Epilepsy Research (2015) 112, 100—113

journal homepage: www.elsevier.com/locate/epilepsyres

REVIEW

VNS for refractory status epilepticus F.A. Zeiler a,b,∗, K.J. Zeiler b,c,1, J. Teitelbaum b,c,2, L.M. Gillman d,e,3, M. West a,4 a

Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, Canada Section of Neurocritical Care, Montreal Neurological Institute, McGill, Montreal, Canada c Section of Neurology, Montreal Neurological Institute, McGill, Montreal, Canada d Section of Critical Care Medicine, Department of Medicine, University of Manitoba, Winnipeg, Canada e Section of General Surgery, Department of Surgery, University of Manitoba, Winnipeg, Canada b

Received 11 July 2014; received in revised form 7 February 2015; accepted 27 February 2015 Available online 9 March 2015

KEYWORDS Vagal nerve stimulation; VNS; Status epilepticus; Refractory status epilepticus

Summary Background: Our goal was to perform a systematic review of the literature on the insertion of vagal nerve stimulators (VNS) for refractory status epilepticus (RSE) and its impact on the control of RSE. Methods: All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to June 2014), reference lists of relevant articles, and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology by two independent reviewers (FZ and MW). Results: Overall, 17 studies were identified, with 7 manuscripts and 10 meeting abstracts. A total of 28 patients were treated. In those with generalized RSE, 76% displayed cessation of RSE with VNS insertion. In cases of focal RSE, 25% responded to VNS insertion. Few adverse effects related to VNS insertion were described. Conclusions: We currently cannot recommend the use of VNS for RSE. Oxford level 4, GRADE D evidence exists to suggest improvement in seizure control with the use of urgent VNS in generalized RSE. No comments can be made on the utility of VNS in focal RSE. Further prospective study is warranted. © 2015 Elsevier B.V. All rights reserved.



Corresponding author at: GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A1R9. Tel.: +1 204 228 6623. E-mail addresses: [email protected] (F.A. Zeiler), ka[email protected] (K.J. Zeiler), [email protected] (J. Teitelbaum), [email protected] (L.M. Gillman), [email protected] (M. West). 1 Address: GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A1R9. 2 Address: Montreal Neurological Institute, 3801 rue University, Montréal, QC, Canada H3A2B4. 3 Address: Section of General Surgery and Critical Care Medicine, Z3053 St. Boniface General Hospital, Winnipeg, MB, Canada. Tel.: +1 204 237 2568. 4 Address: Section of Neurosurgery, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R1A1R9. http://dx.doi.org/10.1016/j.eplepsyres.2015.02.014 0920-1211/© 2015 Elsevier B.V. All rights reserved.

Refractory status epilepticus

101

Contents Introduction.............................................................................................................. Materials and methods ................................................................................................... Search question, population, inclusion and exclusion criteria........................................................ Search strategy...................................................................................................... Study selection...................................................................................................... Data collection ...................................................................................................... Quality of evidence assessment ..................................................................................... Statistical analysis................................................................................................... Results ................................................................................................................... VNS parameters: generalized RSE ................................................................................... VNS parameters: focal RSE .......................................................................................... Treatment response: generalized RSE ............................................................................... Treatment response: focal RSE ...................................................................................... Adverse effects of VNS .............................................................................................. Study limitations ......................................................................................................... Outcome ............................................................................................................ Level of evidence for VNS in RSE .................................................................................... Discussion ................................................................................................................ Conclusions .............................................................................................................. Funding ................................................................................................................ Acknowledgments ...................................................................................................... Appendix A. Supplementary data..................................................................................... References .............................................................................................................

