Elsevier

Epilepsy Research

Volume 172, May 2021, 106591
Epilepsy Research

Cognitive outcomes following vagus nerve stimulation, responsive neurostimulation and deep brain stimulation for epilepsy: A systematic review

https://doi.org/10.1016/j.eplepsyres.2021.106591Get rights and content

Highlights

  • Cognitive data for VNS, DBS and RNS are lacking in number and quality.

  • The majority of studies reported no cognitive changes following chronic VNS.

  • Cognitive improvements after chronic RNS and DBS were reported by most studies.

  • Cognitive changes during acute stimulation are mixed.

Abstract

Background

The cognitive impacts of resective surgery for epilepsy have been well-studied. While seizure outcomes for less invasive, neuromodulatory treatments are promising, there is a paucity of data for cognitive outcomes.

Methods

Medline, EMBASE, and the Cochrane Library were searched on November 2019. Inclusion criteria were studies reporting cognitive outcomes following chronic (>6 months) vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS) for epilepsy in at least five patients. Studies reporting acute on-off effects of stimulation were also included. Studies were screened, extracted of data, and assessed for bias using the Joanna Briggs Institute Critical Appraisal Tools by two independent reviewers. Prospero ID: CRD42020184432.

Results

Of 8443 studies screened, 29 studies were included. Nineteen investigated the effects of chronic stimulation (11 VNS, 6 DBS, 2 RNS): 10 (53 %) reported no change compared to preoperative baseline; 8 (42 %) reported some improvement in one or more cognitive domain; 1 (5%) reported decline. Ten investigated the effects of acute stimulation (5 VNS, 5 DBS): 3 (30 %) reported no change; 4 reported improvement (40 %); 3 (30 %) reported decline. Eight (28 %) did not report statistical analysis.

Conclusions

Long-term cognitive outcomes are at least stable following VNS, DBS and RNS. Acute effects of stimulation are less clear. However, data are limited by number, size, and quality. More robust evidence is needed to properly assess the cognitive effects of each of these treatments.

Introduction

Cognitive deficits in patients with epilepsy are highly prevalent and contribute significant burden on quality of life to patients and their families (Gowers and William, 1881; Jokeit and Ebner, 2002; Kleen et al., 2013; Loughman et al., 2014; Smith et al., 2002). Deficits can affect the whole range of cognitive functions including attention, memory, executive function, IQ and language (Gowers and William, 1881; Jokeit and Ebner, 2002; Kleen et al., 2013; Loughman et al., 2014; Smith et al., 2002). Cognitive dysfunction in epilepsy patients is related to a multitude of factors, including etiology of epilepsy, permanent effects of seizure activity, antiepileptic drugs (AEDs), and surgical management (Bermudez et al., 2019; Cochrane et al., 1998; Copeland et al., 2017; Donos et al., 2018; Hermann et al., 2010; Holmes, 2015; Jokeit and Ebner, 2002; Kleen et al., 2013, 2011). Therefore, balancing ongoing cognitive decline from seizures with cognitive sequelae from surgery remains a challenge.

With the long-term cognitive impact of the traditional anterior temporal lobectomy (ATL) well studied, research into strategies to optimize seizure outcomes with minimal cognitive impact has been a priority. Selective approaches, including selective amygdalohippocampectomy (SAH), have been designed to remove epileptogenic mesial temporal structures while sparing temporal cortex in order to minimize cognitive impact. Studies have reported better cognitive outcomes following SAH versus ATL, but results have been mixed, with one meta-analysis finding no significant difference in IQ (Hu et al., 2013; Tanriverdi et al., 2010).

Less invasive still are electrical neurostimulation techniques including deep brain stimulation (DBS), vagus nerve stimulation (VNS), and responsive neurostimulation (RNS). Nondestructive, reversible and programmable, these techniques precisely target neural structures to modulate seizure activity while minimizing adverse effects. Although the indications for these techniques differ from those of resective surgery, they are thought to offer alternative surgical approaches to epilepsy with lesser adverse cognitive impact.

