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Long-term follow-up of adult patients with genetic generalized epilepsy with typical absence seizures and generalized paroxysmal fast activity in their EEG
Accepted Manuscript Title: Long-Term Follow-up of Adult Patients with Genetic Generalized Epilepsy with Typical Absence Seizures and Generalized Paroxysmal Fast Activity in their EEG ¨ Author: Zeynep Aydin-Ozemir Zeliha Matur Nerses Bebek Candan G¨urses Ays¸en G¨okyi˘git Bet¨ul Baykan PII: DOI: Reference:
S1059-1311(14)00136-8 http://dx.doi.org/doi:10.1016/j.seizure.2014.04.017 YSEIZ 2340
To appear in:
Seizure
Received date: Revised date: Accepted date:
11-3-2014 28-4-2014 30-4-2014
¨ ˙IR Z, MATUR Z, BEBEK N, GURSES ¨ Please cite this article as: AYDIN-OZEM C, ¨ ˘ ˙IT A, BAYKAN B, Long-Term Follow-up of Adult Patients with Genetic ˙IG GOKY Generalized Epilepsy with Typical Absence Seizures and Generalized Paroxysmal Fast Activity in their EEG, SEIZURE: European Journal of Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Long-Term Follow-up of Adult Patients with Genetic Generalized Epilepsy with Typical Absence Seizures and Generalized Paroxysmal Fast Activity in their EEG
Ayşen GÖKYİĞİT1, Betül BAYKAN1
Istanbul University Epilepsy Center (EPIMER) and Istanbul Faculty of Medicine,
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Zeynep AYDIN-ÖZEMİR1,2, Zeliha MATUR1,3, Nerses BEBEK1, Candan GÜRSES1,
Department of Neurology, Clinical Neurophysiology Unit
Istanbul Bilim University, Faculty of Medicine, Department of Neurology
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Memorial Ataşehir Hospital, Department of Neurology
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Corresponding Author: Zeynep AYDIN-ÖZEMİR
Address: Istanbul Faculty of Medicine, Department of Neurology, 34093
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Phone Number: +905058032126
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Arpaemini/Fatih/ Istanbul, Turkey.
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Fax Number:+902163297224
E-mail: [email protected] RUNNING TITLE: Absence Seizures and Paroxysmal Fast Activity Number of text pages: 12 Number of words: 3346 Number of figures: 3 Number of tables: 2 Key Words: Idiopathic epilepsy, absences, prognosis, fast activity
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ABSTRACT; Purpose: Generalized paroxysmal fast activity (GPFA), an EEG pattern with variable frequency and duration, is usually noted in symptomatic/cryptogenic generalized epilepsies.
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However, GPFA has also been reported in a few patients with genetic generalized epilepsy
of long-term follow-up and genetic findings in these patients.
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(GGE) who presented with typical absence seizures (TAS). Our aim was to report the results
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Methods: We investigated all EEGs of adult GGE patients with TAS, and identified 12 patients with GPFA (8.3% of adult GGE patients with TAS). Ten of these patients were
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available for long-term follow up. Their clinical and electroencephalographic courses and genetic features were investigated. The control group was composed of 24 adult GGE patients
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who also had TAS, but lacking GPFA with a similar follow-up duration in the same epilepsy
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center.
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Results: The mean age at GPFA detection was 33±16.6 (16-71 years) and 80% still had GPFA in their last EEG. The duration of epilepsy and persistence of TAS were both
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significantly longer in the GPFA group despite a similar follow-up duration. Sixty percent of the GPFA group had consanguineous parents, whereas this rate was only 4.17% in the control group. Seven relatives of the GPFA group also had epilepsy. We could not show any known mutations in two families. At the end of the follow-up, none of the patients with GPFA was dependent in self-care, despite continuing seizures. Conclusion: Our study shows that GPFA is an ignored EEG pattern of adult GGE patients with TAS, indicating a long and non-remitting course in almost all of the patients.
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Introduction: Generalized paroxysmal fast activity (GPFA), is a rather unique generalized rhythmic EEG finding of unknown significance, with a frequency of 8-26 Hz (mostly 10-14 Hz) lasting
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for 2-50 seconds1. This interesting pattern was usually noted during sleep in symptomatic and cryptogenic generalized epilepsies and it is one of the EEG constituents of Lennox-Gastaut
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Syndrome2,3. Thus, GPFA usually indicates poor prognosis, drug-refractory epilepsy with
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tonic-axial seizures and mental retardation4. However, GPFA was also noted during wakefulness and sleep in patients with genetic (formerly known as idiopathic) generalized
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epilepsy (GGE) usually presenting with TAS5,6,7,8,9,10 . It was suggested that most of these patients with GPFA had drug-refractory TAS, but there are no long-term follow-up studies on
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this issue10.
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Our aim was to report the results of long-term follow-up and genetic features in a
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series of adult GGE patients with TAS having GPFA on their EEG, in comparison to other adult GGE patients with persisting TAS but without GPFA to outline if GPFA is a reliable
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prognostic marker and/or endophenotype for genetic studies.
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Patients and Methods: Selection of patients and clinical analysis We had evaluated consecutive patients who were admitted to our epilepsy center
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between 1997 and 2002, with a diagnosis of TAS based on ILAE criteria for a previous
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study11,12. Out of 2697 cases, 144 (5.34%) were diagnosed as having TAS. All patients had undergone a detailed epileptological examination after obtaining informed consent and those
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having seizures that are associated with change in or loss of consciousness with 3-4 Hz GSW
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on their EEG were included in the study.
In the current study, four investigators acting as two independent groups re-examined
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a total of 476 EEGs and clinical patient files, in order to select those patients with clear-cut EEG discharges compatible with the diagnosis of TAS and GPFA. GPFA was defined as
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diffuse interictal or ictal generalized EEG rhythms with 8-26 Hz frequency, that can be clearly
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differentiated from the background activity and lasting more than one second.
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Eventually 12 adult GGE patients (8.3% of adult GGE patients with TAS), who had GPFA on their EEGs were identified. They were followed-up regularly at our epilepsy center with scheduled outpatient visits. No specific treatment or investigations were planned and they were managed according to their clinical needs, like all the other patients with GGE. Unfortunately, two patients were lost to follow-up despite telephone calls. One patient (Patient 10) has passed away following a middle cerebral artery stroke at the age of 98 years, after 12 years of follow-up in the current study. The following clinical parameters were obtained: age at onset, type and frequency of the seizures, course of seizures, history of febrile seizures, semiological analysis of TAS (either by video or by careful clinical history) concerning tonic, clonic, myoclonic components, presence of automatisms, hypotonia, eye blinking, eye deviation, autonomic
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signs, duration of absence seizure, presence of absence status epilepticus (ASE), family history of epilepsy, type of antiepileptic drugs (AED) used, response to AED, remission, discontinuation of AED, relapse, and last seizure status. Remission was defined as the
evaluated all patients independently during their long-term follow-up.
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absence of seizures during the last two years. At least two experienced epileptologists
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The control group consisted of 24 adult patients, matched for follow-up duration and
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gender, diagnosed with GGE having persistence of TAS after 18 years of age. The characteristics of the study group with GPFA were compared to patients without GPFA, and
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were followed up by the same team.
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EEG investigations
EEG recordings were performed with scalp electrodes placed according to the
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International 10-20 system with both bipolar and referential montages. Standard activating
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procedures were performed in all patients, hyperventilation was applied for 5 minutes and patients were randomly asked to open and close their eyes during the resting EEG to find out
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cases with eye closure sensitivity. Our standard intermittent photic stimulation (IPS) protocol started with eyes open for 5 seconds and then eyes closed for 5 seconds; the stimulus trains of 5-10-15-20-25-30-35 Hz were given in screening phase at a distance of 30 cm in a normally illuminated room. A photic stimulator with a granular diffuser and lamp-housing reflector capable of delivering flash from 1 to 50 Hz at a constant intensity (Medelec DG Compact 32, Vickers Medical-UK) was used. We used one EMG channel in the EEG recordings unless the findings indicated the need for more EMG channels. An experienced EEG technologist tested the level of consciousness by giving brief orders and a short phrase to remember after the event and by ordering to count when GSW discharges were observed. Most of the patients had also undergone synchronous VEM investigations (1-6 hours) and/or sleep studies. The
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patients were tested without modification of AED treatment during the follow-up investigations. The investigators analyzed all available EEGs and VEM independently in two separate
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sessions in a standardized manner, and the following points were evaluated: background activity, effect of IPS and hyperventilation and sleep (when available), frequency of ictal and
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interictal GSW discharges, ictal characteristics and their relation to EEG findings. The
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following characteristics of GPFA were additionally investigated: the frequency, ictal or interictal appearance of GPFA, ictal semiology, number of EEGs in which GPFA was
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determined, age at GPFA determination, existence of GPFA in the last recorded EEG, relationship with GSW discharges, sensitivity to IPS, hyperventilation, sleep and eye closure.