Introduction Vagal nerve stimulators (VNS) have been widely utilized for medically refractory epilepsy (Morris et al., 2013; Ryvlin et al., 2014). Implantation of VNS in both partial and generalized epilepsy has been associated with greater than 50% reduction in seizure frequency in over half of patients in which it was inserted. Currently, VNS carry level C evidence in Lennox—Gestaut syndrome in children (Morris et al., 2013). There is even some indication of superior seizure control when VNS is utilized in combination with anti-epileptic drugs (AED), compared to AED alone (Ryvlin et al., 2014). The mechanism(s) of action on seizure reduction with VNS are not fully understood (Groves and Brown, 2005; Aalbers et al., 2011). It is known through animal models that VNS induces diffuse EEG changes, potentially mediated via vagal nerve C-fibers, and also leads to increased hippocampal theta activity (Groves and Brown, 2005; Zabara, 1992). Furthermore, human studies have demonstrated an increase in CSF gamma-amino-butyric acid (GABA) levels (Carpenter et al., 2004), with up-regulation in GABAA receptors (Marrosu et al., 2003). In addition, animal studies have indicated an increase in noradrenergic secretion via the locus ceruleus (Meurs et al., 2008), and serotonergic transmission via the raphe magnus (Dorr and Debonnel, 2006) with VNS that may lead to seizure inhibition. Finally, there may be an anti-inflammatory effect of VNS that could lead to decrease in epileptogenicity (Pavlov and Tracey, 2005). Despite promising results in medically refractory epilepsy, there have been only a few reports of urgent VNS insertion for refractory status epilepticus (RSE) (Boon et al., 2007; De Benedictis et al., 2013; De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012;

101 101 101 102 102 102 102 103 103 104 110 110 110 110 110 110 110 110 112 112 112 112 112

Thielemann, 2009; Vonck et al., 2007; Winston et al., 2001; Zamponi et al., 2008; Zimmerman et al., 2002). The goal of our study was to perform a systematic review of the literature on urgent VNS insertion for RSE, in order to determine its impact on seizure control in RSE.

Materials and methods A systematic review using the methodology outlined in the Cochrane Handbook for Systematic Reviewers (Higgins and Green, 2014) was conducted. The data was reported following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) (Moher et al., 2009). The review questions and search strategy were decided upon by the primary author (FZ) and supervisor (MW).

Search question, population, inclusion and exclusion criteria The question posed for systematic review was: What is the effectiveness of urgent VNS insertion on control of RSE in humans? Refractory status epilepticus was defined as: The failure to control seizures, electrographically or clinically, after the implementation of an adequate dose of an initial benzodiazepine followed by an acceptable second line AED (Brophy et al., 2012). Generalized RSE was defined in the context of either clinical or electroencephalographic (EEG) evidence of ongoing seizure activity. All studies, prospective and retrospective of any size based on human subjects were included. The reason for an all-inclusive search was based on the small number of studies of any type identified by the primary author during a preliminary search of MEDLINE. The primary outcome measure was electrographic seizure control. Secondary outcome measures were patient

102 outcome (if reported), and adverse effects related to the VNS. Inclusion criteria were: Presence of RSE, all studies including human subjects whether prospective or retrospective, all study sizes, any age category, and the use of urgent VNS insertion for seizure control in RSE. Exclusion criteria were: Animal and non-English studies, any study not describing the seizure response to VNS insertion, and an indication for VNS insertion other than RSE. Of note, the studies identified in the review did not have a uniform definition of RSE, or define generalized or focal seizures. We applied the previously addressed definition of RSE (Brophy et al., 2012) to all studies in order to ensure their cases met the inclusion criteria. As for the definition of generalized/focal RSE subtypes, we elected to allow both the use of clinical and EEG based definitions since both were utilized in the papers identified. Most manuscripts failed to indicate whether clinical or EEG definitions of RSE were utilized in the initial diagnosis.

