Appendix S1- MEDLINE search strategy
1exp Epilepsy/
147007
2epilep*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
143123
3exp Seizures/
48872
4seizure*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
124995
51 or 2 or 3 or 4
205528
6exp Heart Rate/
159772
7heart rate.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
222258
8ictal tachycardia.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
35
9ictal bradycardia.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
70
10cardiovascular change*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
2344
117 or 8 or 9 or 10
223519
125 and 11
1628
13limit 12 to humans
1130
Appendix S2-Quality Assessment Tool
Articles are assigned 1 point for each “yes” received on the following scale for a total score out of 8. If a question is not applicable for the study under review, select “not applicable” so that the final quality denominator is lower (e.g., out of 7) for the given study.
Representativeness of Sample
1. Is the target population clearly defined?
□ Yes □ No □ Unclear □ Not reported
e.g. The target population must be defined by shared characteristics assessed and measure accurately. Some of these characteristics include age, sex, ethnicity, income, etc. Clear inclusion and exclusion criteria.
2. Was either of the following ascertainment method used (must be one or the other)
1) probabilitysamplingOR
2) entire population surveyed
□ Yes □ No □ Unclear □ Not reported
e.g. Members of the target population were identified through a sampling frame or listing of potential respondents. This listing must provide access to all members or the defined target population except for exclusions acknowledged by the study authors.
3. Is the response rate ≥70%/is the number of patients adequate? (modified)
□ Yes □ No □ Not reported □ Not Applicable
4. Are non-responders clearly described?/ are there any subcategories analysed? (modified)
□ Yes □ No □ Not reported □ Not Applicable
5. Is the sample representative of the target population?
□ Yes □ No □ Unclear □ Not reported
e.g. need to ensure that non-responders have similar characteristics as responders (otherwise may have selection bias)
Assessment of Neurological Condition
6. Were data collection methods standardized?For both EEG and HR assessment
□ Yes □ No □ Unclear □ Not reported
e.g. Identical methods of assessment and data collection were used with all respondents so that the information for analysis is completely comparable. Standardization of methods not only refer to eliciting information from respondents but also to interviewing training, supervision, enlistment of respondents and processing of data.
7. Were validated criteria used to assess for the presence/absence of disease? (IT and IB definition)
□ Yes □ No □ Unclear □ Not reported
e.g. or a validated scale, diagnostic tool, survey, etc.
Statistical Analysis
8. Are the estimates of prevalence and incidence given with confidence intervals and in detail by subgroup (if applicable)?Were numbed of seizures and number of seizures with pre-ictal changes reported? (modified)
□ Yes □ No □ Unclear □ Not reported
TOTAL QUALITY SCORE: ______Quality Score Denominator: ______
Table S1. Characteristics of the 30 studies assessing pre-ictal HR changes