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Syndrome classification
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The electro-clinical syndromes were classified according to the current ILAE proposal
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at the end of the follow-up13. Additionally, the syndrome of eyelid myoclonia with absences (EMA) was diagnosed as a distinctive syndrome with brief TAS occurring with rapid and
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prominent eyelid myoclonia and EEG demonstrating GSW following eye closure14,15.. Moreover, patients with otherwise typical GGE with TAS and with onset after the age of 18 years were defined as late-onset absence epilepsy and patients with an earlier onset between a few months and 4 years were accepted as early onset absence epilepsy15,16. Investigation of the family members with epilepsy Five patients with GPFA had a family history of epilepsy. To clarify the possible importance of GPFA as an endophenotype, seven of their relatives were also investigated for the presence of GPFA in their EEG. All were examined clinically, their EEGs were evaluated and epileptic syndromes were classified.
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Two of our patients with GPFA who belonged to two large pedigrees had been previously analyzed as part of the Epicure consortium for the known mutations of GGE, including ion channels (chloride, calcium, sodium, and potassium channels), transporters,
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GABA-receptors, carbonic anhydrases, glutamate receptors, and glycine receptors.
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Statistics
SPSS 15 software was used for statistical analysis. Descriptive statistics were applied
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in relevant parameters such as current age, age at onset, gender, etc. The clinical and EEG variables were evaluated and compared between the groups. Chi-square test was used to
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assess the statistical significance of an association between categorical variables and Fisher's exact test was computed when the table had a cell with an expected frequency of less than
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five. Numeric parameters without a normal distribution were compared with Mann-Whitney
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U test.
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RESULTS Clinical Features In the GPFA group, the mean current age was 49±20.3 (min: 32, max: 98) years,
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whereas it was 31±10.1 (min: 20, max: 55) (p=0.002) in the control group despite their similar
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follow-up duration. Clinical information of the 10 (7-female) patients with GPFA and 24 (13female) patients in the control group is summarized in Table 1. The duration of TAS, duration
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of epilepsy, and remission of seizures were significantly different in the GPFA group (Table 1). In this group, TAS outcome was significantly worse than the control group; only one
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patient (Patient 1, in Table 2) had remission of his TAS for the last 3 years, under AED
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treatment.
There was no significant difference between the groups with regards to the frequencies
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of semiological characteristics of TAS (GPFA group and control group rates are given
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respectively), such as clonic components (10%vs 8.3%), myoclonic jerks in extremities (10% vs 12.5%), eyelid myoclonia (10% vs 12.5%), associated automatisms (none vs 16.7%),
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autonomic signs (none vs 4.2%), atonia-hypotonia (none vs 8.3%), deviation of eyes (10% vs 25%), and blinking (50% vs 37.5%). There were no tonic components. Only one patient (10%) had isolated TAS in the GPFA group, whereas 29% of the control group had simple TAS.
Ictal recordings were available in seven patients of the GPFA group. In all of them,
impairment of consciousness was documented by staring and unresponsiveness for standard questions of the experienced EEG technologists, interruptions of counting, repeating the same number. Additionally, five patients had occasional eyelid blinking, one had prominent eyelid myoclonia, one had eye deviation, one had mild clonia of the left arm and one had myoclonic
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jerks in extremities whereas none showed observable change in tonus, automatisms or autonomic signs. The syndrome classifications of the study groups are shown in Table 1. Two patients
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from the GPFA group (Patients 3 and 4 in Table 2) were siblings but they had different GGE syndromes (Table 2).
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Electroencephalographic Features
There were a mean of 7 (min:2, max: 13) EEG recordings for the GPFA group and 5
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(min:2, max:9) for the control group. Six patients in the GPFA group and 13 patients in the
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control group had ictal VEM recordings. Five patients in the GPFA group had short-term spontaneous sleep EEG recordings (3-4 hours) and GPFA were noted during sleep in four of
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them (Table 2). All but one of the patients had GPFA during wakefulness, remarkably. The EEG background activity of all patients was normal. We recorded interictal as well as
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ictal GSW with variable dominant frequencies of 3±6 Hz associated with GPFA, which
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manifested either in isolation or as the dominant activity in the GPFA group, as seen in Table 2. There was no significant difference between the analyzed EEG and ictal semiological
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features of the groups.
We compared the frequencies and duration of the GPFA of the patients who also had
sleep recordings, but there is no change of these characteristics during sleep. Two had GPFA of 15Hz and one had 9-10 Hz, the last one had a frequency range of 12-14 Hz both in sleep and wakefulness.
In the GPFA group, age at detection was 33±16.6 (min: 16, max: 71) years and 80% of
them still had GPFA in their last EEG at the end of the long-term follow-up. The mean number of pathologic EEG recordings was 6.5±4.24 and the mean number of the EEGs with GPFA was 4±3.9. It was noted that only two (20%) patients had GPFA in their first EEG recording evaluated in our laboratory.
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Genetic features Seven relatives of the GPFA group, who had epilepsy, were also evaluated and GPFA was not seen in any of their 30 available EEGs. The Patient 3 is the brother of Patient 4
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(Table2), and they also had two other first degree relatives who were diagnosed with GGE without GPFA. Patient 5 had two first-degree relatives with GGE and a 56-year-old cousin
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with refractory form of JME; all of whom did not have GPFA. In addition, a 36-year-old sister of Patient 6 was diagnosed with JAE without GPFA in our center previously, before the
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identification of our study patient. The son of Patient 7 diagnosed with EMA had 3 Hz GSW,
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mainly after eye closure and he was sensitive to IPS but did not show GPFA. Additionally, two (Patients 3, 5) of our patients from two different families with GGE
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had been previously investigated in the years of 2007-2011 as part of the Epicure project, by chance. All known candidate GGE genes related to ion channels including GLUT1 were
Outcome
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for15q13.3 microdeletion18.
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sequenced but no mutations was found in these families17. They were also negative
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Nine (90%) of the patients in GPFA group were still using AED due to mild but
recurring TAS, whereas 18 (75%) patients in the control group were under AED in their final evaluation. The AED used for GGE were similar between the two groups and the same team followed them up. Other details are presented in Table 1. It was noted that within the GPFA group; 5 patients were high school graduates, 4
were employed, and 7 of them were married with children. None of them was dependent for their self-care to their family except one female with financial difficulty, who is a housewife and successfully raised three children.
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DISCUSSION We evaluated the long-term course of adult GGE patients with TAS having GPFA on EEG, in comparison to similar patients without this EEG pattern. We found that this
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intriguing EEG phenomenon may indicate a life-long and non-remitting course for GGE patients with TAS but we failed to demonstrate its exact genetic background. In addition, we
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did not observe a complete familial penetrance of GPFA; most of the first-degree relatives of
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the patients with GPFA who also had GGE did not show this unique pattern. Age at onset and seizure characteristics
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Fakhoury et al.8 reported five adults with uncontrolled TAS having these unusual, fast rhythmic discharges; two of their patients had TAS that developed after 20 years of age,
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interestingly. Our series included patients with relatively late-onset TAS, as has been previously reported5. Parallel to the literature, the age at the onset of epilepsy varied among
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our cases6,7,8,9,10. Halasz stated that GPFA could be detected in a later period in some
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patients6. The fact that, studies focusing on the electro-clinical features of TAS in children did
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not report any GFPA-like findings further supports the association of GPFA with adult patients19, 20,21,22,23.
GPFA is mostly associated with rare generalized tonic-clonic seizures in our series,
like other reports5,8,9, but myoclonic seizures and eyelid myoclonia might also be seen. This rare association of “eyelid twitching seizures” was already reported in two neurologically normal adult patients24. Seizure semiology and ictal VEM recordings suggested that our cases did not experience “tonic-absence” seizures, as reported to be associated with GPFA by other authors9. We did not notice any overt tonic components in our patients during GPFA in VEM. It should be noted, however, that we used only one EMG electrode located over the arm muscles, hence subtle tonic components, consisting of mild contraction in the neck muscles
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may be unnoticed. The notably high (60%) association of GPFA with ASE in our study is quite interesting, although it did not reach statistical significance. However, our control group was also constituted of adults with TAS who were followed up in a tertiary center, thus they
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may not be reflecting ordinary patients with TAS with good prognosis.
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EEG characteristics
GPFA itself did not show a homogenous appearance in the EEG of our patients, its
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frequency and duration varied from case to case and even within the same patient; it can be
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seen either ictally or interictally, either separately (Figure 1) or associated with typical GSW discharges (Figure 2). Photosensitivity is also a well-known poor prognostic indicator for
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TAS25 and we noted an association with GPFA and photosensitivity as shown in Figure 3. Moreover our results showed that GPFA is not a sleep-dependent EEG phenomenon in adult
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GGE patients with TAS in contrast to similar EEG pattern in Lennox-Gastaut syndrome.