Search strategy MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, SCOPUS, and Cochrane Library from inception to June 2014 were searched using individualized search strategies for each database. The search strategy for MEDLINE can be seen in Appendix A of the supplementary material, with an identical search strategy utilized for the other databases. All search terms and the process of search term entry/search execution were identical in all databases searched. In addition, the World Health Organizations International Clinical Trials Registry Platform and Clinical Trials.gov were searched looking for studies planned or underway. As well, meeting proceedings for the last 10 years (From June 1994 to June 2014) looking for ongoing and unpublished work based on urgent VNS insertion for RSE were examined. The published meeting proceedings were obtained via searching the individual journals associated with the societies. The meeting proceedings of the following professional societies were searched: Canadian Neurological Sciences Federation (CNSF), American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), European Neurosurgical Society (ENSS), World Federation of Neurological Surgeons (WFNS), American Neurology Association (ANA), American Academy of Neurology (AAN), European Federation of Neurological Science (EFNS), World Congress of Neurology (WCN), American Epilepsy Society (AES), International League Against Epilepsy (ILAE), Society of Critical Care Medicine (SCCM), Neurocritical Care Society (NCS), World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM). Finally, reference lists of any review articles or systematic reviews on seizure management were reviewed for relevant studies on VNS insertion for seizure control in RSE.

Study selection Utilizing two reviewers (FZ and KZ), a two-step review of all articles returned by our search strategies was performed. First, the reviewers independently screened all titles and

F.A. Zeiler et al. abstracts of the returned articles to decide if they met the inclusion criteria. Second, full text of the chosen articles was then assessed to confirm if they met the inclusion criteria and that the primary outcome of seizure control was reported in the study. Any potential discrepancies between the two reviewers were resolved by a third party (MW).

Data collection Data was extracted from the selected articles and stored in an electronic database. Data fields included patient demographics, type of study (prospective or retrospective), number of patients, presence of acute symptomatic SE (i.e. No previous history of SE) or intercurrent SE (i.e. Previous history of SE), etiology of RSE, time from onset of SE to insertion of VNS, details of VNS stimulation parameters, how many other anti-epileptic drugs (AEDs) were utilized prior to insertion of VNS, degree of seizure control, adverse effects, study limitations and patient outcome.

Quality of evidence assessment Assessment of the level of evidence for each included study was conducted by two independent reviewers (FZ and MW), utilizing the Oxford criteria (Phillips et al., 2014) and the Grading of Recommendation Assessment Development and Education (GRADE) criteria (Guyatt et al., 2008a,b,c,d; Schünemann et al., 2008; Jaeschke et al., 2008) for level of evidence. We elected on utilizing two different systems to grade level of evidence given that these two systems are amongst the most commonly used. We believe this would allow a larger audience to follow our systematic approach in the setting of unfamiliarity with a particular grading system. The Oxford criterion consists of a 5 level grading system for literature. Level 1 is split into subcategories 1a, 1b, and 1c which represent a systematic review of randomized control trials (RCT) with homogeneity, individual RCT with narrow confidence interval, and all or none studies respectively. Oxford level 2 is split into 2a, 2b, and 2c representing systematic review of cohort studies with homogeneity of data, individual cohort study or low quality RCT, and outcomes research respectively. Oxford level 3 is split into 3a and 3b representing systematic review of case—control studies with homogeneity of data and individual case—control study respectively. Oxford level 4 represents case-series and poor cohort studies. Finally, Oxford level 5 represents expert opinion. The GRADE level of evidence is split into 4 levels: A, B, C and D. GRADE level A represents high evidence with multiple high quality studies having consistent results. GRADE level B represents moderate evidence with one high quality study, or multiple low quality studies. GRADE level C evidence represents low evidence with one or more studies with severe limitations. Finally, GRADE level D represents very low evidence based on either expert opinion or few studies with severe limitations. Any potential discrepancies between the grading of the reviewers were resolved via a third party (LG).

Refractory status epilepticus

Statistical analysis A meta-analysis was not performed in this study due to the heterogeneity of data within the articles and the presence of a small number of retrospective studies. There was a 100% correlation Oxford and GRADE scores as adjudicated by the two independent reviewers (FZ and MW), thus formal interrater variability calculations were not performed.

