Characteristics of Post-Ictal Headaches in Patients with Epilepsy: a Longitudinal Study

  • F. Caprara
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil

    Postgraduate Program in Pharmacology, Federal University of Santa Maria, RS, Brazil

    Center for Natural and Exact Sciences, Postgraduate Program in Biological Sciences, Federal University of Santa Maria, RS, Brazil

    Toxicological Biochemistry, Federal University of Santa Maria, RS, Brazil

    Physical Education and Sports Center, Exercise Biochemistry Laboratory (BIOEX), Federal University of Santa Maria, RS, Brazil
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  • Ana Letícia
    Correspondence
    Corresponding author at: Av. Roraima n° 1000, Cidade Universitária.Bairro Camobi, Santa Maria, RS, Brazil.
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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  • Jamir P. Rissardo
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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  • Martim T.B. Leite
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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  • Juliana O.F. Silveira
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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  • Paulo G.M Jauris
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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  • Josi Arend
    Affiliations
    Postgraduate Program in Pharmacology, Federal University of Santa Maria, RS, Brazil
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  • Aline Kegler
    Affiliations
    Center for Natural and Exact Sciences, Postgraduate Program in Biological Sciences, Federal University of Santa Maria, RS, Brazil
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  • F. Royes
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil

    Postgraduate Program in Pharmacology, Federal University of Santa Maria, RS, Brazil

    Center for Natural and Exact Sciences, Postgraduate Program in Biological Sciences, Federal University of Santa Maria, RS, Brazil

    Toxicological Biochemistry, Federal University of Santa Maria, RS, Brazil

    Physical Education and Sports Center, Exercise Biochemistry Laboratory (BIOEX), Federal University of Santa Maria, RS, Brazil
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  • Luiz Fernando
    Affiliations
    Toxicological Biochemistry, Federal University of Santa Maria, RS, Brazil

    Physical Education and Sports Center, Exercise Biochemistry Laboratory (BIOEX), Federal University of Santa Maria, RS, Brazil
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  • Michele Rechia Fighera
    Affiliations
    Health Sciences Center, Department of Neuropsychiatry, Federal University of Santa Maria, RS, Brazil
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Open ArchivePublished:August 26, 2020DOI:https://doi.org/10.1016/j.seizure.2020.08.001

      Highlights

      • PIH is associated with family history of migraine;
      • PIH is associated with drug-resistant epilepsy and generalized seizure onset type;
      • Because nearly 80% of people with epilepsy live in low- and middle-income countries, research in these regions is important;

      Abstract

      Objectives

      This study aimed to investigate the clinical predictors of post-ictal headache (PIH) in patients with epilepsy in a tertiary center in Brazil.

      Methods

      302 individuals with adult-onset epilepsy were followed for 9.8 years in our Hospital. Structured questionnaires about headaches were applied. The presence of PIH was the primary outcome. We used multilevel linear modeling in our data analysis.

      Results

      From the total, 46.3% had post-ictal headaches. Tension-type post-ictal headache was present in 55% (N = 77) of the subjects, migrainous in 32.1% (N = 45), and both types in 12.8% (N = 18). Family history of migraine (Odds ratio: 1.696; 95% CI: 1.372 to 2.096), diagnosis of drug-resistant epilepsy (Odds ratio: 1.169; 95% CI: 1.135 to 2.146), months since last visit (Odds ratio: 1.464; 95% CI: 1.243 to 2.888), and generalized seizure onset type of epilepsy (Odds ratio: 1.527; 95% CI: 1.114 to 1.668), were significant determinants of PIH on multilevel linear modeling.

      Discussion

      PIH are associated with drug-resistant epilepsy, generalized seizures, and family history of migraine. The rates of pos-ictal headaches could be influenced by the use of antiepileptic drugs.

      Abbreviations:

      PIH (post-ictal headaches), DRE (drug-resistant epilepsy), AED (antiepileptic drugs)

      Keywords

      1. Introduction

      Since the 19th century, the relation between headaches and epilepsy has been studied.

      Jackson HJTL. HOSPITAL FOR THE EPILEPTIC AND PARALYSED.: CASE ILLUSTRATING THE RELATION BETWIXT CERTAIN CASES OF MIGRAINE AND EPILEPSY. 1875;106(2711):244-245.