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Tatum et al. adopted another approach for similar patients; they assessed TAS in
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adults and reported its association with “polyspike ictal onset” prior to classic 3-Hz GSW and emphasized that this EEG pattern may predict an unfavorable response to treatment
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. It is
noteworthy that they accepted the similarity and noted “overlaps” of polyspikes with GPFA; this suggests that they originate from a similar generator26. Another study has reported 12 GGE patients with TAS, persistent or recurring in adulthood and suggested that the findings including “runs of polyspikes”, similar to GPFA in our study, are distinctive from those that are usually found in infancy or adolescence5. In this series, 83% had GTCS and 33% had frequent episodes of ASE, similar to our series5. Syndrome Classification Panayiotopoulos et al. described adult patients with TAS providing a more detailed syndrome classification of their cases and also emphasized that TAS in adults are more
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difficult to recognize than in children, due to their short duration and mild degree of impaired consciousness27. Our adult patients with GPFA did not easily fall into one of the well-known epileptic syndromes, and this is possibly due to the limited knowledge on this issue, and its
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rare incidence. We believe that awareness of this entity and studies related to this phenomenon will increase in adult patients if a late-onset form of GGE will be included in the
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next ILAE classification.
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Possible modulators of GPFA and its pathogenesis
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The possible modulating effects of AED on GPFA could not be ruled out easily, but our patients in the control group without GPFA have been using similar drugs and doses for a
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similar duration, excluding a simple causal relationship.
Sleep could also be a modulating factor and Guye et al. reported five cases with
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borderline intellect and poor response to AED, showing GPFA of 10-15 Hz only during sleep
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EEG10 and suggested that these cases could be transitional forms between idiopathic and
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cryptogenic/symptomatic generalized epilepsies. However, GPFA was not limited to sleep recordings in all but one of our patients and all had normal intellectual levels with normal social outcome and long life span; one of them even reaching the age of 98 years, despite frequent life-long ASE attacks.
The etio-pathogenesis of GPFA is unknown in GGE patients. Therefore, studies on
Lennox-Gastaut Syndrome patients with similar GPFA patterns may help us understand the pathophysiology. In an EEG-fMRI (functional magnetic resonance spectroscopy) study of 6 Lennox-Gastaut patients, simultaneous GPFA events showed almost uniform increases in blood oxygen level-dependent (BOLD) signal in "association" cortical areas, as well as brainstem, basal ganglia, and thalamus28. They concluded that GPFA is associated with
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activity in a diffuse network that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures. Studies exploring the pathophysiology of absence seizures suggested that increased
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oscillatory activity in reticulothalamocortical circuitry is important for absence seizures29,30,31. In our patients with GPFA, TAS seemed to appear relatively later and persistence of these
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seizures during long years was noted. This may suggest that exposure to pathopysiological
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events underlying TAS, during a long period after adolescence, might lead to some functional changes of reticulothalamocortical circuitry ending up with GPFA in some GGE patients,
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with a possible genetic liability 32. If we consider the significantly high rate of consanguinity of the parents of our GPFA patients, a possible autosomal recessive genetic defect could also
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be hypothesized to result in GPFA. There are two siblings concordant for the presence of GPFA out of 10 patients in our small series but GPFA did not show a complete penetrance in
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the given families and we could not show any known mutations. Thus the question of GPFA
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as an endophenotypic marker remains still unanswered. We think that future genetic studies
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should take this peculiar EEG pattern into account in search for GGE genes. According to our results, the under-recognized association with GPFA seems to be one
of the predictors of unremitting course, but it does not mean an exceptionally poor quality of life for adult patients with TAS33. Our results should be interpreted with caution because our GPFA series is rather small, but it is still the largest study with the longest follow-up. We included the patients at a time where their seizures already have started and therefore the exact timing of appearance of GPFA could not be shown. Furthermore, the control group was younger than the GPFA group even in the cross-sectional start of the study, partly supporting the late-onset and long-duration of TAS in these cases. We also want to emphasize that our
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epilepsy center is a well-known tertiary center, involved in genetic studies; thus, this group is not representative of the general population of epileptic patients. In conclusion, GPFA is an ignored EEG pattern during wakefulness of GGE with
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persisting TAS in adulthood. GPFA does not segregate in a given family with GGE and it is not specific to familial cases. Although it does not show a homogenous clinical picture, it
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indicates a long and non-remitting course in almost all of the patients.
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Acknowledgements We thank to The European Community [FP6 Integrated Project EPICURE, LSHMCT-2006-037315]
for
the
extensive
genetic
investigations
of
two
patients
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(http://www.epicureproject.eu/home.aspx) belonging two families with IGE. This study was supported by the Research Fund of Istanbul University (T-1124/18062001).
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We confirm that we have read the Journal’s position on issues involved in ethical
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publication and affirm that this report is consistent with those guidelines.
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Disclosure of Conflicts of Interest: None of the authors has any conflict of interest to
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disclose.
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26. Tatum WO, Ho S, Benbadis SR. Polyspike ictal onset absence seizures. J Clin Neurophysiol 2010;27:93-99.
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27. Panayiotopoulos CP, Chroni E, Daskalopoulos C, Baker A, Rowlinson S, Walsh P. Typical absence seizures in adults: clinical, EEG, video-EEG findings and diagnostic/syndromic considerations.
J Neurol Neurosurg Psychiatry 1992;55:1002-
1008.
28. Pillay N, Archer JS, Badawy RA, Flanagan DF, Berkovic SF, Jackson G. Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome. Neurology 2013;13;81:665-673. 29. Weiergräber M, Stephani U, Köhling R. Voltage-gated calcium channels in the etiopathogenesis and treatment of absence epilepsy. Brain Res Rev 2010;62:245-271.
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30. Jasper HH, Drooglever-Fortuyn J. Experimental studies on the functional anatomy of petit-mal epilepsy. Asoc Res Nerv Ment Dis 1974;26:272-298. 31. Avanzini G, de Curtis M, Franceschetti S, Sancini G, Spreafico R. Cortical versus
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thalamic mechanism underlying spike and wave discharges in GAERS. Epilepsy Res 1996;26:37-44.
Thalamus
in
Idiopathic
Generalized
Epilepsy.
Archives
of
Neuropsychiatry
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(Noropsikiyatri Arsivi) 2011;48:243-8.
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32. Aydın-Özemir Z, Terzibaşıoğlu E, Sencer S, Yapıcı Z, Baykan B. Volumetry of the
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33. Matur Z, Bebek N, Aydın-Ozemir Z, Baykan B, Gürses C, Gökyiğit A. Generalized Paroxysmal Fast Activity in Idiopathic Epilepsies with Typical Absence Seizures: An
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Unusual Electroencephalographic Finding (in Turkish). Epilepsi-Turkish 2006;12:69-77.
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Figure Legends: Figure 1: Generalized paroxysmal fast activity (GPFA) was prominent, mostly isolated, partly asymmetric and always lasted long in a patient diagnosed with juvenile absence
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epilepsy (Pt 2); EEG recordings in 2005 (a) and in 2010 (b).
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Figure 2: EEG recording of the 27-year-old Pt.1 with absence seizures (a) shows GPFA associated with generalized spike-wave discharges during hyperventilation in 2002. Ten
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years later, EEG recording (b) again shows GPFA after spike-wave discharges but he does not
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report absence seizures since one year under Valproate therapy.
(c) GPFA was observed with a similar frequency and morphology during NREM sleep
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recordings in the same patient.
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Figure 3(a) Patient 7’s EEG recording while she was 58-year-old. In this figure, GPFA
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appears after eye closure and during photic stimulation, always before spike-wave discharges associated with a typical absence seizure, (b) but GPFA may also be seen as isolated interictal
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discharges in the same EEG.
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Table 1. The Clinical Features of the Groups with and without GPFA at the End of the Long-term Follow-up Clinical Features
Group with GPFA
Group without GPFA
Statistical
(n=10)
(n=24)
Results
14.5±6.9 (5-27)
9.4±3.9 (1-17)
p:0.55
15.1±7.9 (5-28)
11±6.9 (1-35)
17.6±8.1 (8-28)
15.2±5.6 (8-31)
33±17.3 (17-63)
18.1±10.1 (3.5-42.3)
p: 0.005
15±18.6 (0.4-42)
p: 0.01
Age at onset of epilepsy in years
Age at onset of TAS in years mean±SD(min-max)*
mean±SD(min-max)*
Duration of TAS in years mean±SD(min-max)* Family history of epilepsy
5 (50) n(%)º Consanguinity of the parents# First seizure type n (%) #
6 (60)
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ABS GTC MYO ABS ABS+GTC ABS+GTC+MYO EMA+GTC+MYO None
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Single
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Absence status epilepticus n (%) #
Recurrent
#
Febrile seizure n (%) Epileptic Syndrome Diagnosis n (%)#
Remission of TAS n(%)# Seizure-free # n(%) #
AED-free n(%)
CAE JAE JME EMA Late-onset Absence Epilepsy Early-onset Absence Epilepsy
8 (33)
1 (4.17)
7 (70)
18 (75)
3 (30)
5 (20.8)
none
1 (4.2)
1 (10) 5 (50) 3 (30) 1 (10)
7 (29.2) 7 (29.2) 7 (29.2) 3 (12.5)
4 (40)
15 (62.5)
2 (20)
2 (8.3)
4 (40)
7 (29.2)
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All seizure types n (%) #
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30.7±18.6 (7-60)
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Duration of epilepsy in years mean±SD(min-max)*
n.s.
n.s.
