Epilepsy with eyelid myoclonia (Jeavons syndrome): Generalized, focal, or combined generalized and focal epilepsy syndrome?

Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE). We report two untreated children on which EEGs were performed several hours after a generalized tonic-clonic seizure (GTCS). These showed a unilateral, nearly continuous posterior slowing. This slow-wave activity was associated with contralateral epileptiform activity in one case, while in the second case, it was associated with an ipsilateral activity. However, in the latter child, a few months later an independent focus on the contralateral side was observed. A diagnosis of focal occipital lobe epilepsy was proposed in both cases, and one child underwent a left occipital lobectomy at 3.5 years of age. Despite surgery, absences with EM persisted in this child, and a marked photosensitivity to photic stimulation was observed two years later. The focal slow wave activity of one occipital lobe several hours after a GTCS in these two subjects was in favor of a focal onset preceding the generalization. The EEG evidence for independent left and right posterior focus in these two cases, the persistence of EM, and the development of a marked photosensitivity to photic stimulation in the child who underwent an occipital lobectomy, allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures.


Introduction
Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE) [29] with onset around seven years of age and a female predominance [13,20].Besides the EM and the photoparoxysmal response (PPR) to intermittent light stimulation (ILS), patients frequently have absence seizures and may have generalized tonic-clonic seizures (GTCS) [20].Interictal EEGs show generalized or incompletely generalized spike-wave discharges with anterior or posterior predominance during wakefulness [15].As commonly observed in GGE, generalized discharges are activated by NREM sleep and awakening [15,20].Hyperventilation can also activate interictal generalized spike-wave discharges [15].Ictal EEGs consist mainly of 3−6-Hz generalized polyspike-waves occurring on eye closure in an illuminated room [18].However, focal abnormalities are frequent in JS, reported in 16−56% of cases [2,3,10,20,23,25].PPR appears different from other photogenic epilepsies, such as juvenile myoclonic epilepsy (JME), and sometimes shows frontal-predominance of the EEG discharges [30].An unusual PPR with spike-wave also characterizes JS with polyspike-waves timelocked to the flashes, suggesting hyperexcitability of the visual occipital cortex [19].Finally, unlike common forms of GGE and even if JS shares the same antiseizure drugs, patients with JS have a high rate of pharmaco-resistance [5,21].
We report on two cases of untreated JS, where the first EEG, performed several hours after a GTCS, showed a sub-continuous slow-wave activity of one posterior region, leading us to discuss a post-ictal state.This slow-wave activity was associated with contralateral epileptiform activity in one case and ipsilateral in the second.untreated girl was performed 24 h after the second GTCS and showed during wakefulness polymorphic nearly continuous slow-wave activity over the right parieto-temporo-occipital region and rarely, only when the eyes were closed, some contralateral spikes and polyspike-waves (Fig. 1A).During NREM sleep, the slow-wave activity on the right posterior region persisted but was less abundant.On the other hand, there was a clear activation of the interictal EEG abnormalities over the left posterior region with polyspikes and polyspike-waves (Fig. 1B).Generalized bursts of spike-waves were also noted.Upon awakening, an increase of slow-wave activity over the right posterior region was observed, as well as some polyspike-waves over the left posterior region just after eye closure (Fig. 2A).Hyperventilation triggered a burst of generalized 3-Hz spike-waves (Fig. 2B).ILS produced a peculiar response, only at 1 and 2 Hz, with bilateral delta waves synchronous with the flashes, with a higher amplitude over the right hemisphere (Fig. 3).The child had no headache or migraine during this EEG or later during the follow-up period.A diagnosis of focal epilepsy was proposed.The brain MRI was normal.She was treated with valproate with good seizure control.EM were reported by the parents three years later, and the EEG showed, after eye closure, polyspikes/polyspike-waves with or without EM (Fig. 4A).An unusual PPR with generalized spike/polyspike-waves time-locked to the flashes was observed (Fig. 4B).Her development was normal.She is presently a university student.
Case 2 (Fig. 5; supplementary S7−S9) This girl, at the age of two, with an unremarkable family history and normal development, experienced three GTCS in less than 24 h in the context of hypokalemia at 2.2 mmol/L, later diagnosed as Gitelman syndrome.The first EEG recorded several hours after the third GTCS, showed nearly continuous slow-wave activity over the left parieto-temporo-occipital region with some spikes and sharp waves.Seizures with upward deviation of the eyes and head were interpreted as focal seizures.Carbamazepine was started.On the EEGs, fast rhythms and spikewaves over the left occipital regions were detected, and nonconvulsive focal status epilepticus was proposed.IV antiseizure drugs were started.Four days later, the EEG showed improvement, with only marked slowwave activity over the left temporo-parieto-occipital junction.Three weeks later, the EEG showed spike-waves only over the left occipital region during wakefulness.During sleep, this activity was more frequent and became diffuse on both hemispheres.ILS was negative.
During the following months, numerous daily episodes of EM with absence were reported but still interpreted as focal seizures.On the EEGs, there were frequent polyspike-waves either generalized or localized over the left temporo-parieto-occipital region but also, to a lesser degree, localized over the right posterior region.At this time, the child was treated with carbamazepine and clobazam.A brain MRI showed left focal occipital atrophy.Interictal SPECT showed left occipital hypoperfusion.Carbamazepine was stopped.Valproate was started, then combined with lamotrigine, and the child remained seizure-free for two months but absences with EM reappeared.Valproate was then switched to topiramate.Despite topiramate, lamotrigine, and clobazam, episodes of daily EM with absences persisted.There were indicators of inattention and hyperactivity.A left occipital lobectomy was decided at 3.5 years of age with no effect on absences with EM.They returned on the day after surgery.Histological examination of the brain was unremarkable.A PPR was reported for the first time at the age of 5.5 years.T a g g e d A P T A R A P She was referred to our center for a presurgical assessment at 11 years of age.Numerous spontaneous EM with impairment of consciousness were recorded during wakefulness (Supplementary video) and also triggered by ILS (Fig. 5).The diagnosis was corrected to JS, and the treatment was adapted by prescribing valproate and levetiracetam.Her waking and sleep EEG at 19 years of age was very much improved.ILS, with eyes closure, still provoked absences with EM with bilateral Fig. 2. Awakening period after a nap A: The child closes her eyes (arrow).Spike-waves on the left posterior region are followed by normal alpha rhythm.On the right hemisphere, slow-wave activity.B: Hyperventilation triggered a burst of generalized spike-waves.