      ,
      • Panayiotopoulos C.P.
      “Migralepsy” and the significance of differentiating occipital seizures from migraine.
      Despite that, according to the Global Burden of Disease Study headache disorders are the third cause of disability worldwide.
      • Steiner T.J.
      • Birbeck G.L.
      • Jensen R.H.
      • Katsarava Z.
      • Stovner L.J.
      • Martelletti P.
      Headache disorders are third cause of disability worldwide: BioMed Central.
      Besides, in 2016 there were 45.9 million individuals with active epilepsy, 126.055 epilepsy-related deaths, and an epilepsy burden of 13.5 million disability-adjusted life years. It is also estimated that nearly 80% of people with epilepsy live in low- and middle-income countries.
      • Beghi E.
      • Giussani G.
      • Nichols E.
      • et al.
      Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      Especially the association of epilepsy and migrainous post-ictal headache (PIH) is interesting since they are paroxysmal, chronic and both often respond to antiepileptic drugs although their specific pathophysiological mechanisms are not well known.
      • Giffin N.
      • Ruggiero L.
      • Lipton R.B.
      • et al.
      Premonitory symptoms in migraine: an electronic diary study.
      • Markley H.G.
      Verapamil and migraine prophylaxis: mechanisms and efficacy.
      • Shank R.P.
      • Gardocki J.F.
      • Streeter A.J.
      • BEJE Maryanoff
      An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.
      • Löscher W.
      Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action.
      PIH is often a comorbidity of patients who suffer from epilepsy. However, this condition is usually neglected in the clinical practice because the motor manifestations and other features of a seizure are sometimes comparatively more dramatic and impactful for the patients and their families.
      • Ito M.
      • Nakamura F.
      • Honma H.
      • et al.
      Clinical factors associated with post‐ictal headache in patients with epilepsy.
      The prevalence of PIH varies widely in the literature, probably because of distinct definitions of epilepsy-related headaches, methodological differences across reports and the short duration of most of the studies.
      • Förderreuther S.
      • Henkel A.
      • Noachtar S.
      • Straube A.
      Headache associated with epileptic seizures: epidemiology and clinical characteristics.
      • Daryan M.D.
      • Güveli B.T.
      • Baslo S.A.
      • et al.
      Prevalence and clinical characteristics of headache in juvenile myoclonic epilepsy: experience from a tertiary epilepsy center.
      • Wang X-q
      • Lang S-y
      • Zhang X.
      • et al.
      Comorbidity between headache and epilepsy in a Chinese epileptic center.
      In this way, the purpose of this study was to investigate the prevalence, characteristics, and clinical predictors of post-ictal headache in a long-term follow-up of patients with epilepsy in a tertiary center in Brazil.

      2. MATERIAL AND METHODS

      A hospital-based prospective observational cohort of 302 subjects with newly diagnosed epilepsy was conducted in the University Hospital of Santa Maria, Brazil. The follow-up was from December 2008 to December 2018. To be considered eligible for our study, patients should have an initial diagnosis of epilepsy based on the International League Against Epilepsy (ILAE) classification
      • Falco-Walter J.J.
      • Scheffer I.E.
      • Fisher R.S.
      The new definition and classification of seizures and epilepsy.
      and confirmed by one participating neurologist and at least two unprovoked seizures occurring on different days.
      Patients were seen every 6 months or more frequently when necessary. Each patient attended to a mean number of 24.7 visits (SD: 5.6) throughout the study. Medical records were reviewed continuously during the follow-up. Structured questionnaires containing questions about headache based in previous studies
      • Ito M.
      • Adachi N.
      • Nakamura F.
      • et al.
      Multi‐center study on post‐ictal headache in patients with localization‐related epilepsy.

      Stevenson SBJJoPHC. Epilepsy and migraine headache: is there a connection? 2006;20(3):167-171.

