Mahmoud Taha MD KFSH-Dammam, KSA VNS for epilepsy Mahmoud Taha MD KFSH-Dammam, KSA

50% of intractable would be suitable for surgery Epilepsy surgery 50% of intractable would be suitable for surgery <10% of those suitable for surgery currently have operation in the UK Epilepsia. 2003 May;44(5):673-6

Criteria for medically intractable epilepsy Quality of life seizures interfere with the patient’s life enough for him/her or guardian and not the physician to consider surgery after counseling about risks Adequate medical treatment trial to toxicity with at least two major anti-epileptic drugs patients uncontrolled after 2 years of medical management are unlikely to become seizure free without surgery even with newer drugs

Aims of surgery Reduction of seizure frequency Improvement of seizure pattern Reduction of anticonvulsants drugs Improve QOL

Pre-surgical Evaluation Phase 1: Non-invasive Phase 2: Invasive Clinical assessment Neuroimaging: MRI, PET,SPECT Electrophysiology Routine EEG 24 H intensive video Neuropsychological tests Psychsocial evaluation Electrophysiological 24 h intensive video monitoring( epidural, subdural, intracerebral electrodes) Neuropsychological tests:Intracarotid amobarbital test ( WADA test)

invasiveness Resective surgery removal of diseased hemisphere removal of diseased lobe removal of epileptogenic tissue Disconnection surgery: functional hemispherotomy division of corpus callosum (callosotomy) multiple subpial transection Functional operations: neurostimulation (vagus nerve , VNS®) Deep brain stimulation Radiosurgery: stereotactic lesioning stereotactic radiosurgery invasiveness

VNS: Historical background 1938, Bailey and Bremer reported that vagal stimulation causes EEG changes J Neurophysiol. 1938;1:405-12. 1951, Dell and Olson studied the route taken by the ascending influence from the nucleus of tractus solitarius (NTS). Soc Biol Fil. Jul 1951;145(13-14):1084-8. 1985, Zabara reported the effects of VNS on seizure control in animal studies. 1988, Penry, Wilder, Ramsay, and colleagues performed the first implant of a vagal stimulating device into a human. Electroencephalography. 1985;61:S162

VNS Trials and approval Two pilot studies (E01, E02), 14 patients found the mean percentage of seizure reduction in the patients to be 46.6%. a randomized active control study (E03) was performed in 1992 In 1994, the European Community approved the use of VNS for seizure prevention and control. 1997, FDA approved the use of VNS as an adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than age 12 years.

VNS: mechanisms of action The precise mode of action of VNS, like that of the antiepileptic drugs (AEDs), is not known. Areas possibly activated by VNS include the medulla, cerebellum, parabrachial nucleus, locus ceruleus, hypothalamus, thalamus amygdala, hippocampus, cingulate gyrus, and contralateral somatosensory cortex.

VNS: mechanisms of action (animals) VNS inhibits seizures in multiple animal models of epilepsy. VNS requires stimulation of C fibers, which is achieved with high-intensity, high-frequency stimulation; it produces desynchronization of the cortical EEG. Investigators have suggested that VNS increases seizure threshold by causing widespread release of GABA and glycine in the brain.

VNS: mechanisms of action (human) Ben-Menachem et al measured amino acid and neurotransmitter metabolite concentrations in cerebrospinal fluid (CSF) samples of patients on clinical trials of VNS before and 3 months after VNS placement and found paradoxical results. On the other hand, free and total GABA levels were higher after long-term VNS Epilepsy Res. Mar 1995;20(3):221-7 In 1993, McLachlan posited that VNS decreased cortical epileptiform activity indirectly by influencing the reticular activating system Epilepsia. Sep-Oct 1993;34(5):918-23

fMRI Significant bilateral changes in blood flow: Thalamus (increase) Hypothalamus (increase) Insular cortex (increase) Amygdala (decrease) Hippocampus (decrease) Posterior cingulate gyri (decrease) Epilepsia. 1998;39(9):983-990.

Who is suitable? VNS: intractable epilepsy: 2 years, 2 drugs Pre-op evaluation: No resective lesion or multiple Or failed resection seizure type not defined age limit

VNS: technique aspects

VNS: stimulation parameters Output current: 0 - 3.5 mA (0.25mA steps) Frequency: 1 - 145 Hz Pulse width: 130 - 1000 sec On time: 7 - 270 sec Off time: 12 sec to 270 min Independent programming of stimulus parameters “on demand” using magnet

Combined data, E01 - E05, n=440 VNS: how effective

Neurosurg Focus. 2012 Mar;32(3):E12. doi: 10.3171

VNS: predictive factors a meta-analysis of 74 clinical studies with 3321 patients suffering from intractable epilepsy average reduction of 45% 36% reduction in seizures at 3-12 months 51% reduction after > 1 year Patients with generalized epilepsy and children benefited significantly. Post-traumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome J Neurosurg. 2011 Dec;115(6):1248-55

VNS: long-term outcome In 24 children (mean age 14.31 y), the mean percentage of seizure reduction after 6 months to 7 years of treatment were as follows : • 22.5% (n=24) (sixth month) • 32% (n=20); (first year) • 42% (n=16) (second year) • 50.45% (n=11) (third year) • 52% (n=10) (fourth year) • 60% (n=8) (fifth year) • 61.25% (n=8) (sixth year) • 61.6% (n=6) (seventh year) Eur J Paediatr Neurol. Jul 2010;14(4):334-9

VNS: Quality of life 40 children with MR/DD and refractory fits VNS, 2 years f/up At least 50% reduction in 25% patients Medication reduced from 3.3 per case to 2.3 overall quality of life improved for the majority of subjects using the Client Development Evaluation Report (CDER), statistically significant improvements were reported at both 1 and 2 years in attention span, word usage, clarity of speech, standing balance, washing dishes, and household chores Epilepsy Behav. 2005 May;6(3):417-23.

VNS: cost effectiveness Cost of each VNS is $ 10000 43 patients, refractory epilepsy have VNS Unplanned hospital costs : ER, ICU, bed stay.. 18 months pre VNS and 18 months post VNS $ 3000 saving with VNS regardless response to VNS treatment. Neurology. 2002 Sep 24;59(6 Suppl 4):S44-7

VNS: Side effects 5%: voice alteration/hoarseness, cough, throat pain, nonspecific pain, dyspnea, paresthesia, dyspepsia, vomiting, infection Most of these adverse effects have a negligible impact on the quality of life of treated patients and are reported as mild 99% of the time. The effects appear during stimulation and tend to diminish over time The NCP device is not affected by microwave transmission, cellular phones, or airport security systems.

conclusions VNS insertion is safe and effective Cost effective Small side effects Mechanism? Small RCT especially in children Long-term?