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CLINICAL REVIEWSAND UPDATESIN NEUROLOGYAND PSYCHIATRY. CNSNEWSONLlNE.COM SEPTEMBER2006 .Val. 8 NO.9

1

EDUCATIONALREVIEWIrritable

Bowel

Syndrome:The Brain-

Gut Axis;'

see pages 23-27

Splitting Headache Experts:

TheDebateOverMigraineSurgerySANDIEGo-Patients who suf-fer from chronic migrainessay they would do anythingto rid themselves of thepain-but heart surgery?

Arising from research instroke and cardiology, thecontroversial new approachis based on observations thatindividuals with the debilitat-ing headaches also oftenhave a small hole known as apatent foramen ovale (PFO)in the septum between theleft and right atria of theheart,I,2 and that surgical clo-sure of the opening (forother reasons) results infewer migraines. 2-4

Now, the first prospective,randomized, double-blind,placebo-controlled study spe-cifically looking at whetherclosure of such a hole canalleviate migraine is causing astir in neurology circles-butnot because it worked.

In the MIST (Migraine In-tervention with STARFlexTechnology) trial, which en-rolled 147 subjects at 13 different centers in theUnited Kingdom, migraine pain was completely elimi-nated in only six subjects-three of whom underwentthe real surgery and three from a control group thatunderwent a "sham procedure." The study was anunequivocal failure.

It generated more interest in the subject, however, aswas evident during a half-day course on PFO-which

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played out more like a debate-during the 2006 annuameeting of the American Academy of Neurology.

Pros, Cons and Dollar SignsProponents of the procedure say that complete elimi

nation of migraine pain (the treatment end point used irMIST) is unrealistic. Rather, they maintain, one shou1c

see SURGERY, page 30 ~

IThis might be interpreted as a half-full glassl which some might !fee as

a positive prompt to do more proceduresl without the perspective of

examining the full data. We all look forward to more studies. I

-Joel Saper, MD

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A Host of Theories, Potential Treatments

In developing fetuses, an opening in the septumbetween the left and right atria of the heart allowsblood to bypass the lungs, which are not used untilbirth. An opening that fails to close naturally shortlyafter birth is a PFO.Most cases of PFO as an isolatedfinding warrant no special intervention, but in thesetting of an otherwise unexplained neurologic

event, treatment includes antiplatelet and/or war-farin therapy to prevent cryptogenic stroke.

For individuals who suffer from recurrent cryp-togenic strokes, surgical closure of the PFO also is

50P=0.038

42%40 . Implant . Sham

30.-

20'-

10

0

PatientsWith 50% Reduction,%

MIST, Migraine Intervention With STARFlexTechnologyTrial

Figure 1. MIST:50% reductionin headachedays.

indicated. In the past, this entailed a risky, invasive,costly procedure, but more recently, catheter-baseddevices have been approved. Among them are theAmplatzer PFO Occluder, from AGA MedicalCorporation, in Golden Valley, Minn.; the CardioSEALSeptal Occlusion System, from NMT Medical; thePremere PFO Closure System, from Velocimed, inMinneapolis; the Sideris Buttoned Device, fromCustom Medical Devices, in Amarillo-;-Texas; and theGuardian Angel, from Microvena Corporation, inWhitebear Lake, Minn. STARFlex, the newer versionof CardioSEAL, is not yet approved .in the UnitedStates. It consists of two wire frameworks holdingpolyester fabric, which look like two tiny openumbrellas. Spring coils hold the device in place, withone umbrella on each side of the hole. Over time, thepatient's own tissue grows into and around the fab-ric and metal framework.

The two main theories behind the PFO-migrainelink are related to blood flow between the left andright atria, Dr. Mauskop said. "The first suggests thatan embolic event, facilitated by the right-to-Ieftshunt, triggers a migraine. The second theory propos-es that the right-to-left shunt permits certain vasoac-tive substances to access the brain because they arenot filtered out by the lungs, and these substances, a~yet uncharacterized, trigger a migraine."

h

Not a Cure, but Effective TreatmentIn previous observational studies, PFO closure wa~

associated with unexpected self-reports of an 80~decrease in migraines among stroke patients an<deep sea divers-who are prone to migraine:because of decreased ventilation. Other research, le(

MIGRAINE

[SURGERYcontinuedfrompage 1...

focus on the 42% of patients who had a 50% reduc-tion in headache, which was nearly double the num-ber of patients who had a similar response (23%) afterthe sham procedure (P=0.038).The opposition coun-ters by likening the MIST results to those of a 1958investigation into surgical treatment for angina. Inthat report, 68% of patients who underwent bilateralinternal mammary artery ligation, a procedure nowknown to be useless, reported a slight or moderatereduction in their angina.