      • Velioglu S.
      • Boz C.
      • Özmenoglu M.J.C.
      The impact of migraine on epilepsy: a prospective prognosis study.
      were applied by the neurologists in each clinical visit. Extensive information was also collected on family history of seizures and migraines, frequency of seizures before the diagnosis, age at seizure onset, types of seizure, epilepsy etiology, race, and years of education. Complete details of the methods have been previously presented.
      • Caprara A.L.F.
      • Rissardo J.P.
      • Leite M.T.
      • et al.
      Course and prognosis of adult-onset epilepsy in Brazil: A cohort study.
      Post-ictal headache was classified according to the International Classification of Headache Disorders criteria
      • Headache Classification Committee of the International Headache S.
      The International Classification of Headache Disorders, 3rd edition (beta version).
      and was diagnosed by a headache specialist neurologist when “caused by and occurring within three hours after an epileptic seizure, and remitting spontaneously within 72 hours after seizure termination”.
      The study was conducted in the adult neurology department, and the cutoff of age for pediatric patients is 14 years; so, subjects were included only if they were 15 years old or more. Patients with severe addictions (alcohol abuse, illicit drugs) and comorbidities, such as chronic kidney disease and hepatic failure were excluded.
      Subjects that were non-compliant to the treatment or who could not attend to the clinical evaluations were also excluded.
      Antiepileptic drugs (AED) were prescribed to all of the subjects. Monotherapy was the chosen regimen at the beginning of the treatment for all subjects. In the cases of failure of the first drug after maximum tolerated doses were given, a second first-choice AED was tried before polytherapy was prescribed. The choice of the AED was made by the participating neurologists and was individualized for each subject, taking into account the type of seizure, epilepsy etiology, drug interactions, side-effects, and socio-economic factors.
      Written informed consent was obtained from all participants. This study was approved by the Institutional Review Board of the Federal University of Santa Maria (“Comitê de Ética em Pesquisa com Seres Humanos” — reference number 10554612100005346).
      Drug-resistant epilepsy was defined as "failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom for one year or for a period equal to three times the seizure-free interval before the beginning of the treatment, whichever is longer", as proposed by International League Against Epilepsy (ILAE).
      • Fisher R.S.
      • Cross J.H.
      • French J.A.
      • et al.
      Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
      Seizure types and etiology were classified according to the latest epilepsy definitions established by the (ILAE).
      • Fisher R.S.
      • Cross J.H.
      • French J.A.
      • et al.
      Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
      ,
      • Fisher R.S.
      • Cross J.H.
      • D’Souza C.
      • et al.
      Instruction manual for the ILAE 2017 operational classification of seizure types.
      Since the classification of seizures changed during the follow-up time, seizure types and etiology were reviewed regularly and modified when appropriate during the study. Seizures were categorized by their onset (focal onset, generalized onset, or unknown onset). Seizure etiology was also classified into structural, unknown, genetic, or infectious.

      2.1 Statistical methods

      Epi Info, version 7.1 (CDC, Atlanta, GA) was used to create a database. Double data entry and standardized procedures were performed for quality checking. The data were then transported to the IBM SPSS software version 23 (IBM Corp., Armonk, NY) for statistical analysis.
      Categorical variables were represented as proportions and continuous variables were represented as means and standard deviations. A p-value <0.05 was considered statistically significant in all of the analyses.
      We used multilevel linear modeling in our data analysis because this is an approach specifically suited for longitudinal studies, where datasets are organized in a multilevel structure, with several assessments for each subject periodically.
      We built two different models for subjects who presented PIH and for those who did not present PIH. The occurrence of seizures during the study period was considered as a longitudinal variable and was assessed at each visit. Explanatory variables were sex, race, years of education, mean age, mean age at epilepsy diagnosis, family history of migraine, family history of seizures, frequency of seizures before treatment, migraine, presence of drug-resistant epilepsy, epilepsy etiology, seizure onset type, AED monotherapy, AED polytherapy, and treatment adjustment. Those variables were included in the models as they were possible confounders.
      Restricted maximum likelihood was used to fit the model, and nonsignificant variables were excluded until only significant variables (P < 0.05) were left. Since not all clinical assessments took place within the same interval of time, we first added the variable “Months since last visit” in our model, to examine the relationship between time and the occurrence of headaches. Then, the baseline variables that were considered as potential confounders were also included.

