Migraine with aura and TCD bubble-test : The significance of positive result Migrena sa aurom i TKD bubble test : zna aj pozitivnog rezultata

Background/Aim. The association between the right-to left shunt (RLS) and migraine with aura (MA) has been proven so far. The aim of this study was to determine if the presence of RLS detected as a result of transcranial doppler (TCD) bubble-test, makes any difference in clinical presentation, aura and headache in patients with MA. Methods. A single-group descriptive study was conducted on 153 patients diagnosed with MA. TCD bubble-test was performed on 135 of them. The recorded demographic and clinical features of patients were analyzed and compared with the results of the TCD bubble test. Results. In the group of 135 patients, 88 (65.2%) had positive TCD bubble-test. The difference in the investigated clinical features of patients of the patients and aura between the patients with and without RLS, was not found. Conclusion. The results of our study confirm a high prevalence of right-to-left shunt in patients with MA, but the clinical relevance of this association was not shown.


Introduction
The association between the cardiac right-to left shunt (RLS) and migraine with aura (MA) has been widely examined [1][2][3][4][5][6] and shown that there is a relationship between migraine with aura and patent foramen oval (PFO).The prevalence of PFO in the MA patients is around 50% according to results of different studies, in contrast to approximately 20% in the migraine without aura patients and even less in healthy control subjects.The tendency of paradoxical emboli for the posterior circulation 7,8 was the basis for the hypothesis about causality of RLS and the cortical spreading depression originating in occipital cortex with subsequent, the most common, visual aura.According to the results of some authors, patients with migraine who have RLS tend to recognize activities that can cause Valsalva's manoeuvre, increasing the extent of shunt as a trigger of their migraine attacks 9 .Nevertheless, a prospective, multicenter, randomized, double blind, placebo-controlled trial revealed no casual relationship between PFO closure and reduction in the number and severity of headache attacks in patients with MA 10 .The pulmonary RLSs, with arteriovenous malformations background, are associated with a high migraine prevalence, as well [11][12][13] .
The aim of this study was to determine if the presence of RLS detected as a result of transcranial Doppler (TCD)

Methods
A single-group, descriptive study was conducted over 153 patients diagnosed with MA, selected from specific outpatient visits for headaches during the period of four years, from 2008 to 2012.Written informed patient consent was obtained from all the examined subjects.Research protocol of the study was approved by the review board of the Neurology Clinic, Clinical Center of Serbia, Belgrade.
All the patients included in the study met the International Headache Society (IHS) criteria for typical aura with migraine headache (diagnostic criteria 1.2.1) 14 .The demographic features (age at the time of examination, age at the time of headache onset, gender) data about family history of migraine and cerebrovascular disorders were recorded together with the duration and symptoms of aura reported by the patients.According to diagnostic IHS criteria aura was diagnosed as visual or sensory, and aura with both, visual and sensory symptoms was labeled as complex aura.Other transitory cortical dysfunctions experiencing regularly during aura, meaning disturbances in color naming, object and face recognition, memory, speech, calculation, spatial orientation and praxia, were also recorded.
The RIMED Digi-Lite (RIMED, Israel), dual channel TCD system was used in the present study.The insonation was performed through the pre-auricular acoustic bone windows according to a standard approach using 2 MHz transducers to visualize the middle cerebral artery (MCA).Bilateral monitoring was performed with each probe held in place over a temporal bone by the head frame.The MCA gate was selected for each spectrogram and the continuous recording and counting of bubble embolic signals was provided by a computer hard disk.All embolic tracks were counted in the bilaterally insonated MCA from a depth of 40 mm to 75 mm.In all the patients, the TCD bubble-test was performed in the supine position with the head inclined forward for the 30 degrees.At least 2 contrast bolus injections with 9 mL of saline, 1 mL of air were agitated and mixed with the small amount of the patient's blood, administered into an antecubital vein.The first injection was performed during normal respiration, the second injection was preformed immediately prior to non-calibrated Valsalva and if no embolic tracks were detected, additional injections were made while the patient performed the second non-calibrated Valsalva.TCD bubble-test was considered to be positive if at least 1 microbubble was detected during the first 12 seconds after injection 15 .To grade RLS, a 6-level logarithmic scale was used for both resting and Valsalva injections 16 .
The recorded demographic and clinical features were analyzed and compared with results of TCD bubble-test.
The data are presented as arithmetic mean or as percentages.The Kolmogorov-Smirnov test was applied to assess the normality of the studied continuous data.Independent-samples t-test and 2 -test were used to compare data between the two groups.The significance level for the analysis was set at 5% (p < 0.05).

Results
TCD bubble-test was performed in the 135 of 153 studied patients diagnosed with MA.The group of 18 patients did not undergo this test due to inadequacy of the bone windows.Positive TCD bubble-test was recorded in 88 (65.2%) of the patients.On a 6-level logarithmic scale that was used to grade RLS, 34 (25.2%) of the patients had RLS grade I, 17 (12.6%)grade II, 27 (20.0%)grade III, 9 (6.7%) grade IV and only 1 (0.7%) patient grade V.
The patients with positive TCD bubble-test, comparing to those with a negative test result, did not show any difference in gender, age at the time of examination and in age at the time of migraine onset (Table 1).Migraine without aura was present in approximately one quarter of the patients and family history of migraine in half of them in both groups (Table 1).
There were no differences between the two groups of the patients in regard to duration of aura, as well as aura symptoms (Table 2).In both groups, the most common type of aura was visual reported by more than 90% of patients, followed by sensory symptoms.More than half of the patients in both groups had complex aura, and the other cortical dysfunctions during aura were reported by one third of the patients in both groups (Table 2).
Also, there were no differences in demographic features, personal and family history nor characteristisc of aura, between the groups of the patients with different grade of RLS, based on a 6-level logarithmic scale.

Discussion
In contrast to a large number of studies examining the potential causal relationship between MA and RLS, there is a few number of papers giving us data about the clinical characteristics of aura types in migraine patients with RLS 17 .The results of our study, completed on 135 patients, confirmed a high prevalence of RLS in the patients with MA, detected in 65.2% of our patients.The obtained results are in accordance with the results of the other authors [1][2][3][4] .In a line with results of these authors 17 , the significant difference of investigated demographic features of patients and clinical characteristics of aura between patients with and without RLS, was not found.The proposed explanation of the comorbidity between MA and RLS is shared genetic inheritance 18 .According to the results of our study, migraine in the family history was equally present in the patients with and without RLS.

Podgorac
A substantial number of studies point to the increased risk of stroke in patients with MA compared to the patients with migraine without aura 19 .The association between MA and RLS could contribute to this increased risk.The mechanism that underlies this association remains unclear, and according to the results of our study is not related to patient's demographic features or aura presentation.

Conclusion
The results of our study confirm a high prevalence of right-to-left shunt in patients with migraine with aura, but the clinical relevance of this association has not been shown yet.