Discussion
Both patients presented unilateral EEG slow-wave activity in one posterior region several hours after a GTCS, and a first diagnosis of focal epilepsy was proposed.The first case showed independent spike/polyspike-waves in the contralateral occipital lobe.In the second case, the epileptiform abnormalities were on the same side as the slow-wave activity, but several months later, contralateral epileptiform activity was also observed.In both cases, the slow-wave activity observed after the first GTCS disappeared over time but was prolonged.EEGs of patients with GTCS that are generalized at onset are characterized by a postictal cortical extinction followed by a bilateral diffuse slow-wave activity in the delta band.This period of postictal cortical depression usually lasts several minutes [6].Focal slowing during the postictal phase suggests a focal onset seizure evolving to GTCS: so, right occipital lobe epilepsy for the first case and left for the second case.In both cases, this slow-wave activity was impressive and unusual due to its duration.It was observed from several hours to 24 h after the GTCS.None reported headaches at the time of the EEG.Migraine is characterized by focal or more or less diffuse and prolonged slow-wave activity [8].None of the children complained of migraines later in the evolution, even after the recurrence of GTCS, which allows us to rule out this hypothesis.The brain MRI was normal for the first patient but showed nonspecific focal atrophy of the left occipital lobe for the second.This atrophy may partly explain why in this patient a focal left posterior slow-wave activity was recorded in subsequent EEGs.
JS is a form of reflex epilepsy involving the occipital lobes.For patient 2, despite a left occipital lobectomy at the age of 3.5 years, a PPR to photic stimulations was observed two years after surgery and confirmed in subsequent EEGs, even though the amplitude of the response was greater over the right hemisphere.JS is also characterized by an unusual PPR with spike/polyspike-waves time-locked to the flashes (Fig. 4B).This PPR would correspond to an activation of preexisting epileptogenic areas of the occipital cortex [19].This is in accordance with the results of a functional study that showed hyperexcitability of the occipital cortex in patients with JS.After eye closure, Vaudano et al. (2014) observed an increase of blood oxygenation level-dependent signal in the visual cortex.The authors demonstrated that eye closure involved a complex circuit encompassing the visual cortex, the thalamic pulvinar, and the frontal lobe networks of controlling eye closure and gaze [27].
The significance of the occipital visual cortex in JS was also emphasized by Viravan et al. (2011).They observed focal posterior epileptiform discharges preceding generalized epileptiform discharges and proposed a speculative model of the epileptic neural network.EM are produced by an activation of the occipital cortex that spreads to the brainstem.When epileptiform discharges spread to the frontocentral cortex, they project generalized spike-waves associated with EM and Fig. 5. A: MRI with left occipital lobectomy.B and C: EEG recorded at 11 years of age.International 10−20 electrode placement system and supplementary anterior/inferior temporal electrodes (TA1/TA2: Temporal-Anterior; T1/T2: zygomatic electrode).Plate B recorded at 15 mm/s: patient closes her eyes (eyelid movement artifacts) followed one second later by fast rhythms at 16 Hz.Note the right anterior and right temporal predominance.Plate C recorded at 30 mm/s.Photic stimulation at 16 Hz combined with eye closure triggers bilateral fast rhythms at 16 Hz with predominance on the right hemisphere.There are very fast eyelid myoclonia during the discharge.Note the muscle artifacts mixed with fast activity on the fronto-polar derivations.These two plates show that despite a left occipital lobectomy seven years ago, a strong photosensitivity was present but more evident on the right side.absences [28].Recording a GTCS in JS is exceptional.Gir aldez and Serratosa (2015) reported one case with an occipito-temporal onset followed by rhythmic spike-waves in the right occipito-temporal region, which then propagated to the left homologous area before generalization with convulsions [9].The initial clinical symptoms observed were asymmetric blinking, predominantly on the left side, and intermittent cephalic and conjugate eye deviation to the left.Blinking is different from EM consisting of jerking of the eyelids immediately after eye closure [14].Blinking corresponds to a tonic closure of the upper and lower eyelids.Ictal blinking has been documented in different focal lobe epilepsies, but an SEEG study showed that it was more prevalent in occipital and occipito-temporal seizures [16].Seizures originating in the occipital lobes were often characterized by bilateral blinking.On the basis of a SEEG study, EM has been reported, albeit rarely, in focal occipital lobe epilepsies [17].
Photosensitive occipital lobe epilepsy (POLE) is a rare epileptic syndrome [12] defined by photic-induced focal occipital seizures −for example, by flickering sunlight, in children and adolescents with normal development [24].One-third of patients have a family history of epilepsy, with possible coexistence of JME and POLE in the same family [26,1].Myoclonic and absence seizures may occur [26], as well as generalized spike-and-wave complexes [4].Treating POLE as a focal epilepsy could have a negative impact [11].In a series of 29 patients with POLE, approximately one-third overlapped with those who had GGE [4].Visual aura and version of the head may be present in JME [26,7].Focal EEG discharges may be found in GGE.The percentage of localization-related EEG abnormalities or asymmetrical changes ranges from 6% to 40% [22].In a cohort of 40 patients with JS, two-thirds had focal abnormalities, higher than expected in GGE [20].More precisely, a posterior localization was observed in approximately 60% of cases and an anterior distribution in 30%.The boundary between JS and POLE is not evident, raising questions as to whether these syndromes are really distinct.Some patients described as POLE could be a subgroup of patients with JS.G omez-Porro et al. (2018) cautions that misusing POLE terminology could possibly have negative implications and instead proposed "genetic generalized epilepsy with occipital semiology" [11].