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Duration of follow-up in years
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mean±SD(min-max)*
n.s.
P:0.01
n.s.
n.s. n.s.
1(10)
8 (33)
n.s.
2 (20) 4 (40) none 1 (10)
7 (29.2) 6 (25.0) 7 (29.2) 2 (8.3)
n.s.
3 (30%)
None
none
2 (8.3)
1 (10)
13 (54)
p:0.02
1 (10)&
13 (54)
p:0.02
1 (10)&
6 (25)
n.s.
ºPearson Chi-Square test # Fisher's exact test *Mann-Whitney U test. ABS: Absence seizure, CAE: Childhood Absence Epilepsy, EMA: Eyelid Myoclonia with Absences, GPFA: Generalized Paroxysmal Fast Activity, GTC: Generalized Tonic-Clonic, JAE: Juvenile Absence Epilepsy, JME: Juvenile Myoclonic Epilepsy, MYO: Myoclonic Seizure, n.s.: not significant, TAS: Typical Absence Seizures. & Note that the AED-free patient is not seizure free; she is still experiencing mild absence seizures, but did not want to use AED whereas the seizure-free patient is still under VPA.
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Table 2. EEG and Clinical Features of the GPFA group Patient No Age (years)/gender
Patient 2 32/F
Patient 3 48/M
Patient 4 44/F
Patient 5 39/F
Patient 6 32/F
Patient 7 68/F
Patient 8 41/F
Patient 9 51/M
Patient 10 98/F
ABS+GTC +MYO
ABS+GTC +ASE
ABS+GTC +ASE
ABS
ABS+GTC +ASE
EMA +GTC +MYO
ABS+GTC +ASE
ABS+ GTC+ MYO + ASE
ABS+GTC
ABS+GTC+ MYO+ASE
28/21/21
11/20/-
5/11/-
27/-/-
12/15/-
9(EMA)/9/9
8/23/-
18/18/18
13/13/-
20/20/20
Late-onset AE
JAE
CAE
Late-onset AE
JAE
EMA
CAE
JAE
JAE
Late-onset AE
29
16
32
33
25
20
50
18
36
71
VPA
VPA +LEV
VPA +ZNS+ BBX+ ETX
None°
VPA
VPA
VPA
Initial ABS/
1/week/
1-2/day/
30/day/
1-2/day/
5-10/day/
7-10/day/
GTC Frequency
totally 4 times None since 3yrs/
totally 5 times Rare/
1/month
None
1/month
totally once
2-3/day/
2/day/
None since 12yrs
None since 5yrs
None since 4yrs
None
None since22yrs
None since 23 yrs
None since 10yrs
None since 3yrs
None since 12yrs
None since 12yrs
6/1/1
13/1/1
4/0/0
2/1/1
6/1/1
3/0/0
7/1/1
12/0/0
13/0/0
7/1/0
3.5-4 Hz GSW
4-5 Hz GSW
3-5 Hz GSW
3.5-4 Hz PSWD
4 Hz PSWD
5 Hz PSWD
3-4 Hz GSW
3-4 Hz PSWD
3.5-4 Hz GSW
4-5Hz theta paroxysm
3-3.5Hz GSW
15Hz GPFA
3-4 Hz GSW
No ictal recording
5Hz PSWD
5Hz PSWD
3.5-4 Hz GSW
3-4 Hz PSWD
3-4 Hz PSWD
3 Hz PSWD
Sensitivity to IPS /EC
No/No
No/No
Yes/No
Yes/No
Yes/No
Yes/Yes
Yes/Yes
No/No
Yes/Yes
Yes/No
Duration of GPFA (sec)
8
1-17
3-4
2
3
1.5
30
8-9
1.5
Frequency of GPFA (Hz)
9-10
15
14
10
15
17
12-14
12-16
15
9-10
Ictal and Interictal, also during NREM sleep
Ictal and Interictal, also during NREM sleep
Ictal and Interictal
Interictal
Interictal∑ (during NREM sleep only)
Ictal
Ictal and Interictal
Interictal
Ictal
After GSW
Isolated and prominent
Isolated or before GSW
Isolated
Isolated or before GSW
Isolated, appears after EC
Before PSWD, seen in ASE
Before GSW
Before GSW
2* (Sister/46/ JME; cousine daughter JAE)
Mother/JA E;sister/35 /JAE; cousin/56/ JME
-
-
-
Numbers of total EEG /VEM/Sleep EEG Interictal discharge Ictal pattern
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GPFA appearance
1-2/day/
Relation of GPFA with other discharges
Relatives with GGE without GPFA (relation/age/syndr ome)
-
-
1.5
2* (Sister/46/JM E; cousine 27/JAE)
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1-2/day/
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Last reported frequency for ABS/ GTC
20/day/
200/day / totally 5 times 1/day/
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Age at diagnosis of GPFA (years) in our EEG lab Current AED
M
Syndrome
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Age at onset of ABS/GTC/MYO
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Seizure Types
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Patient 1 39/M
Sister/36/JAE
Ictal and Interictal also during NREM sleep Appears after EC and IPS, Before SWD
Son/44/ EMA
1-2/month ASE attack/ yearly/
VPA+LEV
1-2/day/ totally 3 times 1/month/
CLZ 1-2/day/ 2-3/month Rare/
ABS: Absence, AE: Absence epilepsy AED: Anti-epileptic drugs, ASE: Absence Status Epilepticus, BBX: Barbexaclone, CAE: Childhood Absence Epilepsy, CLZ: Clonazepam, EC: Eye closure, EMA: Eyelid Myoclonia with Absences, ETX: Ethosuximide, F: Female, GGE: Genetic generalized epilepsy; GPFA: Generalized paroxysmal fast activity, GSW: Generalized spike-waves, GTC: Generalized tonic-clonic, IPS: Intermittan photic stimulation, JME: Juvenile Myoclonic Epilepsy, LEV: Levetiracetam, MYO: Myoclonic seizure, M: Male, PSWD: Poly-spike-slow wave discharges, VPA: Valproate, ZNS: Zonisamide. ° She did not want to use drugs, due to financial problems and the minimal effect of absence seizures on her quality of life. *Note that Patients 3 and 4 with GPFA were siblings. ∑GPFA was recorded only during NREM sleep without clinical symptoms and no change in EMG electrode.
Please note that all but one (pt5) of the patients had GPFA during standard wakefulness EEGs and in all patients who had sleep and wakefulness EEG recordings, GPFA had similar duration, frequency and appearance rate in comparison to sleep EEGs.
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S1059-1311(14)00136-8 http://dx.doi.org/doi:10.1016/j.seizure.2014.04.017 YSEIZ 2340
To appear in:
Seizure
Received date: Revised date: Accepted date:
11-3-2014 28-4-2014 30-4-2014
¨ ˙IR Z, MATUR Z, BEBEK N, GURSES ¨ Please cite this article as: AYDIN-OZEM C, ¨ ˘ ˙IT A, BAYKAN B, Long-Term Follow-up of Adult Patients with Genetic ˙IG GOKY Generalized Epilepsy with Typical Absence Seizures and Generalized Paroxysmal Fast Activity in their EEG, SEIZURE: European Journal of Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Long-Term Follow-up of Adult Patients with Genetic Generalized Epilepsy with Typical Absence Seizures and Generalized Paroxysmal Fast Activity in their EEG
Ayşen GÖKYİĞİT1, Betül BAYKAN1
Istanbul University Epilepsy Center (EPIMER) and Istanbul Faculty of Medicine,
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1
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Zeynep AYDIN-ÖZEMİR1,2, Zeliha MATUR1,3, Nerses BEBEK1, Candan GÜRSES1,
Department of Neurology, Clinical Neurophysiology Unit
Istanbul Bilim University, Faculty of Medicine, Department of Neurology
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Memorial Ataşehir Hospital, Department of Neurology
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Corresponding Author: Zeynep AYDIN-ÖZEMİR
Address: Istanbul Faculty of Medicine, Department of Neurology, 34093
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Phone Number: +905058032126
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Arpaemini/Fatih/ Istanbul, Turkey.
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Fax Number:+902163297224
E-mail: [email protected] RUNNING TITLE: Absence Seizures and Paroxysmal Fast Activity Number of text pages: 12 Number of words: 3346 Number of figures: 3 Number of tables: 2 Key Words: Idiopathic epilepsy, absences, prognosis, fast activity
Page 1 of 30
ABSTRACT; Purpose: Generalized paroxysmal fast activity (GPFA), an EEG pattern with variable frequency and duration, is usually noted in symptomatic/cryptogenic generalized epilepsies.