Results The results of the search strategy across all databases and other sources are summarized in Fig. 1. After removal of duplicates a total of 1686 articles were identified, with 1672 from the database search and 14 from the search of published meeting proceedings. No ongoing clinical trials were identified in the WHO database. By applying the inclusion/exclusion criteria to the title and abstract of the articles, we identified 42 articles that fit these criteria. Of the 42 identified, 32 were from the database search and 10 were from published meeting proceedings. Applying the inclusion/exclusion criteria to the full text documents, only 17 articles were eligible for inclusion in the systematic review, with 7 from database and 10 from meeting proceeding sources. There were 25 articles that were excluded after review of the entire manuscript. These manuscripts were excluded because they either did not report seizure response to implantation of the VNS, did not report the insertion of VNS in the setting of RSE, or because they were review articles. Reference sections from these review articles were searched for any other articles missed in the database search, with none being identified. Of the 17 articles included in the review (Boon et al., 2007; De Benedictis et al., 2013; De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012; Thielemann, 2009; Vonck et al., 2007; Winston et al., 2001; Zamponi et al., 2008), 15 were original studies (De Benedictis et al., 2013; De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012; Thielemann, 2009; Winston et al., 2001; Zamponi et al., 2008), while two were companion articles (Boon et al., 2007; Vonck et al., 2007) containing overlapping patient data. There were 7 manuscripts (De Benedictis et al., 2013; De Herdt et al., 2009; Howell et al., 2012; O’Neill et al., 2011; Patwardhan et al., 2005; Winston et al., 2001; Zamponi et al., 2008), and 10 abstracts overall (Boon et al., 2007; Donahue et al., 2013; Lin and Ko, 2012; Malik and Hernandez, 2004; Shatzmiller et al., 2011; Soto et al., 2009, 2012; Thielemann, 2009; Vonck et al., 2007; Zimmerman et al., 2002). All patients within these manuscripts met the definition of RSE (Brophy et al., 2012), however we could not comment on adequate dosing of the benzodiazepines utilized given that this was not documented clearly within the studies. As mentioned, three articles were case reports on the same patient, with different periods of follow-up (Boon et al., 2007; De Herdt et al., 2009; Vonck et al., 2007). The

103 data in the manuscript (De Herdt et al., 2009) was utilized for inclusion in the summary, while the meeting abstracts (Boon et al., 2007; Vonck et al., 2007) were included for completeness and not included the data summarization process in order to prevent duplication of patient data. Thus a total of 15 articles were included in the data summary (De Benedictis et al., 2013; De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012; Thielemann, 2009; Winston et al., 2001; Zamponi et al., 2008; Zimmerman et al., 2002). One study was a prospective cohort study (Zimmerman et al., 2002). All remaining studies were retrospective, with 6 retrospective case series (De Benedictis et al., 2013; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; Zamponi et al., 2008) and 8 retrospective case reports (De Herdt et al., 2009; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012; Thielemann, 2009; Winston et al., 2001). The retrospective case series were all single center reviews. Six articles described the use of urgent VNS insertion in adults (Lin and Ko, 2012; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Thielemann, 2009; Zimmerman et al., 2002). Eight studies described pediatric patients (De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Malik and Hernandez, 2004; Soto et al., 2009, 2012; Winston et al., 2001; Zamponi et al., 2008). One study had both adult and pediatric patients (De Benedictis et al., 2013). Across all studies, a total of 28 patients were studied utilizing urgent VNS insertion for control of their RSE (mean: 1.9 patients/study; range: 1—5 patients/study). Eighteen patients were pediatric (age range: 7 months to 15 years). Ten patients were adult (age range: 19—82 years). A variety of underlying etiologies for RSE existed in both the adult and pediatric populations. Three studies documented VNS insertion for RSE in patients with a history of inter-current SE (De Herdt et al., 2009; Soto et al., 2009, 2012). Nine studies documented VNS insertion for RSE in patients with acute symptomatic SE (De Benedictis et al., 2013; Howell et al., 2012; Lin and Ko, 2012; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Thielemann, 2009; Winston et al., 2001; Zamponi et al., 2008). Three studies failed to mention any previous history of SE (Donahue et al., 2013; Malik and Hernandez, 2004; Zimmerman et al., 2002). Only one manuscript described VNS insertion for focal RSE, with 4 patients described (De Benedictis et al., 2013). All remaining studies described patients with generalized RSE. Two patients were reported to be in non-convulsive RSE (De Benedictis et al., 2013; Shatzmiller et al., 2011). The individual studies included in the review did not describe which definition of RSE they follow at their individual institutions, though met our definition of RSE (Brophy et al., 2012). Furthermore, the primary method used to diagnose RSE, via EEG or clinically, was not clearly outlined in most studies identified. However, 5 studies mentioned an EEG based RSE diagnosis alone (De Benedictis et al., 2013; De Herdt et al., 2009; Howell et al., 2012; Shatzmiller et al., 2011; Zamponi et al., 2008), 6 studies based diagnosis of RSE both clinically and with EEG (Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Thielemann,