With cognitive outcomes a major factor in guiding management of epilepsy for both clinicians and patients alike, quantification of cognitive outcomes is of utmost importance. However, data for these newer techniques are few and mixed; heterogenous surgical technique, neuropsychological testing and reporting lead to difficulties in comparing studies.

The objective of this systematic review was to investigate neuropsychological outcomes following VNS, DBS and RNS for epilepsy.

Section snippets

Protocol and registration

The protocol for this study was registered on PROSPERO (registration number: CRD42020184432).

Eligibility criteria

Studies were selected that reported neuropsychological outcomes for adult and pediatric patients that underwent vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation for epilepsy. All study designs were considered, with a minimum limit of five patients, and 6 months of follow up postoperatively. Studies with a selective population including exclusively syndromic epilepsy were

Study selection

The database searches yielded 8443 studies including 2575 duplicates. After excluding 5110 studies based on the abstract, 758 underwent full-text review. In total, 29 studies matched the inclusion criteria and were included. PRISMA flow diagram of identification, screening, eligibility, and inclusion of studies is shown in Supplementary information 1 (Moher et al., 2009).

Study characteristic

Nineteen studies investigated the effects of chronic stimulation (11 VNS, 6 DBS, 2 RNS). Of these, two were the open-label

Discussion

Cognitive dysfunction in epilepsy is highly prevalent, and related both to seizure frequency and disease duration (Wang et al., 2019b). A third of patients with epilepsy are refractory to medication and continue to experience seizures during long unsuccessful trials of multiple AEDs before being considered for surgery. While the two goals of epilepsy treatment – medical or surgical – are to reduce seizure frequency while minimizing adverse effects, both modalities are known to contribute to

Funding

No funding was received for this work.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

None.

References (99)

  • A. Grimonprez et al.

    The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus

    J. Psychiatr. Res.

    (2015)
  • C.L. Harden et al.

    A pilot study of mood in epilepsy patients treated with vagus nerve stimulation

    Epilepsy Behav.

    (2000)
  • C. Helmstaedter et al.

    Memory alterations during acute high-intensity vagus nerve stimulation

    Epilepsy Res.

    (2001)
  • B. Hermann et al.

    Cognition across the lifespan: antiepileptic drugs, epilepsy, or both?

    Epilepsy Behav. EB

    (2010)
  • K. Holm et al.

    Immediate effects of vagus nerve stimulation on human cognition and emotion

    Brain Stimul. Basic Transl. Clin. Res. Neuromod.

    (2017)
  • C. Hoppe et al.

    No evidence for cognitive side effects after 6 months of vagus nerve stimulation in epilepsy patients

    Epilepsy Behav.

    (2001)
  • C. Hoppe et al.

    Self-reported mood changes following 6 months of vagus nerve stimulation in epilepsy patients

    Epilepsy Behav.

    (2001)
  • D.R. Hulsey et al.

    Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation

    Exp. Neurol.

    (2017)
  • J. Jacobs et al.

    Direct electrical stimulation of the human entorhinal region and Hippocampus Impairs memory

    Neuron

    (2016)
  • H. Jokeit et al.

    Effects of chronic epilepsy on intellectual functions

    Prog. Brain Res.

    (2002)
  • S.H. Kim et al.

    Long-term follow-up of anterior thalamic deep brain stimulation in epilepsy: a 11-year, single center experience

    Seizure - Eur. J. Epilepsy

    (2017)
  • J.K. Kleen et al.

    Early-life seizures produce lasting alterations in the structure and function of the prefrontal cortex

    Epilepsy Behav. EB

    (2011)
  • S. Klinkenberg et al.

    Behavioural and cognitive effects during vagus nerve stimulation in children with intractable epilepsy – a randomized controlled trial

    Eur. J. Paediatr. Neurol.