Study / Design and setting / Epi type / Participants(N) / Age group, mean (SD) and range / Gender / Drug-resistance/on AEDs during test / Seizure recorded
(N) / Clinical (C)/
Subclinical (Sc) events / Diurnal (D)/ nocturnal (N) events / Seizure focus and side / Seizure type / EEG
(type, duration, video) / Definition of seizure onset / Definition of IT, IB / HR assessment
method / Baseline HR (bpmSD) / Seizures with IT (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRI (N, %) / Time of onset of
pre-ictal HR
change (sec) / Seizure with IB (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRR (N, %)
Van Buren 195821 / R, I / TLE / 13 / Adults, 31.3 / 6M,7F / Drug-resistant, most off AEDs / 20 / C / NR / T / CPS / Scalp single channel,
intermittent during 1-8 months (minimum observational interval 3 hours), no video / clinical / no / Manually counting over a ten-second interval, in the peri-ictal period / 75 / NR,
130 bpm / 19 (95%) / pre-ictally
(timing not reported) / 1 (5%) / none
Blumhardt 198622 / P, O / TLE / 26 / Adults,
33.1,
14-75 / 15M,
11F / 14 drug-resistant,
on AEDs / 74 / 71 C, 3 Sc / 3 N / T
(21R, 21L, 24Bi,
8 unknown) / CPS / Scalp 2 channels, continuous up to 24 hours, no video / Either EEG and clinical / no / Automatic
(R-R interval ratemeter), immediately before seizure onset / NR / 67 (91%),
201 bpm / 35 (47.3%) / 10.2 (3-20) / none / /
Keilson 198938 / R, O / Focal and Gen / 45 / Adults and children, 25.3,
4-69 / NR / NR / 106 / Sc / NR / 21R, 20L / 41 Focal, 65 Gen / Scalp, 7 channels, continuous up to 24 hours, no video / EEG / no / Manual, from 1 minute prior to seizure / NR / 102 (96%),
<100 in 3 seizures,
100-119 in 18, 120-149 in 30 seizures,
>150 in 51 seizures / NR / Tachycardia
can occur
several seconds
before or
after the seizure / none / /
Galimberti 199634 / R, O / Focal / 50 (31T, 12F, 7 other) / Adults and children, 29 (11.7), 12-61 / 25M,
25F / NR
On AEDs / 90 / NR / NR / 56T
(30R,
25L, 1 unknown), 29F,
5 undetermined / NR / Scalp, 8 channels, continuous up to 24 hours, no video / EEG / no / Manually counting consecutive-R intervals for 30 sec before seizure plus visual examination of HR trend throughout the EEG discharge / 69.513 / 44 (49%), 88.621 (186 in 72 seizures) / None / / / 23 (25.5%)60.210 / none
Vaughn 199639 / R, I / Focal and Gen / 12 / Adults and children, 24.1,
4.5-55 / 5M,
7F / Non-drug resistant,
on AEDs / 44 / NR / NR / NR / CPS, sGTCS
and GTCS / Scalp, 14 channels, continuous, video / EEG / yes / Automatic counting 128 R-R interval epochs (from QRS complex), for 10 minutes before seizure onset / NR / 23 (52.3%) / 6 (13.6%) / NR / 7 (25.9%) / none
Study / Design / Epilepsy type / Participants
(N) / Age group, mean (SD) and range / Gender / Drug-resistance/on AEDs during test / Seizure recorded
(N) / Clinical (C)/
Subclinical (Sc) events / Diurnal (D)/ nocturnal (N) events / Seizure focus and side / Seizure type / EEG
characteristics
(type, duration, video) / Definition of seizure onset / Definition of IT / HR assessment / Baseline HR (bpmSD) / Seizures with Ictal tachycardia (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRI (N, %) / Time of onset of
pre-ictal HR
change (sec) / Seizure with IB (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRR (N, %)