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However, GPFA has also been reported in a few patients with genetic generalized epilepsy
of long-term follow-up and genetic findings in these patients.
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(GGE) who presented with typical absence seizures (TAS). Our aim was to report the results
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Methods: We investigated all EEGs of adult GGE patients with TAS, and identified 12 patients with GPFA (8.3% of adult GGE patients with TAS). Ten of these patients were
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available for long-term follow up. Their clinical and electroencephalographic courses and genetic features were investigated. The control group was composed of 24 adult GGE patients
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who also had TAS, but lacking GPFA with a similar follow-up duration in the same epilepsy
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center.
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Results: The mean age at GPFA detection was 33±16.6 (16-71 years) and 80% still had GPFA in their last EEG. The duration of epilepsy and persistence of TAS were both
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significantly longer in the GPFA group despite a similar follow-up duration. Sixty percent of the GPFA group had consanguineous parents, whereas this rate was only 4.17% in the control group. Seven relatives of the GPFA group also had epilepsy. We could not show any known mutations in two families. At the end of the follow-up, none of the patients with GPFA was dependent in self-care, despite continuing seizures. Conclusion: Our study shows that GPFA is an ignored EEG pattern of adult GGE patients with TAS, indicating a long and non-remitting course in almost all of the patients.
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Introduction: Generalized paroxysmal fast activity (GPFA), is a rather unique generalized rhythmic EEG finding of unknown significance, with a frequency of 8-26 Hz (mostly 10-14 Hz) lasting
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for 2-50 seconds1. This interesting pattern was usually noted during sleep in symptomatic and cryptogenic generalized epilepsies and it is one of the EEG constituents of Lennox-Gastaut
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Syndrome2,3. Thus, GPFA usually indicates poor prognosis, drug-refractory epilepsy with
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tonic-axial seizures and mental retardation4. However, GPFA was also noted during wakefulness and sleep in patients with genetic (formerly known as idiopathic) generalized
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epilepsy (GGE) usually presenting with TAS5,6,7,8,9,10 . It was suggested that most of these patients with GPFA had drug-refractory TAS, but there are no long-term follow-up studies on
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this issue10.
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Our aim was to report the results of long-term follow-up and genetic features in a
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series of adult GGE patients with TAS having GPFA on their EEG, in comparison to other adult GGE patients with persisting TAS but without GPFA to outline if GPFA is a reliable
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prognostic marker and/or endophenotype for genetic studies.
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Patients and Methods: Selection of patients and clinical analysis We had evaluated consecutive patients who were admitted to our epilepsy center
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between 1997 and 2002, with a diagnosis of TAS based on ILAE criteria for a previous
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study11,12. Out of 2697 cases, 144 (5.34%) were diagnosed as having TAS. All patients had undergone a detailed epileptological examination after obtaining informed consent and those
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having seizures that are associated with change in or loss of consciousness with 3-4 Hz GSW
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on their EEG were included in the study.
In the current study, four investigators acting as two independent groups re-examined
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a total of 476 EEGs and clinical patient files, in order to select those patients with clear-cut EEG discharges compatible with the diagnosis of TAS and GPFA. GPFA was defined as
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diffuse interictal or ictal generalized EEG rhythms with 8-26 Hz frequency, that can be clearly
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differentiated from the background activity and lasting more than one second.
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Eventually 12 adult GGE patients (8.3% of adult GGE patients with TAS), who had GPFA on their EEGs were identified. They were followed-up regularly at our epilepsy center with scheduled outpatient visits. No specific treatment or investigations were planned and they were managed according to their clinical needs, like all the other patients with GGE. Unfortunately, two patients were lost to follow-up despite telephone calls. One patient (Patient 10) has passed away following a middle cerebral artery stroke at the age of 98 years, after 12 years of follow-up in the current study. The following clinical parameters were obtained: age at onset, type and frequency of the seizures, course of seizures, history of febrile seizures, semiological analysis of TAS (either by video or by careful clinical history) concerning tonic, clonic, myoclonic components, presence of automatisms, hypotonia, eye blinking, eye deviation, autonomic
Page 4 of 30
signs, duration of absence seizure, presence of absence status epilepticus (ASE), family history of epilepsy, type of antiepileptic drugs (AED) used, response to AED, remission, discontinuation of AED, relapse, and last seizure status. Remission was defined as the
evaluated all patients independently during their long-term follow-up.
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absence of seizures during the last two years. At least two experienced epileptologists
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The control group consisted of 24 adult patients, matched for follow-up duration and
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gender, diagnosed with GGE having persistence of TAS after 18 years of age. The characteristics of the study group with GPFA were compared to patients without GPFA, and
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were followed up by the same team.
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EEG investigations
EEG recordings were performed with scalp electrodes placed according to the
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International 10-20 system with both bipolar and referential montages. Standard activating
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procedures were performed in all patients, hyperventilation was applied for 5 minutes and patients were randomly asked to open and close their eyes during the resting EEG to find out
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cases with eye closure sensitivity. Our standard intermittent photic stimulation (IPS) protocol started with eyes open for 5 seconds and then eyes closed for 5 seconds; the stimulus trains of 5-10-15-20-25-30-35 Hz were given in screening phase at a distance of 30 cm in a normally illuminated room. A photic stimulator with a granular diffuser and lamp-housing reflector capable of delivering flash from 1 to 50 Hz at a constant intensity (Medelec DG Compact 32, Vickers Medical-UK) was used. We used one EMG channel in the EEG recordings unless the findings indicated the need for more EMG channels. An experienced EEG technologist tested the level of consciousness by giving brief orders and a short phrase to remember after the event and by ordering to count when GSW discharges were observed. Most of the patients had also undergone synchronous VEM investigations (1-6 hours) and/or sleep studies. The
Page 5 of 30
patients were tested without modification of AED treatment during the follow-up investigations. The investigators analyzed all available EEGs and VEM independently in two separate
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sessions in a standardized manner, and the following points were evaluated: background activity, effect of IPS and hyperventilation and sleep (when available), frequency of ictal and
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interictal GSW discharges, ictal characteristics and their relation to EEG findings. The
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following characteristics of GPFA were additionally investigated: the frequency, ictal or interictal appearance of GPFA, ictal semiology, number of EEGs in which GPFA was
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determined, age at GPFA determination, existence of GPFA in the last recorded EEG, relationship with GSW discharges, sensitivity to IPS, hyperventilation, sleep and eye closure.
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Syndrome classification
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The electro-clinical syndromes were classified according to the current ILAE proposal
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at the end of the follow-up13. Additionally, the syndrome of eyelid myoclonia with absences (EMA) was diagnosed as a distinctive syndrome with brief TAS occurring with rapid and
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prominent eyelid myoclonia and EEG demonstrating GSW following eye closure14,15.. Moreover, patients with otherwise typical GGE with TAS and with onset after the age of 18 years were defined as late-onset absence epilepsy and patients with an earlier onset between a few months and 4 years were accepted as early onset absence epilepsy15,16. Investigation of the family members with epilepsy Five patients with GPFA had a family history of epilepsy. To clarify the possible importance of GPFA as an endophenotype, seven of their relatives were also investigated for the presence of GPFA in their EEG. All were examined clinically, their EEGs were evaluated and epileptic syndromes were classified.
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Two of our patients with GPFA who belonged to two large pedigrees had been previously analyzed as part of the Epicure consortium for the known mutations of GGE, including ion channels (chloride, calcium, sodium, and potassium channels), transporters,
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GABA-receptors, carbonic anhydrases, glutamate receptors, and glycine receptors.
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Statistics
SPSS 15 software was used for statistical analysis. Descriptive statistics were applied
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in relevant parameters such as current age, age at onset, gender, etc. The clinical and EEG variables were evaluated and compared between the groups. Chi-square test was used to
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assess the statistical significance of an association between categorical variables and Fisher's exact test was computed when the table had a cell with an expected frequency of less than
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five. Numeric parameters without a normal distribution were compared with Mann-Whitney
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U test.
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RESULTS Clinical Features In the GPFA group, the mean current age was 49±20.3 (min: 32, max: 98) years,
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whereas it was 31±10.1 (min: 20, max: 55) (p=0.002) in the control group despite their similar
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follow-up duration. Clinical information of the 10 (7-female) patients with GPFA and 24 (13female) patients in the control group is summarized in Table 1. The duration of TAS, duration
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of epilepsy, and remission of seizures were significantly different in the GPFA group (Table 1). In this group, TAS outcome was significantly worse than the control group; only one
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patient (Patient 1, in Table 2) had remission of his TAS for the last 3 years, under AED
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treatment.
