Published June 2023

Publications on the use of vagus nerve stimulation (VNS) Therapy as a treatment for drug resistant epilepsy (DRE) in patients with Cerebral Palsy (CP) are sparse in number, and no studies solely focusing on this topic appears to exist. This is likely due to the limited number of available cases. According to a recent (2022) systematic analysis of population-based prevalence studies, and patient registers, the prevalence of CP is estimated to be 1.6 per 1000 live births [1]. Further limiting the number of available patient data, the prevalence of epilepsy in patients with CP is estimated to be somewhere between 15-55% [1, 2]. Half of these patients develop DRE [1, 2]. However, due to patients with CP having an increased risk of intellectual disabilities/cognitive impairments, these patients are often included in analysis evaluating the effectiveness of VNS Therapy in patients with cognitive deficits [3-5]. Noteworthy, accumulating evidence suggests that DRE patients with intellectual disabilities have a significantly lower responder rate (≥50% seizure frequency reduction) to VNS Therapy [4,5]. In a study by Pipan et al. 2020, the responder rate of patients with cognitive deficits (N=45, including 9 patients diagnosed with CP) was 24% compared to 55% in the non-cognitive deficits group (N= 37, 1 patient diagnosed with CP) [4]. Likewise, a population-based study by Kostov et al. 2021 revealed that the absence of an intellectual disability was a significant predictor of effect in both children and adults with DRE [5]. In this publication, the responder rate for children with an intellectual disability was estimated to be somewhere between 40-50% [5]. Another study examining the effects of VNS Therapy on seizure frequency in patients with hypoxic-ischemic encephalopathy (IHE)-induced epilepsy stated that CP might be a negative predictor for VNS effectiveness in this patient group [6]. However, the study only included 5 patients with CP, warranting larger studies to confirm this observation.

Quality Of Life

Despite the significantly lower responder rate for patients with cognitive deficits observed in Pipan et al. 2020 (discussed above), this patient group reported significantly larger effects on quality-of-life parameters compared to the non-cognitive deficits group [4]. Likewise, many of the patients with intellectual disabilities in the Kostov-study chose to continue VNS treatment due to positive effects on alertness, mood, seizure severity and the number of status epilepticus episodes [5].

An exploratory review by Jaseja et al. 2008 discusses the potential benefits of using VNS Therapy in CP patients with DRE based on its dual effect, seizure frequency reduction and inter ictal epileptiform discharge (IED) suppression [7]. Interestingly, clinical evidence indicates the presence of IEDs to be highly associated with neuro-psychological dysfunction as well as cognitive impairment, behavioural problems (hyperactivity in particular) and arousals during sleep, regardless of epilepsy diagnosis or not [8-12].

Interestingly, multiple studies have shown VNS Therapy to have an IED-suppressive effect [13-15]. For example, Piotr et al. 2001 observed a decreased number of IEDs when using VNS Therapy at a 30 Hz frequency setting, whereas a 5 Hz frequency setting increased the quantity of IEDs [13].

Many patients with CP display IEDs in their electroencephalograms (EEGs). Thus, it is speculated that the use of VNS Therapy might improve the clinical prognosis of those patients by reducing epileptic seizures, if present, as well as improving cognition by IED-suppression [13]. Based on this data, the use of VNS Therapy has been discussed even in CP patients without clinical epilepsy [16].

Reflection

The available scientific data on the efficacy of VNS Therapy in DRE patients with CP is limited and further research is needed to draw any specific conclusions. Patients with a cognitive impairment appears to have a lower responder rate for VNS Therapy and one study suggested a diagnosis of CP to be a negative predictor of effect. However, these patients often reported positive effects on quality of life parameters and chose continue VNS treatment even if the responder rate was low. Thus, the combined effect of VNS Therapy on seizure frequency and quality of life might improve the clinical prognosis of patients with DRE and CP.

References

1. McIntyre S, Goldsmith S, Webb A, Ehlinger V, Hollung SJ, McConnell K, Arnaud C, Smithers-Sheedy H, Oskoui M, Khandaker G, Himmelmann K; Global CP Prevalence Group*. Global prevalence of cerebral palsy: A systematic analysis. Dev Med Child Neurol. 2022 Dec;64(12):1494-1506. doi: 10.1111/dmcn.15346. Epub 2022 Aug 11. PMID: 35952356; PMCID: PMC9804547.