The stakes are high, both for patients and for com-panies that stand to gain from a new application (thetechnology is approved for use in the prevention ofstroke) for devices that seal a PFO, like Boston-basedNMT Medical, which manufacturers the STARFlextranscatheter used in MIST. Migraine and PFO areextremely common in the general population, withestimated prevalence rates of 10% to 12% and 25% to30%, respectively.5 If all migraineurs with a PFObecame candidates for a surgical procedure, the mar-ket for the devices could expand to include millionsof people.

A potential connection between migraine andstroke has been studied in the past. What makes thenew approach so attractive-to the point wherephysicians are recommending a surgical procedurethat is not conclusively proven effective-is thepromise, some believe, of one procedure easingmigraine pain and also protecting the patient from astroke later in life.

"The concept that treating a patent foramen ovalemay relieve migraine as well as decrease the risk ofstroke in patients with migraine with aura is dramat-ic," said Alexander Mauskop, MD, director of the New

IYork Headache Center in New York City.

160 P=0.033136.1%

137%86.1%

116.8%120

80

40

0Implant

. Baseline. Analysis

MIST.Migraine Intervention With STARFlex Technology Trial

117%

f 96.3%

Sham

Figure 2. MIST:reduction in headache burden (frequency x duration).

by Vladimir Kummer, MD, a neurologist at the SarahNetwork of Rehabilitation Hospitals in Brasilia, Brazil,has described a greater prevalence of PFO in migrainewith aura than in other types of headaches. 5

"We have not done closing procedures to treatmigraine, Dr. Kummer said. "Most of these patientshave had good response to conventional migrainetreatments. We advise patients with PFO to avoidsmoking and hormonal contraception, and to watchtheir cholesterol and blood pressure."

The MIST trial, which was sponsored by NMTMedical along with two UK adovcacy groups, Mi-graine Action Association and Migraine in PrimaryCare Advisors, studied patients who had migrainewith aura, 74 of whom were randomized to percu-tanous endovascular closure with STARFlex and 73to the sham procedure. The subjects were found tobe six times more likely than the general populationto have large right-to-left shunts, most of whichwere considered PFOs. The results did not indicate

that PFO closure provides a complete cure formigraine, but they did show a mean reduction inheadache burden of 50 hours per month and a 50%reduction in headache in 42% of patients whounderwent the surgery.

Debate ContinuesWhether the association is causal or coincidental

remains unresolved.6 The Quality Standards Sub-committee of the American Academy of Neurologyconcluded that "there is insufficient evidence toevaluate the efficacy of surgical or endovascular clo-sure" (of a PFO to prevent recurrent stroke).7

The surgery is not without its complications. InMIST,6.8% of patients in the surgical group had seri-ous adverse events, some of which were life-threaten-ing. Even in the sham procedure group, 5.5% had aserious adverse event. Further, at 12 months, up to9% of the patients had a persistent PFO.

"The MIST data cannot rule in or rule out a treat-

ment effect of PFO on migraine with aura. If thereis an effect, it appears to be modest and no greaterthan seen with medical therapy like topiramate[Topamax, Ortho-McNeil] ,"said Robert Shapiro, MD,PhD, director of the Headache Clinic at theUniversity of Vermont College of Medicine inBurlington. "All these limitations make it difficult tomake one enthusiastic about these results. Off-label

closure of PFO solely for migraine prevention istotally unjustified. Phase III trials are needed."

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physicians have recommended percutaneous endo-vascular closure of PFO to their patients withmigraine. A recent survey revealed that cardiologistswere significantly more likely to recommend PFO clo-sure for migraine than were neurologists (P=0.01).8

"It is a disservice to everyone when a study thatcovers a large number of variables and outcomes pre-sents only selected data at one time point, some ofwhich is positive," commented Joel Saper, MD,founder and director of the Michigan Head-Pain andNeurological Institute, in Ann Arbor, Mich. "Thismight be interpreted as a half-full glass, which somemight see as a positive prompt to do more proce-dures, without the perspective of examining the fulldata. We all look forward to more studies."

