Letter by Johansson et al Regarding Article, “Migraine Intervention With STARFlex Technology (MIST) Trial”
To the Editor:
We read with interest the report of the MIST trial,1 designed to answer the intriguing question, “Can elimination of an interatrial shunt mitigate migraine symptoms?” Patent foramen ovale (PFO) closure might be a remedy for thousands of people suffering from migraine. The final report gave a negative answer. Two potential explanations exist for this: Either the PFOs were not closed, or a causal relationship between PFO and migraine with aura does not exist. In our opinion, several procedural issues make it difficult to interpret the results.
First, the authors report a 7% rate of false positives for detection of PFO. The MIST protocol specified transthoracic echocardiography with saline contrast to be used and defined PFO as visible bubbles in the left atrium within 5 beats from bubble appearance in the right atrium. The timing of contrast appearance in the right atrium might, however, be obscured by low image quality during the Valsalva maneuver. Moreover, the sole reliance on a number of beats of delay until contrast appearance can be insufficient for differentiating intrapulmonary from interatrial shunting.2 Because some bubbles often also pass through the lungs in patients without pathological intrapulmonary connection, this is probably a common cause of false-positive examinations, especially when 5 and not 3 beats are used to define PFO.3,4 Modern harmonic imaging is also highly sensitive and makes the appearance of these bubbles brighter.3,5
Second, moderate to large residual shunting was detected in 4 of 69 cases, as determined by the interventionist who performed the PFO procedure. The total number of cases with residual shunting was not reported, and, more importantly, neither was it reported how many injections were made to actually discover residual shunting. Repetition of contrast injections at least up to 5 times will increase the sensitivity for PFO detection.3 False-negative results are frequently caused by absent leftward bulging of the interatrial septum due to a short and insufficient Valsalva maneuver. Another cause is deficient contrast filling of the inferior part of the right atrium due to a prominent Eustachian valve and the inflow of contrast-free blood from the inferior vena cava on release of the Valsalva maneuver.
In our opinion, the MIST trial should be considered inconclusive. The hypothesis linking PFO and migraine should be evaluated within future randomized, properly conducted clinical trials using modern, adequate echocardiographic techniques, including a core laboratory facility. Until then, the indications for PFO closure should remain strict to avoid the explosive increase in the off-label use of occluders reported recently.
Dr Johansson receives honoraria from AGA Medical; Dr Eriksson receives honoraria from Gore, St Jude Medical, AGA Medical, and NMT Medical; and Dr Dellborg receives honoraria from Gore and General Electric.
Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, Lipscombe SL, Rees T, De Giovanni JV, Morrison WL, Hildick-Smith D, Elrington G, Hillis WS, Malik IS, Rickards A. Migraine Intervention with STARFlex Technology (MIST) Trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008; 117: 1397–1404.
Daniels C, Weytjens C, Cosyns B, Schoors D, De Sutter J, Paelinck B, Muyldermans L, Van Camp G. Second harmonic transthoracic echocardiography: the new reference screening method for the detection of patent foramen ovale. Eur J Echocardiogr. 2004; 5: 449–452.