at the onset of the symptoms.
`Optimal long-term management of patients with
`PFO-associated stroke is unclear. Antiplatelet ther-
`apy, anticoagulation, or repair of septal defect are
`considered acceptable treatment options.4,5 We chose
`anticoagulation rather than the other options be-
`cause all our patients are professionals who might be
`at increased risk for DVT because their frequent
`business-related air travel, and two of the three pa-
`tients declined surgical intervention.
`Cases of PE and DVT occurring during or after
`long flights have been reported with increasing
`frequency.1,2,6-9 In 1986, a report observed that over a
`3-year period, PE was the second most common
`cause of sudden death among long-distance air trav-
`elers.10 Two recent prospective studies found that
`4.5% and 10% of passengers developed DVT after
`prolonged flights.6,7 In the case of pulmonary embo-
`lism, a traveling distance of 5000 km or more was a
`significant contributing factor.9
`Individuals who have a PFO and develop DVT are
`theoretically at risk for stroke due to paradoxic em-
`bolism. PFO characteristics such as size and the oc-
`currence of Valsalva maneuver at the time a clot is
`in the right atrium also are important determinants
`for stroke. The prevalence of PFO in the general
`population ranges between 17% and 35%, but is
`greater among young adults with unexplained (cryp-
`togenic) stroke (54–56%).4 Given this high preva-
`lence of PFO and the occurrence of DVT and PE in
`air travelers, a proportion of air travelers is likely to
`be at risk for paradoxical embolism. Prolonged sit-
`ting in a small, confined space during a flight is
`probably the most important cause of venous stasis,
`which predisposes to DVT and PE. Additional cabin-
`related risk factors for hypercoagulability include de-
`hydration, low humidity, relative hypoxia/low air
`pressure, and in-flight alcohol consumption. We have
`called this syndrome “economy class stroke syn-
`drome” to emphasize that cramped seating condition
`is an important risk factor. However, DVT/PE also
`has been described in passengers flying in the busi-
`ness or first class cabin.
`Little is known about the frequency and risk fac-
`tors for stroke during or after air travel. The only
`
`prior report mentioned three patients with ischemic
`stroke that occurred in relation to air travel. Only
`one of these patients had a PFO and DVT; the other
`two patients had other potential stroke risk factors.2
`As air travel increases worldwide, physicians should
`be aware of the potential association between stroke
`during or after prolonged air travel and PFO. It may
`be possible to prevent stroke from paradoxic embo-
`lism in passengers with PFO by preventing the de-
`velopment of DVT. The simplest ways are adequate
`hydration, alcohol avoidance, and frequent, regular
`exercise of lower extremities, although the effective-
`ness has yet to be proven.1,6-9 Using compression
`stockings has been effective in preventing asymp-
`tomatic DVT.6,7 Passengers who are at high risk for
`developing DVT may require additional measures in-
`cluding aspirin or preventive subcutaneous heparin.8
`Screening for PFO may be considered among fre-
`quent flyers who had prior DVT or have a high risk
`for DVT. Further research is needed to determine
`the frequency and risk factor for stroke related to air
`travel.
`
`References
`1. Cruickshank JM, Gorlin R, Jennett B. Air travel and throm-
`botic episodes: the economy class syndrome. Lancet 1988;2:
`497–498.
`2. Beighton PH, Richards PR. Cardiovascular disease in air trav-
`elers. Br Heart J 1968;30:367–372.
`3. Cerebral Embolism Task Force. Cardiogenic brain embolism.
`The second report of the Cerebral Embolism Task Force. Arch
`Neurol 1989;46:727–743.
`4. Albers GW, Amarenco P, Easton JD, Sacco R, Teal P. Anti-
`thrombotic and thrombolytic therapy for ischemic stroke.
`Chest 2001;119(suppl):300S–320S.
`5. Nendaz MR, Sarasin FP, Junod AF, Bogusslavsky J. Prevent-
`ing stroke recurrence in patients with patent foramen ovale:
`antithrombotic therapy, foramen closure or therapeutic ab-
`stention? A decision analytic perspective. Am Heart J 1998;
`135:532–541.
`6. Scur JH, Machin SJ, Baily-King S, Mackie IJ, McDonald S,
`Smith PD. Frequency and prevention of symptomless deep-
`vein thrombosis in long-haul flights: a randomized trial. Lan-
`cet 2001;357:1461–1462.
`7. Belkaro G, Geroulakos G, Nicolaides A, Myers K, Winford M.
`Venous thromboembolism from air travel. The LONFLIT
`study. Angiology 2001;52:369–374.
`8. Eklof B, Kistner RL, Masuda EM, Sonntag BV, Wong HP.
`Venous thromboembolism in association with prolong air
`travel. Dermatol Surg 1996;22:637–641.
`9. Lapostolle F, Surget V, Borron SW, et al. Severe pulmonary
`embolism associated with air travel. N Engl J Med 2001;345:
`779–783.
`10. Sarvesvaran R. Sudden natural deaths associated with com-
`mercial air travel. Med Sci Law 1986;26:35–38.
`
`March (2 of 2) 2002 NEUROLOGY 58 961
`
`

`

`''Economy Class'' stroke syndrome?
`Y. Isayev, R. K.T. Chan and P. M. Pullicino
`2002;58;960-961
`Neurology 
`DOI 10.1212/WNL.58.6.960
`
`This information is current as of March 26, 2002
`
`Updated Information &
`Services
`
`including high resolution figures, can be found at:
` http://www.neurology.org/content/58/6/960.full.html
`
`
`References
`
`Citations
`
`Subspecialty Collections
`
`This article cites 9 articles, 1 of which you can access for free at:
`
` http://www.neurology.org/content/58/6/960.full.html##ref-list-1
`
`This article has been cited by 8 HighWire-hosted articles:
` http://www.neurology.org/content/58/6/960.full.html##otherarticles
`
`
`
`This article, along with others on similar topics, appears in the
`following collection(s):
`All Cerebrovascular disease/Stroke
`http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_s
` troke
`
`Embolism
` http://www.neurology.org//cgi/collection/embolism
`Infarction
` http://www.neurology.org//cgi/collection/infarction
`
`
`
`
`
`Permissions & Licensing
` 
`
`Information about reproducing this article in parts (figures,tables) or in
`its entirety can be found online at:
`http://www.neurology.org/misc/about.xhtml#permissions
`
`
`
`Reprints
` 
`
`Information about ordering reprints can be found online:
`
` http://www.neurology.org/misc/addir.xhtml#reprintsus
`
`® is the official journal of the American Academy of Neurology. Published continuously since
`Neurology 
`1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878.
`Online ISSN: 1526-632X.
`
`