104

F.A. Zeiler et al.

Figure 1

Flow diagram of search results.

2009; Winston et al., 2001; Zimmerman et al., 2002), while 4 studies failed to mention the method of diagnosis (Donahue et al., 2013; Lin and Ko, 2012; Soto et al., 2009, 2012). Thus, the number of patients with EEG defined non-convulsive RSE may be understated. Study demographics and patient characteristics for all studies can be seen in Table 1, while treatment characteristics, study limitations and seizure outcome are reported in Table 2.

VNS parameters: generalized RSE Within the 15 studies identified utilizing urgent VNS insertion for control of RSE, the side of insertion was only documented in two articles (Patwardhan et al., 2005; Winston et al., 2001). One study utilized concurrent ketogenic diet with VNS insertion (Lin and Ko, 2012). Stimulation parameters varied for the patients with generalized RSE (De Herdt et al., 2009; Donahue et al., 2013; Howell et al., 2012; Lin and Ko, 2012; Malik and Hernandez, 2004; O’Neill et al., 2011; Patwardhan et al., 2005; Shatzmiller et al., 2011; Soto et al., 2009, 2012;

Thielemann, 2009; Winston et al., 2001; Zamponi et al., 2008; Zimmerman et al., 2002). The initial current ranged from 0.25 mA to 1.0 mA, which was then titrated to effect with an upper limit ranging from 1.0 mA to 2.0 mA. The starting frequency ranged from 20 to 30 Hz, and remained at this level during the titration process. The initial pulse width ranged from 250 to 500 ␮s, and was titrated to a maximum of 500 ␮s. The cycle durations varied with the initial ranging from 30 s ‘‘on’’ and 3 min ‘‘off’’ to 30 s ‘‘on’’ and 5 min ‘‘off’’. The most rapid cycling was recorded at 7 s ‘‘on’’ and 14 s ‘‘off’’ (Howell et al., 2012). The most common starting stimulation parameters for the VNS in patients with generalized RSE were a current of 0.25 mA or 1 mA, frequency of 30 Hz, pulse width of 250 ␮s, and a cycle of 30 s ‘‘on’’ and 3 min ‘‘off’’. Timing between changes in VNS parameters were not commonly recorded, though a 24 h titration time was mentioned between starting and maximal stimulation. The duration of treatment prior to insertion of VNS (if documented) ranged from 4 to 50 days, with patients on various numbers of AEDs prior to insertion of the VNS, ranging from 4 to 12. Treatment characteristics for the adult studies can be seen in Table 2.

Study characteristics and patient demographics.

