IMPACT OF VAGAL NERVE STIMULATION ON QUALITY OF LIFE IN DRUG-RESISTANT EPILEPSY

Background and objective. Vagal nerve stimulation (VNS) represents an alternative therapy for intractable epilepsy. The aim of this study is to analyse seizure reduction and the life quality of these patients. Material and methods. We prospectively examined 28 adult patients treated with VNS that were followed-up at least 6 months after the surgery and we recorded the number of seizures and any other changes. 16 epilepsy patients completed the Quality of Life in Epilepsy-31 questionnaire (QOLIE-31). Results. Our data revealed that 64% of patients were responders with more than 50% seizure reduction. According to McHugh classifi cation of seizure freedom, 36% patients are in class I (80-100% seizure reduction), 29% class II (50-79% reduction), 21% class III (less than 50% reduction), 7% class IV (magnet benefi t only) and 7% class V (no improvement). Only 8 patients presented mild adverse effects, such as hoarseness, fatigue and cough. Life quality has improved for 68% patients. There is a strong correlation between life quality and health and a mild positive relation with the seizure reduction. Conclusions. VNS improves life quality for more than half of patients and is a therapy to consider in refractory epilepsy.


INTRODUCTION
The failure in keeping seizures under control can lead to a signifi cant decrease in life quality of epileptic patients. Up to one third of patients who suffer from the disease have intractable epilepsy. The International League Against Epilepsy (ILAE) defi nes epilepsy as refractory in case of inability to stop the seizures with at least two complete medical schemes (1).
Vagal nerve stimulation (VNS) is an alternative for medical or surgical refractory epilepsy and it is used in the case of failure or imposibility in performing an antiepileptic surgery, in the case of not obtaining clinical results after at least two medication plans, or in the case of medication intollerance of any kind. It has been used both for partial or generalized seizures, children or adults, for more than 30 years (2).
The device is similar to a cardiac pacemaker and it is attached subcutaneously in the left subclavicu-lar area, while the electrods are placed in the left vagus nerve. Although arrhythmias ar extremely rare, it is connected only the the left vagal nerve to even diminish that risk. The generator delivers intermittent electrical signals of low frequency to the nerve pathways (3). After the surgery, some parameters are noninvasively adjusted, including the intensity (output current), frequency, on time and off time. Patients also receive a magnet which can suspend the electrical stimulation while it is held in the generator area, thus interupting the seizure at its beginning (5).
The mechanism of action is not completely elucidated because of the diffi culty in animal studies, but it is based on the change in neurotransimitters such as serotonin, noradrenalin and GABA. The tenth cranial nerve has wide projections over some structures of the brain that are important in epileptogenesis, such as thalamus, amygdala, raphe nucleus, locus coeruleus. The electrical impulses mi-ght transform synchronous cortical activity to desynchronous and reduce the cortical excitability (4).
Due to the complex pathophysiology, VNS is indicated as an alternative to several diseases in case of medical failure. It is a possible therapy for medical refractory epilepsy, antiepileptic drug severe adverse effects, the impossibility in performing a curative antiepileptic surgery, uncontrolled status epilepticus, chronic headache, neurodegenerative disease, schizophrenia, autism, medical refractory depression (6)(7)(8).
Early complications such as bradycardia, asystole, hematoma, infections, vocal cord paralysis are related to the surgery technique, while the most frequent late complications include hoarseness, dyspnoea and coughing (9).
In an evidence-based guideline which evaluated 1274 studies, it was concluded that 55% of patients had at least a 50% seizure reduction with improvement over time, with the best response for generalized seizure type. The anti-depressive effect is an additional benefi ce. Changes in stimulation parameters are not completely accepted by all authors to increase the effect. The effi cacy of the magnet varies according to different studies from 25 to 75% (10). Another meta-analysis fi nds that only 30% had a 50% seizure reduction (11), but all literature data agrees that VNS has a signifi cant lower hospitalisation rate and it has a benefi ce on epileptic patients.

MATHERIAL AND METODS
Our study included 28 adult patients from Cluj-Napoca Neurology Clinic with the medium age of 32 years old, which were regularly followed-up after the VNS implantation. We recorded the clinical parameters of the patients, the number of seizures and adverse effects for a medium period of 20 months.
The inclusion criteria were the presence of vagal nerve stimulation therapy for epilepsy in adult patients. We excluded all children and the patients who withdrew from the study or deceased from other causes.
For 16 patients we evaluated the Quality of Life in Epilepsy-31 questionnaire (QOLIE-31) consisting of personal ratings of overall life quality, emo-tional well-being, seizure worry, energy, cognitive function, medication effects and social life. For each category we calculated the fi nal score which refl ects the life quality on that specifi c fi eld, and also the total score. Based on a group of 304 epilepsy patients, it was developed a table with pairing between any specifi c or fi nal score and a T-score. T-scores are linear transformations of the scores with the mean of 50 and a standard deviation of 10, representing that a T-score of 50 is correlated with the mean of the standard cohort (12). Values are expressed in mean± standard deviati on (range) or n (%).