Novak 199923 / P, I / TLE / 12 / Adults, 19-62 / 4M, 8F / Non-drug resistant / NR / NR / D / T,
10 R, 2 L / CPS / Scalp continuous and routine, 31 channels, video / EEG / no / Automatic beat-to-beat counts over 30 sec intervals, from 600 sec prior to seizure onset / 78.3 / 100%, 111.1 (max 148.5) / NR / A few seconds before / na / /
Schernthaner 199912 / R, I / focal / 41 / Adults / NR / NR / 127 / NR / NR / T, F / NR / Scalp (30), subdural (11) / NR / yes / Automatic QRS complex identification and consecutive RR intervals plotting from 60 sec prior to seizure / 105 (82.5%) / 86
(67.7%) of which 76.1% on scalp EEG and 45.7% on subdural EEG / 14.85
(8.7 scalp;
11 subdural) / 4 (3.3%) frontal seiz only / none
Saleh 200024 / P, I / TLE / 27 / Adults, 31.3 (8) / 18M, 9F / NR / 26 / NR / NR / T,
11L, 16R / NR / Intracranial, continuous, video / NR / HR increase >1 SD / Manually beat counting in 5 seconds, from 1 minute before / 72.2512.57 / NR, 113.75 / 7 (26.9%) / NR / na / /
Wilder-Smith 200113 / R, I / focal / 37 / Adults, 44,
18-80 / 20M, 17F / NR / 37 / NR / NR / T, F,
18L,
13R,
6 Bilateral / NR / Scalp, routine (up to 30 minutes), standard, no video / EEG / yes / Counting beats in 10 to 20 second epochs / NR / 16 (43%) / NR (HR can also precede seizure start) / NR / 6 (16.2%) / none
Kirchner 200225 / R, I / TLE / 21 / Adults, 31.58.5 / 11M, 10F / NR, off AEDs / 21 / NR / NR / T,
12R,
9L / NR / Subdural, continuous / clinical / no / Manual over 5 second intervals, from 35 seconds prior to seizure / 75.2 15.9 / NR,
86.716.9 / 6 (28.5%) / 15 / none / none
Zijlmans 200230 / R, I / focal / 81 / Adults and children, 34 (11-64) / 32M, 49F / refractory / 281 / C and Sc (11%) / D and N (40%) / 114T, 21ExtraT, 81R, 62L / CPS, sGTCS / Scalp, continuous (1-14days), 43 channels, video / Either clinical or EEG / yes / Manual counting beats over 6 second epochs (x10), 30 seconds before seizure onset / 7815 / 205 (73%),
109 / 65 (23.1%) / Preceded electrographic onset by 1.1 s (SD: 17.1 s); clinical onset by 3.3 s (SD 14.1 s). / 18 (6.4%) / NR
Leutmezer 200314 / R, I / focal / 58 / Adults / NR / refractory / 145 / NR / NR / T (mesial), F, O / NR / Scalp, continuous (5 days), 23 channels, video / EEG / yes / Automatic QRS complex identification and consecutive RR intervals plotting from 60 sec prior to seizure / 71.315.9 / 126 (86.9) / 110 (75.9%): (86 T, 24 xT) / 0.7-49.3 sec
(14.2 sec in mesial,
8.2 in xT) / 2 (1.4%), 46-51 / none
Di Gennaro 200426 / R, I / TLE / 68 (51 mesiolat, 11 mesial, 6 lateral) / Adults, 33.219 / 42M, 26F / Refractory,
on AEDs / 257 / C / NR / 137mTLE, 120 lTLE;134R, 123L / 113 CPS,144 SPS / Scalp, continuous, standard, video / EEG / no / Automatic, first 15 seconds prior to seizure / 77.3 / 237 (92%), 81.2 / 134 (52.1%): mTLE only / 5 sec / 10 (4%) 76.5 / none
Study / Design / Condition and epilepsy type / Number of participants / Age group, mean (SD) and range / Gender / Drug-resistance/on AEDs / Number of seizure recorded / Clinical (C)/
Subclinical (Sc) / Diurnal (D)/ nocturnal (N) / Seizure focus and side / Seizure type / EEG
characteristics
(type, duration, video) / Definition of seizure onset / Definition of IT / RRi assessment / Baseline HR (bpmSD) / Seizures with Ictal tachycardia (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRI (N, %) / Onset of