      3. RESULTS

      Overall, 349 subjects were eligible for the study. Five subjects died during the initial 4 years of study, 6 subjects were lost due to non-compliance, 2 subjects moved to other regions and were excluded because they could no longer attend the clinical visits, and 34 were excluded due to missing data. In all, 302 patients remained and were followed during the entire period.
      Forty-seven patients were classified with drug-resistant epilepsy (DRE) because they met the ILAE criteria for drug-resistant epilepsy by the end of the study. The mean time of follow-up was of 9.8 years.
      The mean age (±SD) at diagnosis was 16.6 years (±8.9). A family history of seizures was present in 38 individuals (12.6%).In all, 35 (11.6%) patients had none or less than one year of education, 174 (57.6%) subjects had from 1 to 10 years of education, 85 patients (28.1%) referred 11 to 14 years of education, and 8 subjects (2.6%) had more than 15 years of education. The frequency of seizures before treatment was of ≥1/day in 17 (5.6%) individuals, of ≥1/week in 125 subjects (41.4%), of ≥1/2 week in 13 patients (4.3%), of ≥ 1/month in 128 individuals (42.4%) and ≤1/month in 19 subjects (6.3%).
      Table 1 presents the clinical and demographic characteristics of the subjects who consistently reported post-ictal headaches (PIH) during the follow-up. Structural epilepsy etiology was present respectively in 90 individuals (29.8%), unknown etiology in 134 (44.4%) subjects, genetic occurred in 8 (2.6%) patients, and infectious in 70 patients (23.2%).
      Table 1Clinical variables from subjects with and without PIH.
      VariablePost-ictal epileptic headache (+)Post-ictal epileptic headache (-)
      No. cases, Mean(%, SD)No. cases, Mean(%, SD)
      TotalN = 140N = 162
      Sex
      Male61(43.6)105(64.8)
      Female79(56.4)57(35.2)
      Race
      White93(66.4)101(62.3)
      Mixed-race (“Pardo”)44(31.4)55(33.9)
      Black3(2.1)6(3.7)
      Mean age at the end of the study27.1(7.3)28.2(8.1)
      Mean age at epilepsy diagnosis (beginning of the study)16.2(6.4)17.4(7.2)
      Family history of seizures27(19.3)11(6.8)
      Family history of migraine92(65.7)65(40.1)
      Drug-resistant epilepsy33(23.6)14(8.6)
      Frequency of seizures before treatment
      ≥1/day8(5.7)9(5.5)
      ≥1/week72(51.4)53(32.7)
      ≥1/2 week5(3.6)8(4.9)
      ≥1/month51(36.4)77(47.5)
      ≤1/month4(2.9)15(9.3)
      Epilepsy Etiology
      Structural42(30)48(29.6)
      Unknown61(43.6)73(45.1)
      Infectious32(22.9)38(23.5)
      Genetic5(3.6)3(1.8)
      Seizure Type
      Generalized onset85(60.7)23(14.2)
      Focal onset (total)52(37.1)138(85.2)
      Focal to bilateral tonic-clonic31(22.1)55(33.9)
      Unknown3(2.1)1(0.6)
      Migraine with aura7(5)4(2.5)
      Migraine without aura64(45.7)29(17.9)
      Probable migraine10(7.1)2(1.2)
      Abbreviations: PIH: Post-ictal headaches (+): present; (-) absent; No.: number; SD: standard deviation.
      Seizure onset type was generalized in 108 subjects (35.8%), in 190 individuals the onset was focal (49.7%), and in 4 individuals the onset was unknown (1.3%). Approximately 46.3% (N = 140) of the subjects reported post-ictal headaches. Within this group of individuals, 65 (46.4%) reported that PIH occurred always, 52 (37.1%) reported frequent PIH, 12 (8.9%) reported occasional PIH, and 11 (7.6%) informed that PIH occurred rarely. Tension-type post-ictal headache was present in 55% (N = 77) of the subjects, the migrainous type occurred in 32.1% (N = 45), and both types were present in 12.8% (N = 18). The mean duration of PIH was more than 4 hours in 101 individuals (72.1%). The intensity of the headache was reported as severe by 23 individuals (16.4%), while 76 (54.3%) subjects reported that the PIH was of moderate-intensity and 41 (29.3%) referred mild headaches.
      Table 2 presents the results of the bivariate analysis of clinical characteristics according to the type of PIH. Table 3 shows the results of multilevel linear modeling. Graph 1 shows the prevalence oh PIH divided by sex at each study year. Graph 2 shows the prevalence of PIH by age and sex at the beginning of the study and Graph 3 shows the prevalence of PIH by age and sex at the end of the study.
      Table 2Clinical characteristics of subjects according with type of PIH
      Migrainous

      N = 45

      (Group 1)
      Tension-type

      N = 77

      (Group 2)
      Mixed

      N = 18

      (Group 3)
      Odds Ratio

      95% CIp-value
      Seizure onset type

      Generalized onset

      Focal onset

      Focal to bilateral tonic-clonic

      Unknown
      25 (55.5)

      19 (42.2)

      14 (31.1)

      1 (2.2)
      46 (59.7)

      29 (37.7)

      16 (20.8)

      2 (2.6)
      14(77.8)

      4 (22.2)

      1 (5.5)

      0
      1.28

      1.13

      0.91

      -
      0.97 –1.34

      0.74 –1.01

      1.15 –1.29

      -
      0.421

      0.633

      0.707

      -
      Etiology

      Structural

      Unknown

      Infectious

      Genetic
      12 (26.7)

      20 (44.4)

      11 (24.4)

      2 (4.4)
      23 (29.9)

      35 (45.4)

      17 (22.1)

      2 (2.6)
      7(38.9)

      6(33.3)

      4(22.2)

      1 (5.5)
      2.15

      1.55

      1.21

      1.12
      1.71–1.92

      0.83–1.69

      0.54–1.23

      1.56–2.33
      0.543

      0.868

      0.997

      0.554
      DRE

      (n = 33)
      21 (46.7)9 (11.7)3 (16.7)1.451.33 – 1.610.004*
      Non-DRE

      (n = 107)
      24 (53.3)68 (88.3)15 (83.3)1.731.45 – 1.820.003*
      AED polytherapy

