Epilepsy and patent foramen ovale: intervene or wait

doi:10.21203/rs.3.rs-2217466/v1

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Epilepsy and patent foramen ovale: intervene or wait

https://doi.org/10.21203/rs.3.rs-2217466/v1

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Background: To date, no large-scale analysis has been conducted examining the association between PFO and epilepsy, especially in the Chinese population. The purpose of this study is to investigate the demographic characteristics of PFO patients, the clinical characteristics of PFO in patients with epilepsy, and the effect of PFO embolization in seizure attack.

Methods: Consecutive patients who are diagnosed as PFO, are recruited for this study. All patients had performed the brain MRI examination, transesophageal echocardiograpy (TEE), EEG, ECG, transthoracic echocardiogram with bubble contrast (TTE). Epilepsy patients has a definite diagnosis of epilepsy determined by at least two epileptologists.

Results: One hundred and ten patients finished the entire estimation. The patients went to see the doctor with different chief complaints, which included seizure, headache, dizziness, cerebral infarction or TIA, chest pain or palpitation and conventional examination. The proportion of chief complaints of chest tightness or palpitation is higher in the group less than 18 years old, and the proportion of headache and seizure are higher in the group older than 18 years old (p<0.05). The age of admission in the epileptic group (27.00±13.58) is significantly lower than the non-epileptic group (37.64±20.56), and also lower than the patients with headache as the chief complaint (38.73±12.09) (p<0.05). Comparison of general condition and therapeutic effect between PFO occlusion group and non-PFO closure group, there is no significant difference in sex, age, seizure type, number of AEDs and seizure frequency before and after PFO closure.

Conclusion: No difference between PFO closure or not. Due to the small number of cases, it is necessary to further expand the sample size to obtain accurate results.

epilepsy

Patent foramen ovale

closure

Patent foramen ovale (PFO) is a condition that the foramen ovale, which normally closes at birth due to the elevation in the left atrial pressure during the transition to pulmonary circulation, is left unclosed [1]. It has been reported that 15-35% of healthy people have PFO [2,3], which is found to decrease with increasing age. PFO causes the formation of right-to-left shunts (RLs) during the Valsalva maneuver or at rest. Although several diseases, such as arteriovenous malformation (AVM) or atrial septum deficits, can cause RLs, PFO is the most common underlying factor for RLs[4]. Some studies have suggested that the presence of PFO may affect the structure of the cerebral cortex and the integrity of the white matter[5,6], which may be related to epilepsy. To date, no large-scale analysis has been conducted examining the association between PFO and epilepsy.

The purpose of this study is to investigate the demographic characteristics of PFO patients, the clinical characteristics of PFO in patients with epilepsy, and the effect of PFO closure in seizure attack.

Consecutive patients who are diagnosed as PFO, are recruited for this study, which is a prospective study. The project is approved by the Scientific Research Ethics Committee of PLA General Hospital, and select PFO patients who were admitted to the epileptic clinic or hospitalization in the department of cardiology, the PLA General Hospital, from January 2015 to December 2020. All patients sign informed consent. PFO was diagnosed by transthoracic, esophageal echocardiogram and right heart contrast echocardiography. Patients with other abnormal heart diseases such as ventricular septal defect are excluded.

On the first visit, we collect a detailed medical history including history of vascular risk factors, chief complaints, migraine, cerebrovascular disease, as well as clinical features of the epilepsy (onset age, auro, trigger factors, frequency, et al). All patients has performed the brain MRI examination, transesophageal echocardiograpy (TEE), EEG, ECG, transthoracic echocardiogram with bubble contrast (TTE). Epileptic patients has a definite diagnosis of epilepsy determined by at least two epileptologists.

Percutaneous transcatheter closure of patent foramen ovale is performed by a senior chief physician in the department of cardiology. Patients in both the PFO closure group and the non-PFO closure group are treated with aspirin 100mg for 6 months.

Statistics:

All the data are analyzed by SPSS 25.0 software, the frequency and percentage of classified variables are calculated, the mean value of continuous variables is calculated, and the measurement data are analyzed by t-test. The calculated data are tested by x² test.