Seizure frequency
For the patients in our study, the seizure frequency is extremely varied from one to 150 episodes per month, as it is presented in Fig. 2. At least 6 months after VNS implantation, we can observe in Fig. 3 a different distribution of frequencies with a general lower severity.

Seizure frequency reduction
For each patient we calculated the reduction rate according to the declared frequency anterior and after VNS implantation and we analysed the data using the McHugh and modifi ed Engel classifi cations.
After a medium period of 20 months, the majority of patients presented important improvements in epileptic episodes. According to McHugh classifi cation from Fig. 4, 10 patients were in class I with a reduction rate of more than 80%, 8 patients were included in class II with a reduction of 50-79%, 6 were in class III with less than 50% reduction, 2 presented no improvement and 2 had some benefi c effects of the magnet.
In modifi ed Engel classifi cation from Fig. 5, complete seizure freedom was declared by 6 patients, one presented with more than 90% reduction, 11 with 50-90% reduction and 1-patients had less than 49% reduction in seizure frequency.
Regarding the gender, our evaluation revealed no differentiation between females and males in the effi cacy of the VNS therapy. The type of epilepsy might be a predictor of the outcome, idiopathic etiology remaining with the best response.

3.The overall response to VNS
We classifi ed all 28 patients in responders(with a reduction in seizure frequency of more thena 50%) and non responders (<50% reduction). 64% of patients responded to this form of treatment and 36% did not declared a signifi cant effi cacy (Fig. 6).

Adverse effects
A majority of 20 patients had only temporary adverse effects, but 6 patients had a persistent dysphonia, one presented cough and one patients had fatique.

Overall life quality and health
The 16 patients from the study who completed the questionnaire accorded a grade from 1 to 10 for the overall life quality they consider to be characteristic most of the time.
To analyse the correlation between the overall life quality and seizure frequency reduction, we used Pearson correlation (Fig. 7). With an r of 0,39 there is a mild positive correlation between the two variables.
The way patients consider their overall health is very strong related to their life quality. In a Pearson correlation between overall life quality grade and the health grade (Fig. 8), we fi nd a strong positive linear relation with a r=0,76.

QOLIE-31 scores
We calculated the T-scores for all categories, a score equal to 50 refl ecting the mean of the responses from the standard epilepsy cohort. The results were very closed to the 50 value, in general lower. The mean from all T-scores from worries about a new seizure was 43,1, overall life quality had a T-scores mean of 46,1, emotions 46, energy 48,9, cognitive function 49,8, medication adverse effects 51,3, social implications were the most affected with a mean of 40.
We evaluated a possible correlation between the fi nal T-score and seizure reduction rate using Pearson correlation (Fig. 9). With a result of 0,13, there is not any signifi cant correlation between seizure reduction and the score which represents the life quality considered by the patient.

Life quality changes
We asked the 16 patients in the questionnaire to evaluate how VNS therapy has changed their lives, Overall life quality and seizure reducti on rate correlati on by choosing one of the predefi ned answers. 10 patients declared a moderate improvement, one considered a total life changing treatment, one has been a little infl uenced and 4 noticed no difference. From these patients, 11 consider a favourable treatment.

DISCUSSION
Vagal nerve stimulation is an accepted alternative treatment for refractory epilepsy. It has a documented role in reducing seizure frequency and intensity in time and interrupting the seizure at its beginning.
A large number of literature studies are focused on the reduction rate and its effi cacy, but only a few evaluate the impact of VNS therapy on life quality. The contribution of our study consists in analysing a therapeutic method not as well known and which, although in use for many years in other countries, it is still just at its beginning in our region. Also, studying QOLIE-31 on patients with vagal nerve stimulation represents a less common approach.
The limitations of the study are based on the small number of subjects, due to the extremely rare

CONCLUSIONS
Our data show that 64% of total 28 patients had more than 50% response in seizure reduction and the adverse effects were minor.
The quality of life scores in QOLIE-31 applied to the 16 patients were similar to the mean value of epileptic patients, with a lower tendency. The data show no correlation between the QOLIE-31 fi nal score and the seizure reduction rate, which suggests that vagal nerve stimulation is a possible therapy for reducing the number of seizures, but it is not necessarily related to the patient's perception about their life.
Finally, vagal nerve stimulation is an effective option for medical and surgical resistant epilepsy.