There was no significant difference between the groups with regards to the frequencies
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of semiological characteristics of TAS (GPFA group and control group rates are given
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respectively), such as clonic components (10%vs 8.3%), myoclonic jerks in extremities (10% vs 12.5%), eyelid myoclonia (10% vs 12.5%), associated automatisms (none vs 16.7%),
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autonomic signs (none vs 4.2%), atonia-hypotonia (none vs 8.3%), deviation of eyes (10% vs 25%), and blinking (50% vs 37.5%). There were no tonic components. Only one patient (10%) had isolated TAS in the GPFA group, whereas 29% of the control group had simple TAS.
Ictal recordings were available in seven patients of the GPFA group. In all of them,
impairment of consciousness was documented by staring and unresponsiveness for standard questions of the experienced EEG technologists, interruptions of counting, repeating the same number. Additionally, five patients had occasional eyelid blinking, one had prominent eyelid myoclonia, one had eye deviation, one had mild clonia of the left arm and one had myoclonic
Page 8 of 30
jerks in extremities whereas none showed observable change in tonus, automatisms or autonomic signs. The syndrome classifications of the study groups are shown in Table 1. Two patients
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from the GPFA group (Patients 3 and 4 in Table 2) were siblings but they had different GGE syndromes (Table 2).
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Electroencephalographic Features
There were a mean of 7 (min:2, max: 13) EEG recordings for the GPFA group and 5
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(min:2, max:9) for the control group. Six patients in the GPFA group and 13 patients in the
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control group had ictal VEM recordings. Five patients in the GPFA group had short-term spontaneous sleep EEG recordings (3-4 hours) and GPFA were noted during sleep in four of
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them (Table 2). All but one of the patients had GPFA during wakefulness, remarkably. The EEG background activity of all patients was normal. We recorded interictal as well as
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ictal GSW with variable dominant frequencies of 3±6 Hz associated with GPFA, which
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manifested either in isolation or as the dominant activity in the GPFA group, as seen in Table 2. There was no significant difference between the analyzed EEG and ictal semiological
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features of the groups.
We compared the frequencies and duration of the GPFA of the patients who also had
sleep recordings, but there is no change of these characteristics during sleep. Two had GPFA of 15Hz and one had 9-10 Hz, the last one had a frequency range of 12-14 Hz both in sleep and wakefulness.
In the GPFA group, age at detection was 33±16.6 (min: 16, max: 71) years and 80% of
them still had GPFA in their last EEG at the end of the long-term follow-up. The mean number of pathologic EEG recordings was 6.5±4.24 and the mean number of the EEGs with GPFA was 4±3.9. It was noted that only two (20%) patients had GPFA in their first EEG recording evaluated in our laboratory.
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Genetic features Seven relatives of the GPFA group, who had epilepsy, were also evaluated and GPFA was not seen in any of their 30 available EEGs. The Patient 3 is the brother of Patient 4
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(Table2), and they also had two other first degree relatives who were diagnosed with GGE without GPFA. Patient 5 had two first-degree relatives with GGE and a 56-year-old cousin
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with refractory form of JME; all of whom did not have GPFA. In addition, a 36-year-old sister of Patient 6 was diagnosed with JAE without GPFA in our center previously, before the
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identification of our study patient. The son of Patient 7 diagnosed with EMA had 3 Hz GSW,
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mainly after eye closure and he was sensitive to IPS but did not show GPFA. Additionally, two (Patients 3, 5) of our patients from two different families with GGE
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had been previously investigated in the years of 2007-2011 as part of the Epicure project, by chance. All known candidate GGE genes related to ion channels including GLUT1 were
Outcome
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for15q13.3 microdeletion18.
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sequenced but no mutations was found in these families17. They were also negative
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Nine (90%) of the patients in GPFA group were still using AED due to mild but
recurring TAS, whereas 18 (75%) patients in the control group were under AED in their final evaluation. The AED used for GGE were similar between the two groups and the same team followed them up. Other details are presented in Table 1. It was noted that within the GPFA group; 5 patients were high school graduates, 4
were employed, and 7 of them were married with children. None of them was dependent for their self-care to their family except one female with financial difficulty, who is a housewife and successfully raised three children.
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DISCUSSION We evaluated the long-term course of adult GGE patients with TAS having GPFA on EEG, in comparison to similar patients without this EEG pattern. We found that this
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intriguing EEG phenomenon may indicate a life-long and non-remitting course for GGE patients with TAS but we failed to demonstrate its exact genetic background. In addition, we
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did not observe a complete familial penetrance of GPFA; most of the first-degree relatives of
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the patients with GPFA who also had GGE did not show this unique pattern. Age at onset and seizure characteristics
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Fakhoury et al.8 reported five adults with uncontrolled TAS having these unusual, fast rhythmic discharges; two of their patients had TAS that developed after 20 years of age,
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interestingly. Our series included patients with relatively late-onset TAS, as has been previously reported5. Parallel to the literature, the age at the onset of epilepsy varied among
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our cases6,7,8,9,10. Halasz stated that GPFA could be detected in a later period in some
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patients6. The fact that, studies focusing on the electro-clinical features of TAS in children did
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not report any GFPA-like findings further supports the association of GPFA with adult patients19, 20,21,22,23.
GPFA is mostly associated with rare generalized tonic-clonic seizures in our series,
like other reports5,8,9, but myoclonic seizures and eyelid myoclonia might also be seen. This rare association of “eyelid twitching seizures” was already reported in two neurologically normal adult patients24. Seizure semiology and ictal VEM recordings suggested that our cases did not experience “tonic-absence” seizures, as reported to be associated with GPFA by other authors9. We did not notice any overt tonic components in our patients during GPFA in VEM. It should be noted, however, that we used only one EMG electrode located over the arm muscles, hence subtle tonic components, consisting of mild contraction in the neck muscles
Page 11 of 30
may be unnoticed. The notably high (60%) association of GPFA with ASE in our study is quite interesting, although it did not reach statistical significance. However, our control group was also constituted of adults with TAS who were followed up in a tertiary center, thus they
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may not be reflecting ordinary patients with TAS with good prognosis.
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EEG characteristics
GPFA itself did not show a homogenous appearance in the EEG of our patients, its
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frequency and duration varied from case to case and even within the same patient; it can be
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seen either ictally or interictally, either separately (Figure 1) or associated with typical GSW discharges (Figure 2). Photosensitivity is also a well-known poor prognostic indicator for
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TAS25 and we noted an association with GPFA and photosensitivity as shown in Figure 3. Moreover our results showed that GPFA is not a sleep-dependent EEG phenomenon in adult
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GGE patients with TAS in contrast to similar EEG pattern in Lennox-Gastaut syndrome.
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Tatum et al. adopted another approach for similar patients; they assessed TAS in
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adults and reported its association with “polyspike ictal onset” prior to classic 3-Hz GSW and emphasized that this EEG pattern may predict an unfavorable response to treatment
26
. It is
noteworthy that they accepted the similarity and noted “overlaps” of polyspikes with GPFA; this suggests that they originate from a similar generator26. Another study has reported 12 GGE patients with TAS, persistent or recurring in adulthood and suggested that the findings including “runs of polyspikes”, similar to GPFA in our study, are distinctive from those that are usually found in infancy or adolescence5. In this series, 83% had GTCS and 33% had frequent episodes of ASE, similar to our series5. Syndrome Classification Panayiotopoulos et al. described adult patients with TAS providing a more detailed syndrome classification of their cases and also emphasized that TAS in adults are more
Page 12 of 30
difficult to recognize than in children, due to their short duration and mild degree of impaired consciousness27. Our adult patients with GPFA did not easily fall into one of the well-known epileptic syndromes, and this is possibly due to the limited knowledge on this issue, and its
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rare incidence. We believe that awareness of this entity and studies related to this phenomenon will increase in adult patients if a late-onset form of GGE will be included in the
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next ILAE classification.
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Possible modulators of GPFA and its pathogenesis
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The possible modulating effects of AED on GPFA could not be ruled out easily, but our patients in the control group without GPFA have been using similar drugs and doses for a
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similar duration, excluding a simple causal relationship.
Sleep could also be a modulating factor and Guye et al. reported five cases with
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borderline intellect and poor response to AED, showing GPFA of 10-15 Hz only during sleep
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EEG10 and suggested that these cases could be transitional forms between idiopathic and
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cryptogenic/symptomatic generalized epilepsies. However, GPFA was not limited to sleep recordings in all but one of our patients and all had normal intellectual levels with normal social outcome and long life span; one of them even reaching the age of 98 years, despite frequent life-long ASE attacks.