      (n = 58)
      22 (48.9)30 (38.9)6 (33.3)1.840.91 – 2.650.423
      AED monotherapy

      (n = 82)

      Valproate

      Topiramate

      Carbamazepine

      Lamotrigine

      Other
      23 (51.1)

      7 (15.5)

      3 (6.7)

      6 (13.3)

      4 (8.9)

      3 (6.7)
      47 (61)

      15 (19.5)

      9 (11.7)

      11 (14.3)

      8 (10.4)

      4 (5.2)
      12(66.7)

      3 (16.7)

      1 (5.5)

      5 (27.8)

      2 (11.1)

      1 (5.5)
      0.984

      -

      -

      -

      -

      -
      0.652–1.04

      -

      -

      -

      -

      -
      0.562

      -

      -

      -

      -

      -
      Migraine

      with aura
      2 (4.4)5 (6.5)01.151.23 – 1.360.622
      Migraine without aura15 (33.3)42 (54.5)7 (38.9)1.261.05 – 2.870.023*
      Probable migraine5 (11.1)3 (3.9)2 (11.1)0.850.71 – 3.240.570
      Abbreviations: N: Number; () represent percentages, CI: Confidence Interval; *: P < .05.
      ¶For the bivariate analysis, only Groups 1 and 2 were compared.
      Table 3Estimated Fixed Effects of Predictors in the Multilevel Linear Regression Model.
      Dependent variable
      Seizures in the last follow-up
      GroupVariableOdds ratio95% CIp valueParameter estimate
      Parameter estimates represents the effects of a determined predictor on the population.
      Post-ictal headache (+)Family history of migraine1.6961.372 to 2.0960.032*0.015
      Drug-resistant epilepsy1.1691.135 to 2.1460.029*0.002
      Months since last visit1.4641.243 to 2.8880.035*0.006
      Seizure Onset Type

      “Generalized”
      1.5271.114 to 1.6680.004*0.001
      Family history of seizures1.0010.851 to 1.530
      School performance

      (poor)
      1.0210.989 to 1.244
      Migraine1.5390.867 to 1.622
      AED monotherapy1.0150.763 to 2.691
      AED polytherapy1.0580.952 to 2.029
      Treatment adjustment1.0130.875 to 1.384
      Frequency of seizures before treatment1.0051.225 to

      3.641
      Post-ictal headache (-)Family history of seizures0.8840.547 to 1.973
      Drug-resistant epilepsy0.9850.622 to 0.9910.032*−0.025
      Months since last visit0.6320.854 to 1.751
      Seizure Onset Type

      “Generalized
      0.7390.421 to 0.8950.009*−0.013
      Family history of migraine0.7780.545 to 1.215
      Generalized (Focal as baseline)0.6920.531 to 1.790
      AED monotherapy0.8150.967 to 1.741
      AED polytherapy0.7440.854 to 1.298
      Treatment adjustment0.7320.525 to 1.642
      Frequency of seizures before treatment0.8210.774 to

      2.658
      Migraine0.9920.855 to 1.249
      Variables that were not included in the model have empty entries.
      Abbreviations: CI: Confidence Interval; *: P < .05.
      a Parameter estimates represents the effects of a determined predictor on the population.
      Graph 1
      Graph 1Prevalence of PIH by sex at the end of each study year.
      Graph 2
      Graph 2Prevalence of PIH by age and sex at the end of 2008.
      Graph 3
      Graph 3Prevalence of PIH by age and sex at the end of 2018.