pre-ictal HR
change (sec) / Seizure with IB (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRR (N, %)
Mayer 200430 / R, I / TLE / 20 / Children, 9,
3-17 / 7M, 13F / Refractory,
19 on AEDs / 72 / NR / NR / T,
40R, 32L / CPS / Scalp, continuous standard, video / EEG / yes / Manual counting QRS over 6 second epochs (x10), 30 seconds before seizure onset / 86.414.5 / 71 (98.6%) / 20 (27.8%) / NR / NR / 3. (4.2%)
De Oliveira 200727 / R, I / TLE / 27 / Adults, 24.92 / 11M, 16F / NR, off AEDs / 59 / C / NR / T, 36R, 23L / CPS, SPS / Scalp, video / Either EEG or clinical / no / Counting QRS complex in 10 second epochs every minute from 5 minutes until the ictal onset / 79.62.5 / NR, 109 (3.2) / none / / / none / /
Standridge 201032 / R, I / Focal and Gen / 58 / Children, 9.34.7, 1-18.3 / 29M, 29F / NR, off AEDs / 244 (187 focal and 57 Gen) / NR / NR / T and Gen / Focal and GTCS / Scalp, continuous (1-8days), standard, video / EEG / yes / Counting consecutive RR intervals in two 15 second epochs prior to seizure / NR / 78 (32%) / 18 (7.4%) / NR / 6 (2.4%) / 6 (2.4%)
Nilsen 201015 / R, I / focal / 38 / Adults, 33 (13) / 11M, 27F / Refractory, 34 on AEDs / 38 / C / D and N / T, F; 18R, 11L, / CPS (27), sGTCS (11) / Scalp, continuous (>24 hours), standards 21 channels, video / Either EEG or clinical / no / Automatic, based on 30 seconds from 2 minutes prior to seizure / 65.95.8 / 28 (73.5%), 20 (74) CPS (n=27); 8 (73) GTC (N=11), 109.3 (CPS 99.9+27.6, SGTCS 126.9+29.1, frontal 105.7+35, temporal 104.9+25.8) / NR (HR in pre-ictal periods was higher in patients with SGTC compared with patients with CPS) / 120 / na / /
Toth 201016 / R, I / focal / 31 / Adults, 35.515.5 / 14M, 17F / Refractory,
on AEDs / 31 / C / NR / T, xT / GTCS (9), CPS (15), SPS (7) / Scalp, continuous (2 days minimum), standards 21 channels, video / EEG / no / Automatic, 300-second long epochs prior to seizure / 72.5 (1.2) / NR / none / / / na / /
Surges 201028 / R, I / TLE / 25 / Adults, 341.6 / 10M, 15F / Refractory / 50 / NR / NR / T / CPS (25) sGTCS (25) / Scalp, intracranial (2), standards, video / NR / no / 1 min before seizure, by averaging 3 to 5 consecutive RR intervals (30 s epochs) / NR / NR / none / / / na / /
Study / Design / Condition and epilepsy type / Number of participants / Age group, mean (SD) and range / Gender / Drug-resistance/on AEDs / Number of seizure recorded / Clinical (C)/
Subclinical (Sc) / Diurnal (D)/ nocturnal (N) / Seizure focus and side / Seizure type / EEG
characteristics
(type, duration, video) / Definition of seizure onset / Definition of IT / RRi assessment / Baseline HR (bpm) (SD) / Seizures with Ictal tachycardia (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRI (N, %) / Onset of
pre-ictal HR
change (sec) / Seizure with IB (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRR (N, %)
CalandraBuonaura 201240 / P, I / NFLE / 10 / Adults+1 child, 25.32.8,
12-41 / 6M, 4F / Not refractory, drug free / 45 / C / N / F / 12ParoxArousal, 12Asymmetric Tonic Seizure, 21Hyperkinetic Seizure / Scalp, 8 hours standard PSG, video / EMG and clinical / no / Automatic, measuring RRi intervals, from 10 sec prior to seizure / NR / NR, 140 / NR / 1 sec / na / /