The etio-pathogenesis of GPFA is unknown in GGE patients. Therefore, studies on
Lennox-Gastaut Syndrome patients with similar GPFA patterns may help us understand the pathophysiology. In an EEG-fMRI (functional magnetic resonance spectroscopy) study of 6 Lennox-Gastaut patients, simultaneous GPFA events showed almost uniform increases in blood oxygen level-dependent (BOLD) signal in "association" cortical areas, as well as brainstem, basal ganglia, and thalamus28. They concluded that GPFA is associated with
Page 13 of 30
activity in a diffuse network that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures. Studies exploring the pathophysiology of absence seizures suggested that increased
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oscillatory activity in reticulothalamocortical circuitry is important for absence seizures29,30,31. In our patients with GPFA, TAS seemed to appear relatively later and persistence of these
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seizures during long years was noted. This may suggest that exposure to pathopysiological
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events underlying TAS, during a long period after adolescence, might lead to some functional changes of reticulothalamocortical circuitry ending up with GPFA in some GGE patients,
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with a possible genetic liability 32. If we consider the significantly high rate of consanguinity of the parents of our GPFA patients, a possible autosomal recessive genetic defect could also
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be hypothesized to result in GPFA. There are two siblings concordant for the presence of GPFA out of 10 patients in our small series but GPFA did not show a complete penetrance in
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the given families and we could not show any known mutations. Thus the question of GPFA
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as an endophenotypic marker remains still unanswered. We think that future genetic studies
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should take this peculiar EEG pattern into account in search for GGE genes. According to our results, the under-recognized association with GPFA seems to be one
of the predictors of unremitting course, but it does not mean an exceptionally poor quality of life for adult patients with TAS33. Our results should be interpreted with caution because our GPFA series is rather small, but it is still the largest study with the longest follow-up. We included the patients at a time where their seizures already have started and therefore the exact timing of appearance of GPFA could not be shown. Furthermore, the control group was younger than the GPFA group even in the cross-sectional start of the study, partly supporting the late-onset and long-duration of TAS in these cases. We also want to emphasize that our
Page 14 of 30
epilepsy center is a well-known tertiary center, involved in genetic studies; thus, this group is not representative of the general population of epileptic patients. In conclusion, GPFA is an ignored EEG pattern during wakefulness of GGE with
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persisting TAS in adulthood. GPFA does not segregate in a given family with GGE and it is not specific to familial cases. Although it does not show a homogenous clinical picture, it
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indicates a long and non-remitting course in almost all of the patients.
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Acknowledgements We thank to The European Community [FP6 Integrated Project EPICURE, LSHMCT-2006-037315]
for
the
extensive
genetic
investigations
of
two
patients
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(http://www.epicureproject.eu/home.aspx) belonging two families with IGE. This study was supported by the Research Fund of Istanbul University (T-1124/18062001).
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We confirm that we have read the Journal’s position on issues involved in ethical
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publication and affirm that this report is consistent with those guidelines.
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Disclosure of Conflicts of Interest: None of the authors has any conflict of interest to
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disclose.
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2. Dulac O, N’Guyen T. The Lennox-Gastaut syndrome. Epilepsia 1993;34:7-17. 3. Gastaut H, Roger J, Soulayrol R, Tassinari CA, Régis H, Dravet C, et al. Childhood
variant”) or Lennox syndrome. Epilepsia 1966;7:139-179.
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epileptic encephalopathy with diffuse slow spike-waves (otherwise known as “petit mal
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4. Halasz P. Runs of rapid spikes in sleep: a characteristic EEG expression of generalized
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malignant epileptic encephalopathies. A conceptual review with new pharmacological data. Epilepsy Res 1991;2:49-71.
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5. Michelucci R, Rubboli G, Passarelli D, Riguzzi P, Volpi L, Parmeggiani L, et al. Electroclinical features of idiopathic generalised epilepsy with persisting absences in adult
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life. J Neurol Neurosurg Psychiatry 1996;61:471-477.
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6. Halasz P, Janszky J, Barcs G, Szucs A. Generalised paroxysmal fast activity (GPFA) is not always a sign of malignant epileptic encephalopathy. Seizure 2004;13:270-276.
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7. Gastaut H, Zifkin BG, Mariani E, Puig JS. The long term course of primary generalized epilepsy with persisting absences. Neurology 1986;36:1021-1028. 8. Fakhoury T, Abou-Khalil B. Generalized absence seizures with 10-15 Hz fast discharges. Clin Neurophysiol 1999;110:1029-1035. 9. Shih TT, Hirsch LJ. Tonic-absence seizures: an underrecognized seizure type. Epilepsia 2003;44:461-465.
10. Guye M, Bartolomei F, Gastaut JL, Chauvel P, Dravet C. Absence epilepsy with fast rhythmic discharges during sleep: an intermediary form of generalized epilepsy? Epilepsia 2001;42:351-356.
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11. Baykan B, Matur Z, Gürses C, Aykutlu E, Gökyiğit A. Typical absence seizures triggered by photosensitivity. Epilepsia 2005;46:159-163. 12. Commission on Classification and Terminology of the International League Against
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Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.
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13. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W et al. Revised terminology and concepts for organization of seizures and epilepsies: report of
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the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia
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2010;51:676-685.
14. Appleton RE, Panayiotopoulos CP, Acomb BA, Beirne M. Eyelid myoclonia with typical
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absences: an epilepsy syndrome. J Neurol Neurosurg Psychiatry 1993;56:1312–1316. 15. Panayiotopoulos CP. Syndromes of idiopathic generalized epilepsies not recognized by
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the International League Against Epilepsy. Epilepsia 2005;46:57-66.
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16. Panayiotopoulos CP, Koutroumanidis M, Giannakodimos S, Agathonikou A. Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic
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seizures, and frequent absence status. J Neurol Neurosurg Psychiatry 1997;63:622-627. 17. Striano P, Weber YG, Toliat MR, Schubert J, Leu C, Chaimana R, et al. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 2012;78:557-662.
18. Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA, Bellows S, et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 2009;18:3626-3631. 19. Penry JK, Porter RJ, Dreifuss RE. Simultaneous recording of absence seizures with video tape and electroencephalography. A study of 374 seizures in 48 patients. Brain 1975;98:427-440.
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20. Panayiotopoulos CP, Obeid T, Waheed G. Differentiation of typical absence seizures in epileptic syndromes. A video EEG study of 224 seizures in 20 patients. Brain 1989;112:1039-1056.
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21. Dieterich E, Doose H, Baier WK, Fichsel H. Longterm follow-up of childhood epilepsy with absences. II. Absence-epilepsy with initial grand mal. Neuropediatrics 1985;16:155-
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22. Sadleir LG, Farrell K, Smith S, Connolly MB, Scheffer IE. Electroclinical features of
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absence seizures in childhood absence epilepsy. Neurology 2006;67:413-418.
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23. Loiseau P, Duche B, Pedespan JM. Absence epilepsies. Epilepsia 1995;36:1182-1186. 24. Miller JW, Ferrendelli JA. Eyelid twitching seizures and generalized tonic-clonic
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convulsions: a syndrome of idiopathic generalized epilepsy. Ann Neurol 1990;27:334-336. 25. Covanis A, Skiadas K, Loli N, Lada C, Theodorou V. Absence epilepsy: early prognostic
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signs. Seizure 1992;1:281-289.
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26. Tatum WO, Ho S, Benbadis SR. Polyspike ictal onset absence seizures. J Clin Neurophysiol 2010;27:93-99.
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27. Panayiotopoulos CP, Chroni E, Daskalopoulos C, Baker A, Rowlinson S, Walsh P. Typical absence seizures in adults: clinical, EEG, video-EEG findings and diagnostic/syndromic considerations.
J Neurol Neurosurg Psychiatry 1992;55:1002-
1008.
28. Pillay N, Archer JS, Badawy RA, Flanagan DF, Berkovic SF, Jackson G. Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome. Neurology 2013;13;81:665-673. 29. Weiergräber M, Stephani U, Köhling R. Voltage-gated calcium channels in the etiopathogenesis and treatment of absence epilepsy. Brain Res Rev 2010;62:245-271.
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30. Jasper HH, Drooglever-Fortuyn J. Experimental studies on the functional anatomy of petit-mal epilepsy. Asoc Res Nerv Ment Dis 1974;26:272-298. 31. Avanzini G, de Curtis M, Franceschetti S, Sancini G, Spreafico R. Cortical versus
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thalamic mechanism underlying spike and wave discharges in GAERS. Epilepsy Res 1996;26:37-44.
Thalamus
in
Idiopathic
Generalized
Epilepsy.
Archives
of
Neuropsychiatry
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(Noropsikiyatri Arsivi) 2011;48:243-8.
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32. Aydın-Özemir Z, Terzibaşıoğlu E, Sencer S, Yapıcı Z, Baykan B. Volumetry of the
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33. Matur Z, Bebek N, Aydın-Ozemir Z, Baykan B, Gürses C, Gökyiğit A. Generalized Paroxysmal Fast Activity in Idiopathic Epilepsies with Typical Absence Seizures: An
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Unusual Electroencephalographic Finding (in Turkish). Epilepsi-Turkish 2006;12:69-77.
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Figure Legends: Figure 1: Generalized paroxysmal fast activity (GPFA) was prominent, mostly isolated, partly asymmetric and always lasted long in a patient diagnosed with juvenile absence
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epilepsy (Pt 2); EEG recordings in 2005 (a) and in 2010 (b).