2. Kułak W, Sobaniec W. Risk factors and prognosis of epilepsy in children with cerebral palsy in north-eastern Poland. Brain Dev. 2003 Oct;25(7):499-506. doi: 10.1016/s0387-7604(03)00040-8. PMID: 13129594.

3. Andersen GL, Irgens LM, Haagaas I, Skranes JS, Meberg AE, Vik T. Cerebral palsy in Norway: prevalence, subtypes and severity. Eur J Paediatr Neurol. 2008 Jan;12(1):4-13. doi: 10.1016/j.ejpn.2007.05.001. Epub 2007 Jun 15. PMID: 17574886.

4. Pipan E, Apostolou A, Bograkou M, Brooks P, Vigren P, Gauffin H. Vagal Nerve Stimulation in Epilepsy: Experiences of Participants with Cognitive Deficits. Neuropsychiatr Dis Treat. 2020 May 8;16:1181-1188. doi: 10.2147/NDT.S241716. PMID: 32440133; PMCID: PMC7217302.

5. Kostov KH, Kostov H, Larsson PG, Henning O, Eckmann CAC, Lossius MI, Peltola J. Norwegian population-based study of long-term effects, safety, and predictors of response of vagus nerve stimulation treatment in drug-resistant epilepsy: The NORPulse study. Epilepsia. 2022 Feb;63(2):414-425. doi: 10.1111/epi.17152. Epub 2021 Dec 21. PMID: 34935136.

6. Guo M, Wang J, Tang C, Deng J, Zhang J, Xiong Z, Liu S, Guan Y, Zhou J, Zhai F, Luan G, Li T. Effectiveness of vagus nerve stimulation therapy in refractory hypoxic-ischemic encephalopathy-induced epilepsy. Ther Adv Neurol Disord. 2022 Dec 21;15:17562864221144351. doi: 10.1177/17562864221144351. PMID: 36578694; PMCID: PMC9791287.

7. Jaseja H. (2008). Vagal nerve stimulation: exploring its efficacy and success for an improved prognosis and quality of life in cerebral palsy patients. Clinical neurology and neurosurgery, 110(8), 755–762.

8. Ung H, Cazares C, Nanivadekar A, Kini L, Wagenaar J, Becker D, Krieger A, Lucas T, Litt B, Davis KA. Interictal epileptiform activity outside the seizure onset zone impacts cognition. Brain. 2017 Aug 1;140(8):2157-2168. doi: 10.1093/brain/awx143. PMID: 28666338; PMCID: PMC6167607.

9. Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain. 1984 Mar;107 ( Pt 1):293-308. doi: 10.1093/brain/107.1.293. PMID: 6421454.

10. Kotagal S, Gibbons VP, Stith JA. Sleep abnormalities in patients with severe cerebral palsy. Dev Med Child Neurol. 1994 Apr;36(4):304-11. doi: 10.1111/j.1469-8749.1994.tb11850.x. PMID: 8157152.

11. Fois A, Borghesi S, Luti E. Clinical correlates of focal epileptic discharges in children without seizures. A study of 110 cases. Helv Paediatr Acta 1968;23:257–65.

12. Binnie CD, Channon S, Marston DL. Behavioral correlates of interictal spikes. Adv Neurol. 1991;55:113-26. PMID: 2003401.

13. Piotr WO, Bruce JF, Michael C, Grant B, Lee H, Carmela T. The effect of vagal nerve stimulation on epileptiform activity recorded from hippocampal depth electrodes. Epilepsia 2001;42(3):423–9.

14. Hallböök T, Lundgren J, Blennow G, Strömblad LG, Rosén I. Long term effects on epileptiform activity with vagus nerve stimulation in children. Seizure. 2005 Dec;14(8):527-33. doi: 10.1016/j.seizure.2005.07.004. Epub 2005 Aug 10. PMID: 16098769.

15. McLachlan RS. Suppression of interictal spikes and seizures by stimulation of the vagus nerve. Epilepsia. 1993 Sep-Oct;34(5):918-23. doi: 10.1111/j.1528-1157.1993.tb02112.x. PMID: 8404747.