One hundred and fifty-six PFO patients are recruited for this study, who are admitted to the epileptic clinic or hospitalization in the department of cardiology. One hundred and ten patients finish the entire estimation. The patients went to see the doctor with different chief complaints, including seizure, headache, dizziness, cerebral infarction or TIA, chest pain or palpitation and conventional examination. According to the chief complaint, we divide into two groups: non-epileptic group (n = 87, 72 patients age≧18 y), and epileptic group (n = 23, 20 patients age≧18y). (Table 1)

The age of admission in the epileptic group (27.00±13.58) is significantly lower than the non-epileptic group (37.64±20.56), and also lower than the patients with headache as the chief complaint (38.73±12.09) (p<0.05). At age 18 years or more group, 9.78% (9/92) chief complaint is chest tightness or palpitation, 13.04% (12/92) was cerebral infarction or TIA, 28.26% (26/92) is headache, 4.35% (4/92) is dizziness, 21.73% (20/92) is epilepsy, 7.61% (7/92) is syncope, and 15.22% (14/92) is conventional examination (Figure 1 A). At age less than 18 years old group: 33.33% (6/18) chief complaint is chest tightness or palpitation, 11.11% (2/18) is cerebral infarction or TIA, 11.11% (2/18) is headache, 16.67% (3/18) is epilepsy, 5.56% (1/18) is syncope, and 22.22% (4/18) is conventional examination (Figure 1 B).

The proportion of chief complaints of chest tightness or palpitation are higher in the group less than 18 years old, and the proportion of headache and seizure are higher in the group older than 18 years old (p<0.05).

In the age 18y or more group, the average admission age is 34.82±16.72 (18-81y), including 53 females and 39 males. (Table 2)

Table 2: The demographic characteristics of PFO patients (age≧18 y)

Demographic characteristics	No. (%)
Gender
Female	53 (57.61%)
Male	39 (42.39%)
Age (y)
(x±SD)	34.82±16.72
Range	18-81
Chief complaints
Chest tightness or palpitation	9 (9.78%)
Headache	26 (28.26%)
Dizziness	4 (4.35%)
Cerebral infarction or TIA	12 (13.04%)
syncope	7 (7.61%)
epilepsy	20 (21.73%)
Conventional examination	14 (15.22%)
Size of PFO diameter
≥ 4.0 mm	8 (8.70%)
2.0-3.9 mm	19 (20.65%)
≤ 1.9 mm	65 (70.65)

The clinical features of epileptic patients with PFO (age≧18 y) are shown in the table 3,4. In total, 20 patients (five males and 15 females ) are identified, with a mean age of 29.10±13.35 (range 18-66) years old. There is an obviously female preponderance (female: male = 3:1), and majority of the patients are 20-40 years old (14/20, 70%). Demographic data, seizure data, EEG recordings, brain MRI, and seizure outcome were shown in Table 4. Six patients are performed PFO closure by percutaneous transcatheter. Comparison of general condition and therapeutic effect between PFO closure group and non-PFO closure group, there is no significant difference in sex, age, seizure type, number of AEDs and seizure frequency before and after PFO closure.

Table 3: The demographic characteristics of epileptic patients with PFO (age≧18 y)

Demographic characteristics

PFO closure group (n=6)

Non-PFO closure group (n=14)

F/M

5/1

10/4

Age of diagnosis

25.00±7.04

30.86±15.17

Age of seizure onset

18.92±9.90

23.71±16.24

duration

6.67±5.82

7.11±5.11

Auro

6 (100%)

10 (71.43%)

Blackout

Dizziness

Headache

Hallucination

Absent

Palpitate

Uncomfortable felling

With Migraine

Yes

5 (X²=2.08, p=0.15 )

EEG

Normal

Focal spike

6 (X²=0.75, p=0.39 )

Seizure type

Focal

GGE

unknown

AEDs

Monotherapy

Polytherapy

No treatment

5 (X²=2.54, p=0.28)

Seizure frequency (baseline)

≥1/month

< 1/month≥1/year

< 1/year

5 (X²=3.44, p=0.18)

Seizure outcome (1 year later)

seizure free

less than 75%

less 50-75%

no change

1 (X²=2.28, p=0.52)