      4. DISCUSSION

      The present study of 302 subjects with epilepsy newly diagnosed in a University Hospital in Brazil shows that post-ictal headaches were a prevalent condition, reported by almost half of the patients (46.3%) during the follow-up. The rates of PIH in our study were higher when compared to other reports of PIH in adults in the literature.
      • Ito M.
      • Nakamura F.
      • Honma H.
      • et al.
      Clinical factors associated with post‐ictal headache in patients with epilepsy.
      ,
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      Duchaczek et. al reported 30.3% of PIH in their study
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      . Ito et. al reported 37% of epilepsy patients with PIH
      • Ito M.
      • Nakamura F.
      • Honma H.
      • et al.
      Clinical factors associated with post‐ictal headache in patients with epilepsy.
      . This could be due to methodological differences since our study had many years of follow-up and thus allowed a longer period to detect the occurrence of PIH.
      • Ito M.
      • Nakamura F.
      • Honma H.
      • et al.
      Clinical factors associated with post‐ictal headache in patients with epilepsy.
      Also, in our study a headache specialist neurologist and an epilepsy specialist neurologist evaluated all the patients with PIH and epilepsy. However, in the studies by Duchaczek et. al and Ito et. al, it is not mentioned whether or not specialists evaluated the cases, which could have contributed to a decreased detection of PIH.
      On the other hand, the high incidence of PIH found in our study could be age-related since the mean age of our study population was of 16.2 years at the beginning of the study. Also, when divided by age and sex as represented in Graph 2, the prevalence of PIH was 58.8% in females and 34.9% in males with 15-17 years of age by the end of 2008, which was the year our study began.
      At the last year of our study, the prevalence of PIH in these same subgroups decreased and was of 49% and 31.7% respectively, as shown in Graph 3, which could probably be explained by the fact that during the years, most of our patients achieved better control of seizures, leading to a decrease in the rates of PIH.
      An Italian
      • Verrotti A.
      • Coppola G.
      • Spalice A.
      • et al.
      Peri-ictal and inter-ictal headache in children and adolescents with idiopathic epilepsy: a multicenter cross-sectional study.
      cross-sectional multi-center study about peri-ictal and inter-ictal headache in children and adolescents with idiopathic epilepsy found an even higher PIH incidence of 62%. They also found that within the group of 81 patients with PIH, 61 (75.3%) had migraine without aura features and 5 (6.1%) had migraine with aura features.
      However, in our study, we found that 45.7% of the subjects from the PIH group had migraine without aura, 5% had migraine with aura features and 7.1% had a probable migraine. We also found a significant statistical association on the bivariate analysis between tension-type PIH and migraine without aura as it is shown in Table 2 (OR: 1.26, 95% CI: 1.05 to 2.87).
      Tension-type post-ictal headache was present in 55% of the subjects, the migrainous type occurred in 32.1%, and both types were present in 12.8%. Those numbers also differed when compared to other studies. The Italian study
      • Verrotti A.
      • Coppola G.
      • Spalice A.
      • et al.
      Peri-ictal and inter-ictal headache in children and adolescents with idiopathic epilepsy: a multicenter cross-sectional study.
      found migrainous characteristics in 93% of pre-ictal and 81.4% of post-ictal headaches. A German study
      • Förderreuther S.
      • Henkel A.
      • Noachtar S.
      • Straube A.
      Headache associated with epileptic seizures: epidemiology and clinical characteristics.
      reported migraine in 34% of patients with PIH, tension-type occurred only in 34% of the patients. This could also be because this was a cross-sectional study and possibly the diagnostic criteria for tension-type headache were not met due to the short study duration.
      In our study, DRE was associated in bivariate analysis with migrainous PIH (Odds ratio: 1.45; 95% CI: 1.33 to 1.61), while non-DRE was associated with tension-type PIH (Odds: 1.73; 95% CI: 1.45 to 1.82).
      We also found that only a family history of migraine (Odds ratio: 1.696; 95% CI: 1.372 to 2.096), diagnosis of drug-resistant epilepsy (Odds ratio: 1.169; 95% CI: 1.135 to 2.146), months since the last visit (Odds ratio: 1.464; 95% CI: 1.243 to 2.888), and generalized seizure onset type of epilepsy (Odds ratio: 1.527; 95% CI: 1.114 to 1.668), were significant determinants of PIH on multilevel linear modeling.
      In this context, a study from the Departments of Neurology and Paediatric Neurology of the University Hospital in Rome
      • Piccioli M.
      • Parisi P.
      • Tisei P.
      • Villa M.
      • Buttinelli C.
      • Kasteleijn-Nolst Trenité D.G.A.
      Ictal headache and visual sensitivity.
      investigated if headache could be an epileptic symptom related to photosensitivity in patients with photosensitivity epilepsy and migrainous headache. Video-EEG with extensive intermittent photic stimulation and pattern stimulation was performed in the patients’ first-degree family members. Twelve subjects from four families were investigated. From these, 1 had epilepsy, 3 had a headache, 5 had epilepsy, and headache. Two subjects had epileptic EEG signs correlated with headaches during photic or pattern stimulation. Nine subjects showed photo paroxysmal response.
      • Piccioli M.
      • Parisi P.
      • Tisei P.
      • Villa M.
      • Buttinelli C.
      • Kasteleijn-Nolst Trenité D.G.A.
      Ictal headache and visual sensitivity.