Reference

Number of patients treated with VNS

Study type

Article location

Mean age (years)

Etiology of RSE

Type of seizures

Mean # meds prior to VNS

Mean time until VNS placement (days)

Boon et al. (2007)a

1

Retrospective case report

Meeting abstract

7

Generalized non-convulsive Dx by: EEG

8

11

De Benedictis et al. (2013)

4

Retrospective case series

Manuscript

13.8 (range: 6—24) 3 Childeren

Epilepsia partialis continua Dx by: EEG

5.8 (range: 5—7)

22.5 mons. (range: 6—60)

De Herdt et al. (2009)a

1

Retrospective case report

Manuscript

7

Generalized Non-convulsive Dx by: EEG

8

11

Donahue et al. (2013)

5

Retrospective case series

Meeting abstract

5.3 (range: 0.7—9)

Generalized Dx by: unknown

Median 10 (range: 5—11)

Median 26 (range: 4—50)

Howell et al. (2012)

7 (only 1 with VNS for RSE)

Retrospective case series

Manuscript

Unknown (was child)

Generalized Dx by: EEG

Unknown

14

Lin and Ko (2012)

2

Retrospective Case Series

Meeting abstract

19 and 49

Generalized Dx by: unknown

Unknown

‘‘Weeks to months’’

Malik and Hernandez (2004)

3

Retrospective case series

Meeting abstract

Unknown (all pediatric)

Generalized Dx by: clinical and EEG

Unknown

Unknown

O’Neill et al. (2011)

1

Retrospective case report

Manuscript

23

3 weeks

1

Retrospective case report

Manuscript

30

Generalized Dx by: clinical and EEG Generalized Dx by: clinical and EEG

9

Patwardhan et al. (2005)

8

Unknown

Shatzmiller et al. (2011)

1

Retrospective case report

Meeting abstract

19

Inter-current SE: Cause: Thalamic ICH and IVH at birth, refractory epilepsy since Acute symptomatic SE (2); inter-current SE (2) Cause: Chronic inflammatory encephalopathy (2), rasmussen encephalitis (1), poliodystrophy (1) Inter-current SE: Cause: Thalamic ICH and IVH at birth, refractory epilepsy since Unknown previous history of SE AED withdrawal (1), leigh’s disease (1), viral encephalitis (3) Acute symptomatic SE in all Cause: FIRES Acute symptomatic SE (2) Cause: Anti-NMDA encephalitis (1), and unknown (1) Unknown previous history of SE Cause: Unknown Acute symptomatic SE Cause: Post traumatic epilepsy Acute symptomatic SE Cause: Idiopathic Epilepsy since age 24, withdrawal of meds due to allergy Acute symptomatic SE Cause: Anti-NMDA encephalitis and NORSE

Generalized non-convulsive Dx by: EEG

10

Unknown

Refractory status epilepticus

Table 1

105

106

Table 1 (Continued) Reference

Number of patients treated with VNS

Study type

Article location

Mean age (years)

Etiology of RSE

Type of seizures

Mean # meds prior to VNS

Mean time until VNS placement (days)

Soto et al. (2012)

1

Retrospective case report

Meeting abstract

4

Generalized Dx by: unknown

10 plus ketogenic diet

20

Soto et al. (2009)

1

Retrospective case report

Meeting abstract

15

Generalized Dx by: unknown

7 plus ketogenic diet

Unknown

Thielemann (2009)

1

Retrospective case report

Meeting abstract

23

Generalized Dx by: clinical and EEG

12

25

Vonck et al. (2007)a

1

Retrospective case report

Meeting abstract

7

Generalized non-convulsive Dx by: EEG

8

11

Winston et al. (2001)

1

Retrospective case report

Manuscript

13

Generalized Dx by: clinical and EEG

Unknown

7

Zamponi et al. (2008)

6 (only 2 with VNS for RSE)

Retrospective case series

Manuscript

9 and 7 mons.