Table 4: General characteristics of epileptic patients with PFO

NO	Sex	age	onset age	classification of seizure types	auro	Brain MRI	EEG	with migraine ^a	Frequency baseline ^b	AEDs	follow up 1 year later ^c
Non-PFO closure group
1	M	24	13	Focal onset secondary bilateral tonic-clonic	eye black/can not speak	N	N	0	3	OXC	1
2	M	40	25	focal with unawareness	black	Punctate ischemic foci in the white matter	N	0	1	LEV、LTG、OXC	2
3	F	20	12	focal onset secondary bilateral tonic-clonic	No	Post-operation of brain cyst	Spike (left temporal)	1	2	CBZ、LEV	4
4	F	50	47	focal onset secondary bilateral tonic-clonic	dizziness	N	N	0	2	No	4
5	F	32	22	focal with unawareness	headache	N	N	2	1	TPM	4
6	F	18	13	unknown onset secondary bilateral tonic-clonic	No	N	N	0	1	LEV、OXC	3
7	F	22	20	focal onset secondary bilateral tonic-clonic	dizziness	N	N	1	1	VPA、LEV	3
8	M	28	25	focal onset secondary bilateral tonic-clonic	No	Punctate ischemic foci in Subcortical	Spike (right forehead-central -parietal)	0	2	VPA	2
9	F	25	9	focal onset with hallucination	hallucination	N	Spike (right occipital)	0	2	No	4
10	F	20	20	focal onset secondary bilateral tonic-clonic	Absent, can not speak	N	Spike (bilateral frontal、central)	0	1	No	2
11	F	18	5	focal onset secondary bilateral tonic-clonic	auditory hallucination	Lesion in the right temporo parietal cortex	Spike (right frontal)	0	2	CBZ、LTG	4
12	F	51	45	focal onset secondary bilateral tonic-clonic	No	N	Spike (left frontal、middle temporal)	1	2	VPA	4
13	F	18	15	focal onset secondary bilateral tonic-clonic	black	N	Spike (frontal, left parietal)	1	3	No	4
14	M	66	61	focal onset secondary bilateral tonic-clonic	Absent, can not speak	Lesion in the left temporal parietal cortex	Spike (left temporal)	0	3	LEV	3
PFO closure group
1	F	18	9	focal onset secondary bilateral tonic-clonic	black	N	N	0	2	No	3
2	F	20	14	focal onset secondary bilateral tonic-clonic	Absent, cannot speak	N	N	1	2	LEV	1
3	F	23	21	focal onset secondary bilateral tonic-clonic	dizziness	Old lesion in right parietal occipital and temporal	Spike (right occipital, central)	2	2	LEV、LTG	4
4	M	25	24	focal onset secondary bilateral tonic-clonic	palpitate	N	N	0	2	No	2
5	F	38	33	focal onset secondary bilateral tonic-clonic	auditory hallucination	Lesion in right temporal-parietal-occipital junction	Spike (Sphenoid electrode)	0	2	No	1
6	F	26	9	focal with complex cognition	Uncomfortable felling	N	N	2	3	No	4

^a 0 without migraine;1 migraine with auro; 2 migraine without auro; ^b ：1>1/month；2 2-12/year；3:0-1/year; ^c: 1 year later, 1 seizure free; 2 less than 75%; 3 less 50-75%; 4 no change; N=normal.

Auras are relatively more often reported in patients with PFO (80%), including 4 blackout, 3 dizziness, 3 absent, 1 palpitate, 1 headache, 3 hallucination and 1 uncomfortable feeling. (Figure 2) All patients performed brain MRI examination, 6 patients (30%) showed brain lesions, including post-operation lesion of brain cyst, old lesion in right parietal occipital, temporal encephalomalacia focus after trauma, multiple punctate ischemic foci in subcortical or cortical. Only one patient maybe related with left-to-right shunting, who has an encephalomalacia focus in right temporal-parietal-occipital junction, indicated asymptomatic vascular disease (case 5 in PFO closure group). 10 of 20 patients (50%) who had interictal scalp EEG recordings showed interictal spikes. After a mean follow-up duration of 2 year, 11 patients (55%) show a favourable seizure outcome (frequency decreased more than 50%, 3 patients obtained seizure free). But no difference between PFO closure or not. Because of the small number of cases, it is necessary to further expand the sample size to obtain accurate results.