At least three are currently recruiting (Sidebar),seeking out just those patients who would try any-thing-any thing-to beat a migraine.

-Andrew N Wilner, MD, FAAiY, FACPand Jennifer Kulpa

References

1. Reisman M, Christofferson RD,Jesumm J, et al. Migraineheadache relief after transcatheter closure of patent foramenovale.] Am Coil Cal'dio!. 2005;45:493-495.

2. Schwerzmann M,Wiher S, Nedeltchev K, et al. Percutaneousclosure of patent foramen ovale reduces the frequency ofmigraine attacks. Neurology. 2004;62: 1399-1401.

3. Post MC, Thijs V;Herroelen L, Budts WIHL. Closure of a patentforamen ovale is associated with a decrease in prevalence ofmigraine. Neum/ogy. 2004;62: 1439-1440.

4. Wilmshurst PT, Nightingale S,Walsh KP, Morrison WL. Effect onmigraine of closure of cardiac right-to-left shunts to preventrecurrence of decompression illness or stroke or for haemody-namic reasons. Lancet. 2000;356:1648-1651.

5. Artal I:JC, Kummer W; Ribeiro L, Braga H, Mesquita HM, VargasAI' Prevalence of patent foramen ovale in migraine patientswith and without aura compared to stroke patients. A trans-cranial Doppler study [abstract]. Presented at: 58th annualmeeting of the American Academy of Neurology; San Diego,Calif.; April 1-8,2006. Abstract P03.195.

6. Diener HC, Weimar C, Katsarava Z. Patent foramen ovale: para-doxical connection to migraine and stroke. Curl' Opin Neum/.2005; 18:299-304.

7. Messe SR, Cucchiara B, Luciano J, Kasner SE. FPO management:neurologists vs. cardiologists. Neum/ogy. 2005;65: 172-173.

8. Messe SR, Silverman IE, Kizer JR, et al. Practice parameter:recurrent stroke with patent foramen ovale and atrial septalaneurysm. Report of the Quality Standards Subcommittee ofthe American Academy of Neurology. Neum/ogy.?OO4'h2'1 042-1 O'jO.

CNS NEWS. SEPTEMBER 2006 131

MIGRAINE

MigraineSurgeryTrialsSeekPatientsMIST II (a Prospective,Multicenter,Double-Blinded,Placebo-Controlled TrialTo Evaluate the Effectiveness ofPatent Foramen Ovale Closure With the STARFlexSeptal

Repair Implant To Resolve Refractory Migraine HeadacheWith Aura)

Purpose: To investigate the safety and effectiveness ofPFO closure with the STARFtexSeptal Repair Implant

System in migraine reduction

Criteria: age between 18 and 60 years, history ofmigraine before age 50, refractory migraine with aura,PFO

Sponsor: NMT Medical

Contact: Karen Doyle, kbd@nmtmedical.com

Study ID Number: G050119; MIST II

ClinicalTrials.gov Identifier: NCTO0283738

PREMIUM (Prospective Randomized Investigation ToEvaluate the Incidence of Headache Reduction in SubjectsWith Migraine and PFO Using the AMPLATZERPFOOccluder Compared to Medical Management)

Purpose: To evaluate the impact of percutaneous closureof a PFO,with use of the AMPLATZERPFO Occluder; on

the incidence of migraine headaches

Criteria: age between 18 and 55 years, refractorymigraine with or without aura, PFO

Sponsor: AGA Medical Corporation

Contact: Maren Yurick,myurick@amplatzer.com

Study ID Number: AGA-010; G050054

ClinicalTrials.gov Identifier: NCTO0355056

ESCAPE(Effect of Septal Closure of Atrial PFO on E\(entsof Migraine With Premere)

Purpose: To determine the safety and effectiveness ofPFO closure in reducing the frequency of migraineheadaches compared with medical therapy alone

Criteria: age between 28 and 55 years, refractorymigraine, PFO

Sponsor: St. Jude Medical

Contact: Barb Denardo, cdresearch@sjm.com

Study IDNumber: 1202-001

ClinicalTrials.govIdentifier: NCTO0267371