16. Jaseja H. Treatment of interictal epileptiform discharges in cerebral palsy patients without clinical epilepsy: hope for a better outcome in prognosis. Clin Neurol Neurosurg. 2007 Apr;109(3):221-4. doi: 10.1016/j.clineuro.2006.11.003. Epub 2006 Dec 8. PMID: 17157435.

Published March 2023

The efficacy and safety of VNS Therapy in older patients have been examined in a few publications. Generally, VNS Therapy appears to be well tolerated with a similar responder rate in the geriatric epilepsy population as in younger patients [1-4]. Already in 2000 Sirven and colleagues conducted a retrospective study to evaluate the efficacy, side effect profile, and potential quality of life improvements after VNS implantation in elderly patients (N=45, age: ≥50 years) [2]. They found a responder rate of 68% at the 12-month follow-up and a significant improvement in quality of life scores (as measured by interviewer global evaluation and Patient global evaluation, respectively). Furthermore, the adverse events were transient and did not warrant discontinuation.

On the contrary, an abstract by Suller-Marti et al. 2021 describes the occurrence of stimulation-related side effects to be slightly higher in the geriatric population (present in 75% of the patients) with the most prevalent adverse effect being hoarseness (41%) and throat pain (25%) [5]. The responder rate for these patients was 41.7% after a median follow-up of 44.5 months.

Chrastina et al. 2017 evaluated the responder rate of VNS Therapy in adult patients (N=103) stratified by age groups (<40 or ≥40 and <50 or ≥ 50 years) and epilepsy duration (<20 or ≥20, <30 or ≥30 and <50 or ≥50 years) [1]. They found no significant difference between a ≥50% (or a ≥90%) reduction in seizure frequency between age groups. Regarding epilepsy duration, the responder rate was significantly larger for patients with an epilepsy duration of ≥20 years. However, the time-dependent improvement that is usually observed during VNS follow-up was markedly reduced in older patients [1].

As a final remark, there are no known pharmacodynamic interactions for VNS Therapy as an adjunctive treatment to antiseizure medications [2]. This is of particular interest for geriatric patients who commonly have multiple comorbidities treated with a large number of pharmaceuticals. Another common obstacle in the pharmacological treatment of elderly patients is compliance, which is not an issue with VNS Therapy.

Reflection

VNS Therapy appears to be effective and well-tolerated in geriatric epilepsy patients. However, the number of publications on the elderly population is low, and larger prospective studies are needed.

References

1.Chrastina J, Kocvarova J, Novak Z, Dolezalova I, Svoboda M, Brazdil M. Older Age and Longer Epilepsy Duration Do Not Predict Worse Seizure Reduction Outcome after Vagus Nerve Stimulation. J Neurol Surg A Cent Eur Neurosurg. 2018 Mar;79(2):152-158. doi: 10.1055/s-0037-1607396. Epub 2017 Nov 27. PMID: 29179237.

2.  Sirven JI, Sperling M, Naritoku D, Schachter S, Labar D, Holmes M, Wilensky A, Cibula J, Labiner DM, Bergen D, Ristanovic R, Harvey J, Dasheiff R, Morris GL, O'Donovan CA, Ojemann L, Scales D, Nadkarni M, Richards B, Sanchez JD. Vagus nerve stimulation therapy for epilepsy in older adults. Neurology. 2000 Mar 14;54(5):1179-82. doi: 10.1212/wnl.54.5.1179. PMID: 10720294.

3. Thompson EM, Wozniak SE, Roberts CM, Kao A, Anderson VC, Selden NR. Vagus nerve stimulation for partial and generalized epilepsy from infancy to adolescence. J Neurosurg Pediatr. 2012 Sep;10(3):200-5. doi: 10.3171/2012.5.PEDS11489. Epub 2012 Jul 6. PMID: 22768964.

4. Elliott RE, Rodgers SD, Bassani L, Morsi A, Geller EB, Carlson C, Devinsky O, Doyle WK. Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr. 2011 May;7(5):491-500. doi: 10.3171/2011.2.PEDS10505. PMID: 21529189.

5. Suller Marti A, McLachlan R, Mirsattari S, Steven D, Parrent A, MacDougall K, Burneo J. VNS Used In The Elderly Population (4719). Neurology Apr 2021, 96 (15 Supplement) 4719.