      In this way, according to the authors, headache could be an ictal sign of epilepsy and relatives of patients with migraines and photosensitive epilepsy complain more often about headache than the relatives of patients with other types of epilepsy. Also according to the study, another sign that migraine has possibly an epileptic origin is the fact that in the four families studied, all patients that received AEDs had complete remission of headache attacks and seizures.
      • Piccioli M.
      • Parisi P.
      • Tisei P.
      • Villa M.
      • Buttinelli C.
      • Kasteleijn-Nolst Trenité D.G.A.
      Ictal headache and visual sensitivity.
      It is not possible to compare the results from our multilevel linear modeling to those from most of the other studies about PIH and epilepsy since most of them used regular multiple logistic regression analyses to evaluate clinical predictors associated with PIH.
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      ,
      • Ito M.
      • Adachi N.
      • Nakamura F.
      • et al.
      Multi-center study on post-ictal headache in patients with localization-related epilepsy.
      But, drug-resistant epilepsy or the use of polytherapy and generalized tonic-clonic seizures were found as significantly predictive of PIH in logistic regression analyses from other studies.
      • Ito M.
      • Adachi N.
      • Nakamura F.
      • et al.
      Multi-center study on post-ictal headache in patients with localization-related epilepsy.
      ,
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      To the authors’ knowledge, this is the first study to use multilevel linear modeling to evaluate PIH and epilepsy in a long-term follow-up. In our view, this is an interesting type of analysis to be implemented in future longitudinal studies about PIH because it is more adequate for sets of data that include repeated measures. Thus, the significant predictors found with this type of analysis are more specific and reliable.
      As for the treatment of headaches, it is well established experimentally and clinically that anti-epileptic drugs could decrease the number of headaches episodes or even mitigate them.
      In this context, according to an American study
      • Nye B.L.
      • Thadani V.M.
      Migraine and epilepsy: review of the literature.
      , topiramate and valproate are the most effective anti-epileptic drugs for the prophylaxis of migraine. Nevertheless, the exact mechanism by which these drugs prevent migraines is unknown. Both of these drugs are broad-spectrum AED widely used to treat epilepsy worldwide and have shown a 50% reduction in the migraine occurrence in approximately 25-50% of patients.
      • Nye B.L.
      • Thadani V.M.
      Migraine and epilepsy: review of the literature.
      Topiramate mechanisms of action include antagonism at the AMPA-type glutamate receptor, blockage of voltage-gated sodium channels, and enhancement of the action of GABA on chloride channels. It also decreases the opening of L-type calcium channels.
      • Shank R.P.
      • Gardocki J.F.
      • Streeter A.J.
      • BEJE Maryanoff
      An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action.
      Valproate mechanisms involve the enhancement of GABA action, serotoninergic modulation, and glutamatergic inhibition.
      • Freitag F.G.
      • Collins S.D.
      • Carlson H.A.
      • et al.
      A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis.
      Therefore, it is possible that the glutamatergic action of Topiramate and Valproate is one of the most important mechanisms in the prevention of headaches.
      Thus, even though our cohort study shows elevated rates of PIH, the prevalence of this condition is possibly underestimated, not only in the present report but also in most of the previous studies since the use of AED might have reduced the cases of PIH. In this way, the true number of patients suffering from PIH could only be revealed in individuals not using any AED.
      We also hypothesize that, in some patients with epilepsy who presented PIH, perhaps the spectrum of the AED used was not enough to prevent the occurrence of headaches.
      Other studies have stated that glutamate is important in the pathophysiology of migraine. It has been proposed that during a seizure, glutamate is massively released, leading to a transitory reduction in the levels of glutamate that could be responsible for the occurrence of post-ictal headaches.
      • Ekstein D.
      • Schachter S.C.
      Postictal headache.
      • Lado F.A.
      • Moshé S.L.
      How do seizures stop?.
      • Goadsby P.J.
      • Charbit A.R.
      • Andreou A.P.
      • Akerman S.
      • Holland P.R.
      Neurobiology of migraine.
      We would like to further elaborate this hypothesis by taking into account the probable inhibition of the glutamatergic action by Topiramate and Valproate which seems to paradoxically decrease post-ictal headaches. We think that a possible explanation for this is the fact that what causes PIH is an imbalance in the levels of glutamate. In this way, patients with epilepsy who have excessively increased basal levels of glutamate in the brain could benefit from the use of these AED since their levels of glutamate would be depleted, but not enough to cause PIH.
      On the other hand, patients who have not so elevated basal levels of glutamate would have even lower levels of this substance after taking Topiramate or Valproate, and this could lead to post-ictal headaches. This relative reduction in the threshold for headaches in predisposed patients caused by an excessive depletion of glutamate could also be an explanation for the fact that some patients experience headaches as a side effect of antiepileptic drugs.
      • Grant R.
      Side Effects of Therapies for Brain Tumours.
      We also would like to comment on the fact that definitions of epilepsy-related headaches differ across most of the studies
      • Daryan M.D.
      • Güveli B.T.
      • Baslo S.A.