Behnahani 201317 / R, I / focal / 12 / Adults, 43.9110.16 / 7M, 5F / Refractory / 133 / C / D / T, F, P / CPS, SPS, sGTCS / Scalp, continuous (from 93 to 243 hours), no video / EEG / no / Automatic, QRS complex counting,
from 240 (90-30,30-10,10-5 and 5) minutes before seizure / NR / NR / NR / HR start
to increase
from 30 minutes
before / na / /
Jansen 201333 / R, I / Focal and Gen / 35 / Children 9.2,
3-16 / 4M, 31F / Refractory / 80
(20 T, 20F, 40 Gen) / NR / NR / F, T (9R,11L) , Gen / GTCS, myoclonic, clonic, CPS / Scalp, continuous (up to 24 hours), standard, video / EEG / no / Automatic, QRS counting plus RR interval from 3 min before seizure / NR / 40 (50) / 25 (31.3) / 3.59 sec (0.2-29sec) / 5 (6.25%) / 3 (3.75%)
Chen 201436 / R, O / focal / 81 / Adults and children, 22.8,
3-49 / 56M, 25F / NR / 181 / C / D and N / 47 F,
101 T,
33 O,
96L,
85R / SPS, CPS, sGTCS / Scalp, continuous, standard, video / EEG / yes / Manual counting QRS complex in 10 seconds epochs (x6) from 10 sec (60, 40, 30, 20, 10) prior to seizure / NR / 152 (84.0), 128.125.15 / NR / 10 / 2 (1.1%) / NR
Kato 201429 / R, I / TLE / 21 / Adults, 35.9,
13-67 / 7M, 14F / NR, off AEDs / 77 / C / NR / T (mesial), 20 R, 48 L / CPS / Scalp, continuous (4-5 days), standard with additional channels, video / EEG / no / Automatic, from the 5-second moving mean RR, from 100 sec prior to seizure / NR / 17 (92.2), 29 (100%) RTLE, 42/48 (87.5%) LTLE / 27/77 (35.1%),
11/48 (22.9%)LTE and 22/29 (75.9%)RTLE / NR / none / /
Behbahani 201618 / R, I / Focal / 24 (21 T, 3F) / Adults, 49.2 7.02,
41-65 / 12M, 12 F / Refractory / 232 / NR / D / T, F / CPS, SPS, sGTCS / Scalp, continuous, no video / EEG / no / RR intervals measured from 5 minutes prior to seizure / 70.14.5 / 109.37.5 (112.6 (9.3) in male and 106 (5.6) in female; 105.98 (5.6) in right-sided and 112.63 (9.3) in left sided) / NR,112.69.3 male and 1065.6 female; 105.985.6 R and 112.639.3 L / 300 / na / /
Study / Design / Condition and epilepsy type / Number of participants / Age group, mean (SD) and range / Gender / Drug-resistance/on AEDs / Number of seizure recorded / Clinical (C)/
Subclinical (Sc) / Diurnal (D)/ nocturnal (N) / Seizure focus and side / Seizure type / EEG
characteristics
(type, duration, video) / Definition of seizure onset / RRi assessment / Baseline HR (bpm) (SD) / Seizures with Ictal tachycardia (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRI (N, %) / Onset of
pre-ictal HR
change (sec) / Seizure with IB (N, %) and mean peak HR frequency (bpm) / Seizures with
pre-ictal HRR (N, %)
Chen 201637 / P, I / Focal / 102 / Adults (49) and children (53), 20.5 (6.2),3-49 / NR / Refractory / 202 (106 children, 96 adults) / C / Not reported / T (106), F (57), O(39);
105L,
97R / SPS, CPS, sGTCS / Scalp, continuous, standard, video / EEG / yes / Manual counting QRS complex in 10 seconds epochs (x6) from 10 sec (60, 40, 30, 20, 10) prior to seizure / Not reported / 195 (96.7); children 93.4%, adults 100%), 120bpm / NR (HR higher in children) / 10 / none / /
Hampel 201619 / P, I / Focal / 37 (23 T, 14 xT) / Adults 37.111.1 / 17M, 20F / Refractory and not / 45 / NR / NR / T and xT / 35CPS,