    (2013)
  • A. Loughman et al.

    Cognitive functioning in idiopathic generalised epilepsies: a systematic review and meta-analysis

    Neurosci. Biobehav. Rev.

    (2014)
  • L.M. McDermott et al.

    A meta-analysis of depression severity and cognitive function

    J. Affect. Disord.

    (2009)
  • M. Miatton et al.

    The cognitive effects of amygdalohippocampal deep brain stimulation in patients with temporal lobe epilepsy

    Epilepsy Behav.

    (2011)
  • Y. Nakano et al.

    Executive dysfunction in medicated, remitted state of major depression

    J. Affect. Disord.

    (2008)
  • J.A. Nichols et al.

    Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors

    Neuroscience

    (2011)
  • Y.-S. Oh et al.

    Cognitive improvement after long-term electrical stimulation of bilateral anterior thalamic nucleus in refractory epilepsy patients

    Seizure - Eur. J. Epilepsy

    (2012)
  • Y. Paelecke-Habermann et al.

    Attention and executive functions in remitted major depression patients

    J. Affect. Disord.

    (2005)
  • T.D. Parsons et al.

    Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson’s disease: a meta-analysis

    Lancet Neurol.

    (2006)
  • R.W. Roosevelt et al.

    Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

    Brain Res.

    (2006)
  • J.-D. Tsai et al.

    The neuropsychological outcome of pediatric patients with refractory epilepsy treated with VNS — a 24-month follow-up in Taiwan

    Epilepsy Behav.

    (2016)
  • R. Tyrand et al.

    Effects of amygdala-hippocampal stimulation on interictal epileptic discharges

    Epilepsy Res.

    (2012)
  • V. Voltzenlogel et al.

    The influence of seizure frequency on anterograde and remote memory in mesial temporal lobe epilepsy

    Seizure

    (2014)
  • K. Vonck et al.

    Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study

    Seizure

    (2008)
  • Y. Wang et al.

    Improvement of intellectual outcomes in 20 children with refractory epilepsy after individualized surgery

    Surg. Neurol. Int.

    (2018)
  • H.-J. Wang et al.

    Predictors of seizure reduction outcome after vagus nerve stimulation in drug-resistant epilepsy

    Seizure

    (2019)
  • Y. Zhang et al.

    Transcutaneous auricular vagus nerve stimulation at 1 Hz modulates locus coeruleus activity and resting state functional connectivity in patients with migraine: an fMRI study

    Neuroimage Clin.

    (2019)
  • S.T. Aaronson et al.

    A 5-Year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality

    Am. J. Psychiatry

    (2017)
  • J.H. Aarts et al.

    Selective cognitive impairment during focal and generalized epileptiform EEG activity

    Brain J. Neurol.

    (1984)
  • G.M. Alexander et al.

    Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex

    J. Neurochem.

    (2017)
  • S. Baxendale et al.

    Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults

    Epileptic Disord. Int. Epilepsy J. Videotape

    (2019)
  • C.I. Bermudez et al.

    Cognitive Outcomes Following Laser Interstitial Therapy for Mesiotemporal Epilepsies

    (2019)
  • S.M. Berry et al.

    A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression

    Med. Devices Auckl. NZ

    (2013)
  • P. Boon et al.

    Deep brain stimulation in patients with refractory temporal lobe epilepsy

    Epilepsia

    (2007)
  • J. Cao et al.

    Vagal nerve stimulation triggers widespread responses and alters large-scale functional connectivity in the rat brain

    PLoS One

    (2017)
  • D. Cheng et al.

    The effect of interictal epileptiform discharges on cognitive and academic performance in children with idiopathic epilepsy

    BMC Neurol.

    (2020)
  • K.B. Clark et al.

    Enhanced recognition memory following vagus nerve stimulation in human subjects

    Nat. Neurosci.

    (1999)
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