      • et al.
      Prevalence and clinical characteristics of headache in juvenile myoclonic epilepsy: experience from a tertiary epilepsy center.
      ,
      • Ito M.
      • Adachi N.
      • Nakamura F.
      • et al.
      Multi‐center study on post‐ictal headache in patients with localization‐related epilepsy.
      ,
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      , and change constantly in the Headaches Criteria Guidelines which adds difficulties and confusion for the identification of this condition by neurologists in the clinical practice and also for researchers of the field. For example, the International Classification of Headaches Disorders 3rd edition (ICHD-3)
      • Headache Classification Committee of the International Headache S.
      The International Classification of Headache Disorders, 3rd edition (beta version).
      brings the term “ictal epileptic headache” but it does not include the diagnostic criteria for this condition described in the previous edition of the guideline.
      • Headache Classification Subcommittee of the International Headache S.
      The International Classification of Headache Disorders: 2nd edition.
      It appears also that due to the lack of uniform and clear definitions of epilepsy-related headaches in the Headaches Criteria Guidelines, many researchers work with their versions of headache definitions and diagnostic criteria. A German study for example
      • Duchaczek B.
      • Ghaeni L.
      • Matzen J.
      • Holtkamp M.
      Interictal and periictal headache in patients with epilepsy.
      defines the interictal headaches as “All other headaches that manifested within 1 year before or after an epileptic seizure”. On the other hand, a Japanese study defines interictal headache as “headache independent of seizure”, without specifying the time.
      • Ito M.
      • Adachi N.
      • Nakamura F.
      • et al.
      Multi-center study on post-ictal headache in patients with localization-related epilepsy.
      As for ictal headache, an Italian study
      • Parisi P.
      • Paolino M.C.
      • Raucci U.
      • et al.
      “ICTAL EPILEPTIC HEADACHE”: A TERMINOLOGY THAT IS NOT JUST A MOOT QUESTION.
      ,
      • Parisi P.
      • Striano P.
      • Negro A.
      • Martelletti P.
      • Belcastro V.
      Ictal epileptic headache: an old story with courses and appeals.
      interestingly first suggested and published in 2012 the new concept that the "ictal epileptic headache" should be classified as an "autonomic seizure”. This definition could facilitate and increase the detection of this clinical manifestation by neurologists in the clinical practice if implemented on the Guidelines.
      The evaluation of the impact of headaches on the quality of life of subjects with epilepsy also lacks a proper questionnaire developed specifically for this purpose. Some studies have attempted to evaluate the burden of headache in patients with epilepsy by applying the Qolie-10 questionnaire and a Headache-Attributed Lost Time (HALT) index
      • Mameniškienė R.
      • Karmonaitė I.
      • Zagorskis R.
      The burden of headache in people with epilepsy.
      but possibly neither of these is effective for analyzing those conditions as comorbidities in the same patient since they originally designed to evaluate the quality of life associated with each condition - epilepsy and headache – separately.
      Limitations of our study include the fact that it was only an observational study and we were not able to objectively test the clinical response of the PIH of our patients to different drugs. Our sample was also relatively small-sized and we included subjects with heterogeneous epilepsy etiologies in our analyses.
      We could not evaluate ictal epileptic headaches properly because we were unable to perform ictal-peri-ictal EEG recordings regularly in all of the patients. We performed a first EEG in all of the patients at the beginning of the study and after that, routine EEGs were performed when clinically indicated, for example, for the determination of seizure types and monitoring of the treatment response. Also, our cohort was hospital-based and not population-based, which could have biased our results.
      Another limitation is that, although we did not find any patients who presented seizures in association with clinical manifestations and a medical history suggestive of an immune or metabolic epilepsy etiology, we had limited access to more specific diagnostic methods such as antibody testing, which could have led to a decreased detection of these etiologies.
      The advantages of our study are the fact that we analyzed the occurrence of PIH in a long-term follow-up. Also, regular visits occurred during the entire study period, increasing the accuracy of our data collection.
      In sum, almost half of the subjects from our study consistently reported PIH, although this rate could be influenced by the use of AED. The factors that most influenced the occurrence of PIH were a family history of migraine, drug-resistant epilepsy, and generalized seizure onset type. We also hypothesized that PIH is caused by an imbalance in the levels of glutamate.
      Future studies and guidelines must focus on the basic-elements of epilepsy-related headaches such as the creation of more practical and less subjective definitions and the validation of more specific and structured questionnaires for a better evaluation of patients who suffer from epilepsy and headaches.
      Also, patients with epilepsy could be benefited if they were more frequently asked about the occurrence of PIH since this is a neglected condition in many cases.

      Funding

      This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      The authors report no declarations of interest.

      Acknowledgments

      Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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