10 sGTCS / Scalp and intracranial, continuous, standard, video / NR / no / Average of 5 consecutive beat-to-beat values at 2 minutes prior to seizure / 71.6511.9 / NR, 115.7 (21.2) (109.8 +21.3 in focal, 121.6+21.5 in sec gen)) / none / / / na / /
Jaychandran 201620 / P, I / Focal / 42 (26 T, 16 xTl) / Adults, 24.17.7 / 28M, 14F / Refractory on AEDs / 57 / NR / NR / T and xT (14 R, 24 L, 4 bilateral) / CPS, SPS / Scalp, continuous, standard, video / EEG / no / Automatic, from RR intervals calculated during a 1 minute period, from 5 minutes prior to seizure / 74.0311.15 / 38 (68.4), 89.4921.57 / NR / 60 / 1 (1.7%) / NR
Moridani 201741 / R, I / focal / 7 / NR / NR / NR / 11 / NR / NR / NR / NR / scalp / NR / no / Automatic , from RR intervals 10-5 minutes before seizure (mean HR) / 73.438.58 / NR / NR 106.3213.23 / 10-5 min / na / /
Whealy 201731 / R, I / TLE / 49 / Children and teens, 9.5; 0.3-19.5 / 27M,22F / On AEDs / 172 / NR / NR / T / CPS, sGTCS / Scalp, continuous, standard / EEG and clinical / yes / From 60 seconds / NR / NR / 65 (38%) / NR / NR / 1 (1%)
Table S2. Meta-regression of incidence of pre-ictal HR increase, univariate analysis
Covariates / No. of studies / p-value / Heterogeneity (2) / Percent heterogeneityStudy design
Prospective / 2
Retrospective / 13 / 0.97 / 0.070 / -7.52
Setting
Inpatients / 13
Outpatients / 2 / 0.42 / 0.067 / -1.80
Number of participants
35 (median) / 8
35 / 7 / 0.96 / 0.071 / -7.76
Age group
Adults / 8
Children / 4 / 0.004 / 0.034 / 47.08
Adults and Children / 3
Epilepsy type
Focal and Generalized / 3
Focal / 4 / 0.17 / 0.060 / 8.08
Temporal lobe epilepsy / 8
Drug-resistance
Non-refractory / 1
Refractory / 6
Refractory and not / 2 / 0.4 / 0.067 / -1.56
Unclear / 6
Anti-epileptic drugs
Off / 3
On / 7 / 0.4 / 0.074 / -3.57
Unclear / 5
Cardiac comorbidities
None / 8
Not-assessed / 7 / 0.36 / 0.066 / -1.08
Number of seizure
80 (median) / 8
80 / 7 / 0.95 / 0.071 / -7.76
Seizure type
Complex partial seizures / 5
Multiple seizure types / 4 / 0.89 / 0.071 / -7.65
Not reported / 6
Epileptogenic focus
Mainly right sided / 6
Mainly left-sided / 2 / 0.51 / 0.068 / -4.17
Right and left-sided / 1
Not reported / 6
Seizures presentation
Clinical / 3
Subclinical / 2 / 0.46 / 0.068 / -3.36
Not reported / 10
Seizure onset definition
EEG / 8
Clinical / 2 / 0.42 / 0.067 / -2.02
Either EEG or clinical / 3
Unclear / 2
EEG type
Scalp / 12
Intracranial / 2 / 0.49 / 0.068 / -3.39
Scalp and intracranial / 1
EEG duration
Continuous / 13
Intermittent / 1 / 0.51 / 0.068 / -3.37
Unclear / 1
No. EEG electrodes
Standard / 8
Non-standard / 4 / 0.76 / 0.070 / -6.66
Unclear / 3
Video EEG
Yes / 10
No / 3 / 0.34 / 0.065 / 0.22
Unclear / 2
Heart rate assessment methods
Automatic / 7
Manual / 8 / 0.26 / 0.064 / 2.89
Pre-ictal time duration
<60 sec (median) / 6
60 sec / 7 / 0.016 / 0.043 / 33.44
Not reported / 2
ECG time-epoch
<15 sec (median) / 6
15 sec / 6 / 0.69 / 0.070 / -6.21
Not reported / 3
Definition of Ictal tachycardia and bradycardia
Reported / 8
Not specified / 7 / 0.82 / 0.070 / -7.22
Proportion of seizures with IT
<82.5 % (median) / 5
82.5% / 6 / 0.004 / 0.023 / 58.92
Not reported / 4
Time of onset of pre-ictal HRI (seconds prior to seizure onset)
≤5 sec (median) / 4
>5 sec / 3 / 0.039 / 0.017 / 55.54
Not reported / 8