The prevalence of PFO on autopsy is around 25% and is generally regarded as a common and benign condition.Patients are usually asymptomatic because the defect is flap-like and does not permit significant left-to-right shunting. If the right-to-left shunt is persistent, systemic hypoxemia or paradoxical emboli may result[7-9].

In patients under the age of 55 years with cryptogenic stroke, a PFO has been checked in 40-50% of cases. But there is no consensus to recommend primary stroke prevention in patients with asymptomatic PFO, as there is in patients with epilepsy. Options for secondary treatment of cryptogenic stroke associated with PFO include antiplatelet therapy, anticoagulation, surgical and transcatheter closure of PFO. In considering management strategies it is important to note that there is a lack of good quality randomized controlled trials in this area and insufficient evidence to recommend warfarin and/or PFO closures.

The relationship between PFO and epilepsy has not been reported. Syros G described a young patient with a prior undiagnosed PFO, who presented seizure with solitary brain abscess without any underlying primary source of infection [10].

Thomas SV ascertain the prevalence of cardiac malformation (CM) and its association with antenatal exposure to an antiepileptic drug (AED) in infants of mothers with epilepsy (IMEs). PFO and interatrial septal defects of <5 mm in size were excluded from CM[11]. In our epileptic center database from 1999, the number of epileptic patients with PFO is very low, suggesting that we need more attention to the real relationship between epilepsy and PFO. In our center, echocardiography was not performed on all patients with epilepsy, so it is hard to obtain the exact data about the incidence of PFO in epileptic patients.

We examine the experiential phenomenon in seizure patients with PFO and found that auras were detected in 80% of patients with PFO. Palmini and Gloor noted that auras were found in 93% of patients with temporal lobe onset versus only 61% with frontal lobe onset. Non-specific auras have been reported in patients with seizure foci in the frontal lobe. Patients usually report unexplainable feeling, often localized to the head (“cephalic aura”).

A coincidence of two conditions, however, does not necessarily imply a causal relationship. Moreover, it is difficult to imagine how PFO could lead to a seizure –a neural event in the cortex caused by neural discharging. In this study, only one epileptic patient maybe related with left-to-right shunting, who had an encephalomalacia focus in right temporal-parietal-occipital junction, indicated asymptomatic vascular disease, who had no stroke event or TIA attack before. Also some patients showed scattered ischemic foci on MRI, there was no clear evidence that intracranial ischemic foci are related to PFO.

Should PFO be closed in patients with epilepsy?[12] Even if we assume there is a causal relationship between PFO and epilepsy, closure of PFO should then result in seizure improvement or free. To date, no randomized and controlled prospective trial has been performed. In this study, patients are asked about their seizure frequency before and after PFO closure one year later, to determine whether this intervention affected seizure attacks. PFO closure group did not show a statistically significant effect on reducing seizure frequency in epileptic patients with PFO.

There is a lack of clear evidence regarding superiority of either medical or invasive treatment. Is it acceptable to expect patients to wait for a second seizure and potentially devastating stroke before closing their defect?[13-16] Spontaneous closure rate of patent foramen ovale is high[17], The spontaneous closure of patent foramen ovale was positively correlated with early diagnosis and small defect area. Given the prevalence of PFO in the general population, closure is indicated only in some pathological situations such as recurrent paradoxical embolism or when systemic anti-coagulation is contraindicated. On the basis of current evidence, patient perspective is the key. Further randomized controlled trials are needed to strengthen the evidence base.

We hope that our study would possibly contribute in filling the lacunae of our current understanding the relationship between epilepsy and PFO in developing countries. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect.

Authors’ contributions

ZX, SCJ, BSF, XF, LDS, AR, SXB, YSY, LSY and WXQ carried out the studies. ZX and WXQ drafted the manuscript. WXQ participated in the design of the study and performed the statistical analysis. Professor WXQ, the PI of this study, conceived of the study and participated in its design and helped to draft the manuscript. All authors read and approved the final manuscript.

Funding

None.

Availability of data and materials

All data generated or analyzed data in study are included in this article.

Ethics approval and consent to participate

The Scientific Research Ethics Committee of PLA General Hospital approved this study. All patients sign informed consent. All methods were carried out in accordance with relevant guidelines and regulations

Consent to publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

The authors would like to thank all of the referring clinicians.

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No competing interests reported.

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Epilepsy and patent foramen ovale: intervene or wait

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