Generalized Dx by: EEG

Unknown

Unknown

Zimmerman et al. (2002)

3

Prospective cohort

Meeting abstract

55.3 (range: 20—82)

Inter-current SE Cause: Neonatal hypoxemic encephalopathy Inter-current SE Cause: Post-meningitis epilepsy Acute symptomatic SE Cause: Primary generalized epilepsy, non-compliance Inter-current SE: Cause: Thalamic ICH and IVH at birth, refractory epilepsy since Acute symptomatic SE Cause: Primary generalized epilepsy Acute symptomatic SE Cause: Partial migrating epilepsy of infancy (2) Unknown previous history of SE Cause: Medically refractory multifocal epilepsy

Generalized Dx by: clinical and EEG

4.7 (range: 4—5)

1—5 weeks

VNS = vagal nerve stimular, RSE = refractory status epilepticus, mons. = months, ICH = intracerbral hemorrhage, IVH = intraventricular hemorrhage, AED = anti-epileptic drug, Dx = diagnosed, FIRES = febrile infection related epilepsy syndrome, NMDA = n-methyl D-aspartate, NORSE = new onset refractory status epilepticus, ADNFLE = autosomal dominant frontal lobe epilepsy. a Boon et al. (2007), De Herdt et al. (2009) and Vonck et al. (2007) are publications on the same patient, with Boon et al. (2007) and Vonck et al. (2007) meeting abstracts. De Herdt et al. (2009) is the final, long term follow up on this patient.

F.A. Zeiler et al.

Treatment characteristics, seizure response, and outcome.

Reference

VNS parameters

Side of VNS

Electrographic seizure response

Time to seizure response (days)

Rating of SE response

Adverse effects to VNS

Patient outcome

Study limitations

Boon et al. (2007)a

Titrated to 1.5 mA over 48 h

Unknown

Cessation of seizures

3

Excellent

Recurrent bradycardia day #4, asystolic arrest

Seizure free at 6 months, unknown meds

De Benedictis et al. (2013)

Titrated to effect: 1.5—2.5 mA Over mean 40.5 days (range: 21—60)

Unknown

Cessation of EPC in all; ongoing intermittent seizures in 3, no seizure in 1

37.5 (range: 15—60)

Moderate

None

De Herdt et al. (2009)a

Titrated to 1.5 mA over 48 h

Unknown

Cessation of seizures

3

Excellent

Donahue et al. (2013)

Initial settings: 0.25 mA, 30 Hz freq., 250 ␮s pulse width. 30 s on, 3 min off cycle Unknown upper limit of titration

Unknown

Cessation of seizures in 2, persistent status for 21—84 days after VNS in 3

7

Poor; only 2/5 responded

Recurrent bradycardia day #4, asystolic arrest None

Ongoing intermittent focal seizures in 3, no seizures in 1 (went for hemispherectomy anyways given RE). All on AEDs 13 month F/U report: no seizures, AEDs tapering

-Retrospective -Meeting abstract -Single case -Poor F/U -Publication bias -Retrospective -Small series -Poor F/U -Publication bias

Howell et al. (2012)

Titrated up to 1.75 mA over 36 h Tried both: −30 s on, 3 min off −7 s on, 14 s off Unknown but combined with ketogenic diet

Unknown

Failure

No response for 15 days

Failure

None

Died

Unknown

Cessation of status in both

14

Excellent

None

Home (1); in rehab. following commands (1)

Unknown

Cessation of status in all, one seizure free initially after VNS, two reduction of seizures >60%

Unknown

Excellent

None

Significant seizure reduction (3)

Lin and Ko (2012)

Malik and Hernandez (2004)