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Figure 2: EEG recording of the 27-year-old Pt.1 with absence seizures (a) shows GPFA associated with generalized spike-wave discharges during hyperventilation in 2002. Ten
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years later, EEG recording (b) again shows GPFA after spike-wave discharges but he does not
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report absence seizures since one year under Valproate therapy.
(c) GPFA was observed with a similar frequency and morphology during NREM sleep
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recordings in the same patient.
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Figure 3(a) Patient 7’s EEG recording while she was 58-year-old. In this figure, GPFA
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appears after eye closure and during photic stimulation, always before spike-wave discharges associated with a typical absence seizure, (b) but GPFA may also be seen as isolated interictal
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discharges in the same EEG.
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Table 1. The Clinical Features of the Groups with and without GPFA at the End of the Long-term Follow-up Clinical Features
Group with GPFA
Group without GPFA
Statistical
(n=10)
(n=24)
Results
14.5±6.9 (5-27)
9.4±3.9 (1-17)
p:0.55
15.1±7.9 (5-28)
11±6.9 (1-35)
17.6±8.1 (8-28)
15.2±5.6 (8-31)
33±17.3 (17-63)
18.1±10.1 (3.5-42.3)
p: 0.005
15±18.6 (0.4-42)
p: 0.01
Age at onset of epilepsy in years
Age at onset of TAS in years mean±SD(min-max)*
mean±SD(min-max)*
Duration of TAS in years mean±SD(min-max)* Family history of epilepsy
5 (50) n(%)º Consanguinity of the parents# First seizure type n (%) #
6 (60)
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ABS GTC MYO ABS ABS+GTC ABS+GTC+MYO EMA+GTC+MYO None
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Single
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Absence status epilepticus n (%) #
Recurrent
#
Febrile seizure n (%) Epileptic Syndrome Diagnosis n (%)#
Remission of TAS n(%)# Seizure-free # n(%) #
AED-free n(%)
CAE JAE JME EMA Late-onset Absence Epilepsy Early-onset Absence Epilepsy
8 (33)
1 (4.17)
7 (70)
18 (75)
3 (30)
5 (20.8)
none
1 (4.2)
1 (10) 5 (50) 3 (30) 1 (10)
7 (29.2) 7 (29.2) 7 (29.2) 3 (12.5)
4 (40)
15 (62.5)
2 (20)
2 (8.3)
4 (40)
7 (29.2)
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All seizure types n (%) #
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30.7±18.6 (7-60)
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Duration of epilepsy in years mean±SD(min-max)*
n.s.
n.s.
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Duration of follow-up in years
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mean±SD(min-max)*
n.s.
P:0.01
n.s.
n.s. n.s.
1(10)
8 (33)
n.s.
2 (20) 4 (40) none 1 (10)
7 (29.2) 6 (25.0) 7 (29.2) 2 (8.3)
n.s.
3 (30%)
None
none
2 (8.3)
1 (10)
13 (54)
p:0.02
1 (10)&
13 (54)
p:0.02
1 (10)&
6 (25)
n.s.
ºPearson Chi-Square test # Fisher's exact test *Mann-Whitney U test. ABS: Absence seizure, CAE: Childhood Absence Epilepsy, EMA: Eyelid Myoclonia with Absences, GPFA: Generalized Paroxysmal Fast Activity, GTC: Generalized Tonic-Clonic, JAE: Juvenile Absence Epilepsy, JME: Juvenile Myoclonic Epilepsy, MYO: Myoclonic Seizure, n.s.: not significant, TAS: Typical Absence Seizures. & Note that the AED-free patient is not seizure free; she is still experiencing mild absence seizures, but did not want to use AED whereas the seizure-free patient is still under VPA.
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Table 2. EEG and Clinical Features of the GPFA group Patient No Age (years)/gender
Patient 2 32/F
Patient 3 48/M
Patient 4 44/F
Patient 5 39/F
Patient 6 32/F
Patient 7 68/F
Patient 8 41/F
Patient 9 51/M
Patient 10 98/F
ABS+GTC +MYO
ABS+GTC +ASE
ABS+GTC +ASE
ABS
ABS+GTC +ASE
EMA +GTC +MYO
ABS+GTC +ASE
ABS+ GTC+ MYO + ASE
ABS+GTC
ABS+GTC+ MYO+ASE
28/21/21
11/20/-
5/11/-
27/-/-
12/15/-
9(EMA)/9/9
8/23/-
18/18/18
13/13/-
20/20/20
Late-onset AE
JAE
CAE
Late-onset AE
JAE
EMA
CAE
JAE
JAE
Late-onset AE
29
16
32
33
25
20
50
18
36
71
VPA
VPA +LEV
VPA +ZNS+ BBX+ ETX
None°
VPA
VPA
VPA
Initial ABS/
1/week/
1-2/day/
30/day/
1-2/day/
5-10/day/
7-10/day/
GTC Frequency
totally 4 times None since 3yrs/
totally 5 times Rare/
1/month
None
1/month
totally once
2-3/day/
2/day/
None since 12yrs
None since 5yrs
None since 4yrs
None
None since22yrs
None since 23 yrs
None since 10yrs
None since 3yrs
None since 12yrs
None since 12yrs
6/1/1
13/1/1
4/0/0
2/1/1
6/1/1
3/0/0
7/1/1
12/0/0
13/0/0
7/1/0
3.5-4 Hz GSW
4-5 Hz GSW
3-5 Hz GSW
3.5-4 Hz PSWD
4 Hz PSWD
5 Hz PSWD
3-4 Hz GSW
3-4 Hz PSWD
3.5-4 Hz GSW
4-5Hz theta paroxysm
3-3.5Hz GSW
15Hz GPFA
3-4 Hz GSW
No ictal recording
5Hz PSWD
5Hz PSWD
3.5-4 Hz GSW
3-4 Hz PSWD
3-4 Hz PSWD
3 Hz PSWD
Sensitivity to IPS /EC
No/No
No/No
Yes/No
Yes/No
Yes/No
Yes/Yes
Yes/Yes
No/No
Yes/Yes
Yes/No
Duration of GPFA (sec)
8
1-17
3-4
2
3
1.5
30
8-9
1.5
Frequency of GPFA (Hz)
9-10
15
14
10
15
17
12-14
12-16
15
9-10
Ictal and Interictal, also during NREM sleep
Ictal and Interictal, also during NREM sleep
Ictal and Interictal
Interictal
Interictal∑ (during NREM sleep only)
Ictal
Ictal and Interictal
Interictal
Ictal
After GSW
Isolated and prominent
Isolated or before GSW
Isolated
Isolated or before GSW
Isolated, appears after EC
Before PSWD, seen in ASE
Before GSW
Before GSW
2* (Sister/46/ JME; cousine daughter JAE)
Mother/JA E;sister/35 /JAE; cousin/56/ JME
-
-
-
Numbers of total EEG /VEM/Sleep EEG Interictal discharge Ictal pattern
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GPFA appearance
1-2/day/
Relation of GPFA with other discharges
Relatives with GGE without GPFA (relation/age/syndr ome)
-
-
1.5
2* (Sister/46/JM E; cousine 27/JAE)
cr VPA
1-2/day/
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Last reported frequency for ABS/ GTC
20/day/
200/day / totally 5 times 1/day/
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Age at diagnosis of GPFA (years) in our EEG lab Current AED
M
Syndrome
d
Age at onset of ABS/GTC/MYO
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Seizure Types
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Patient 1 39/M
Sister/36/JAE
Ictal and Interictal also during NREM sleep Appears after EC and IPS, Before SWD
Son/44/ EMA
1-2/month ASE attack/ yearly/
VPA+LEV
1-2/day/ totally 3 times 1/month/
CLZ 1-2/day/ 2-3/month Rare/
ABS: Absence, AE: Absence epilepsy AED: Anti-epileptic drugs, ASE: Absence Status Epilepticus, BBX: Barbexaclone, CAE: Childhood Absence Epilepsy, CLZ: Clonazepam, EC: Eye closure, EMA: Eyelid Myoclonia with Absences, ETX: Ethosuximide, F: Female, GGE: Genetic generalized epilepsy; GPFA: Generalized paroxysmal fast activity, GSW: Generalized spike-waves, GTC: Generalized tonic-clonic, IPS: Intermittan photic stimulation, JME: Juvenile Myoclonic Epilepsy, LEV: Levetiracetam, MYO: Myoclonic seizure, M: Male, PSWD: Poly-spike-slow wave discharges, VPA: Valproate, ZNS: Zonisamide. ° She did not want to use drugs, due to financial problems and the minimal effect of absence seizures on her quality of life. *Note that Patients 3 and 4 with GPFA were siblings. ∑GPFA was recorded only during NREM sleep without clinical symptoms and no change in EMG electrode.
Please note that all but one (pt5) of the patients had GPFA during standard wakefulness EEGs and in all patients who had sleep and wakefulness EEG recordings, GPFA had similar duration, frequency and appearance rate in comparison to sleep EEGs.
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