Conclusion
Several hours after a GTCS, the focal slow wave activity in one occipital lobe in these two patients suggested a focal onset preceding the generalization.The EEG evidence of independent left and right posterior focus in these two patients, and the persistence of EM with the development of a marked PPR in the second case after an occipital lobectomy allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures.

Fig. 1 .
Fig. 1.A: Awake.Polymorphic delta waves on the right posterior region.The child closes her eyes (arrow).Normal alpha rhythm with physiological posterior slow waves of youth on the left hemisphere.At the end of the plate, left polyspike-waves at the parieto-temporo-occipital region (*).B: NREM sleep, persistence of delta waves on the right posterior region, less abundant.Marked activation of the interictal abnormalities on the left posterior region with polyspikes/polyspike-wave (*).

Fig. 3 .
Fig. 3. A: Intermittent light stimulation (ILS) at 1 Hz.Bilateral delta waves at 1 Hz.Note the slow-wave activity on the right posterior region before ILS.B: ILS at 2 Hz.Bilateral delta waves at 2 Hz.Higher amplitude of the delta waves on the right hemisphere.

Fig. 4 .
Fig. 4. Same patient as Figs.1−3, three years later.A: Awakening period after a nap.After each eye closure (arrow), polyspike-waves appear predominately on the anterior and left hemispheres (*).B: Same recording.Eye-closure (arrow) with bilateral polyspikes (*).There are very fast eyelid myoclonia during the discharge.Note the muscle artifacts on the fronto-polar derivations.Intermittent light stimulation combined with eye closure elicits generalized polyspikes at the same frequency of the flashes.Some spikes are forked.