Unknown

All have ongoing intermittent seizures on AED and VNS

107

-Retrospective -Single case -Poor details in F/U -Publication bias -Retrospective -Small series -Meeting abstract -Unknown method of RSE determination -Poor F/U details -Publication bias -Retrospective -Small series -Unknown ages -Unknown # AED -Publication bias -Retrospective -Single case -Meeting abstract -Unknown method of RSE determination -Unknown # of AED -Unknown VNS parameters -Publication bias -Retrospective -Small series -Meeting abstract -Unknown ages -Unknown # AED -Unknown VNS parameters -Unknown duration of RSE prior to VNS -Unknown duration of VNS use -Poor F/U -Publication bias

Refractory status epilepticus

Table 2

108

Table 2 (Continued) Reference

VNS parameters

Side of VNS

Electrographic seizure response

Time to seizure response (days)

Rating of SE response

Adverse effects to VNS

Patient outcome

Study limitations

O’Neill et al. (2011)

1.0 mA, 25 Hz, pulse width of 250 ␮s 7 s on, 0.3 min off cycle Started at: 0.25 mA, 20 Hz, pulse width 250 ␮s. At 30 s on, 5 min off Titrated to: 1.0 mA. At 30 s on, 3 min off Unknown

Unknown

Cessation of status, seizure stopped at 5 days

2

Excellent

None

-Retrospective -Single case -Publication bias

Left

Cessation of status, and seizure free at discharge (POD 18)

1

Excellent

None

2 months of rehab., then home at pre-hospital functional status Discharged home; weak and memory issues

Unknown

Failed

N/A

Failure

None

Responded to cyclophosphamide and in rehab.

Soto et al. (2012)

Started at: 1.0 mA, 30 Hz, pulse width 500 ␮s. At 30 s on, 5 min off

Unknown

Cessation of seizures

Unknown

Excellent

None

Unknown

Soto et al. (2009)

Started at: 1.0 mA, 30 Hz, pulse width 500 ␮s. At 30 s on, 5 min off Titrated to 1.5 mA

Unknown

Cessation of status, reduction in partial motor seizures by 70%

Unknown

Excellent

None

No seizures for 4 months

Thielemann (2009)

Started at: 1.0 mA, pulse width 250 ␮s. At 7 s on, 0.3 min off Titrated to: 30 s on, 1.1 min off Titrated to 1.5 mA over 48 h

Unknown

Cessation of status

3

Excellent

None

Discharged to rehab. 1 seizure per week

Unknown

Cessation of seizures

3

Excellent

Recurrent bradycardia day #4, asystolic arrest

8 month F/U report: no seizures, AEDs tapering

Patwardhan et al. (2005)

Shatzmiller et al. (2011)

Vonck et al. (2007)a

-Retrospective -Single case -Unknown duration of RSE prior to VNS -Publication bias -Retrospective -Single case -Meeting abstract -Unknown duration of RSE prior to VNS -Unknown VNS parameters -Poor F/U data -Publication bias -Retrospective -Single case -Meeting abstract -Unknown method of RSE determination -Unknown F/U -Publication bias -Retrospective -Single case -Meeting abstract -Unknown method of RSE determination -Unknown duration of RSE prior to VNS -Publication bias -Retrospective -Single case -Meeting abstract -Publication bias

F.A. Zeiler et al.

-Retrospective -Single case -Meeting abstract -Poor details on VNS parameters used and titration -Publication bias

Refractory status epilepticus

Winston et al. (2001)

Zamponi et al. (2008)

Zimmerman et al. (2002)

Started at: 0.25 mA, 30 Hz, pulse width 500 ␮s. At 7 s on, 120 s off Titrated to (max 0.25 mA every 2 days): 2.0 mA, 20 Hz, pulse width 250 ␮s. At 7 s on, 120 s off Started at: 0.25 mA, 30 Hz, unknown pulse width. At 30 s on, 5 min off Titrated to: 1.75 mA and 2.0 mA

Left

Immediate cessation of Status post-op. Titrated to reduce seizures over following year

VNS for refractory status epilepticus.

Our goal was to perform a systematic review of the literature on the insertion of vagal nerve stimulators (VNS) for refractory status epilepticus (RSE...
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