Jeavons syndrome existing as occipital cortex initiating generalized epilepsy

Authors


Address correspondence to Hiroshi Otsubo, MD, Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: hiotsubo@rogers.com or hiroshi.otsubo@sickkids.ca

Summary

Purpose: Jeavons syndrome (JS) is one of the underreported epileptic syndromes characterized by eyelid myoclonia (EM), eye closure–induced seizures/electroencephalography (EEG) paroxysms, and photosensitivity. JS has been proposed as idiopathic generalized epilepsy (IGE) because of normal posterior dominant background activity and paroxysmal generalized ictal epileptiform discharges (EDs). However, we noticed subtle occipital EDs preceding EM and interictal posterior EDs using digital video-EEG. We studied clinical and EEG findings in JS to determine the specific occipital lobe relation to this “eye closure–induced” reflex IGE.

Methods: We identified 12 children who met the diagnostic criteria of JS from January 2004 to April 2009 at the Hospital for Sick Children, Toronto, Canada. All patients had EM captured by video-EEG. We reviewed and described ictal EEG patterns, interictal abnormalities, and demographics, clinical, and neuroimaging findings.

Key Findings: All patients but one were female (92%). Age at seizure onset ranged from 1.5 to 9 years, with a mean age of 4.9 years. Six patients (50%) were previously diagnosed as having absence epilepsy and 10 patients were on antiepileptic medications. All 12 patients had normal posterior dominant alpha rhythm, reactive to eye opening and closure. Spiky posterior alpha activity was noted with sustained eye closure in six patients (50%). Interictally, there were generalized EDs found in 10 patients (83%); four of them also had focal interictal EDs over the posterior head region. Eleven patients (92%) had evidence of focal posterior ictal EDs. EM and/or paroxysmal EDs were induced by photic stimulation in 9 (75%) and hyperventilation in 7 (58%).

Significance: We observed two neurophysiologic findings in JS: (1) focal interictal EDs from posterior head region; and (2) predominant focal posterior ictal EDs preceding generalized EDs. Further clinical observations of seizures induced by eye closure, photic stimulation, and hyperventilation along with EEG paroxysms would raise the possibility of the occipital cortex initiating generalized epilepsy network involving the brainstem, and thalamocortical and transcortical pathways in JS.

Jeavons first described eyelid myoclonia (EM) in 1977; thereafter Jeavons syndrome (JS) or EM with absences (EMA) has been one of the underreported epileptic syndromes characterized by (1) EM; (2) eye closure–induced seizures/electroencephalography (EEG) paroxysms; and (3) photosensitivity (Jeavons, 1977; Panayiotopoulos, 2005a; Covanis, 2010).

First, EM is a main seizure type for JS but is also observed in other idiopathic generalized epilepsies or cryptogenic and symptomatic epilepsies (Panayiotopoulos, 2005b). Second, eye closure–induced seizures/EEG paroxysms occur within 2–4 s after closing the eyes. This eye closure–induced seizure is seen only in the presence of uninterrupted light but not triggered by simple eye blinking (Panayiotopoulos, 2005a). Eye closure–induced seizures have been reported in either idiopathic generalized epilepsy or idiopathic occipital lobe epilepsy (Sevgi et al., 2007). Third, photosensitivity, including photosensitive seizures or photoparoxysmal EEG findings, is triggered by intermittent photic stimulation (IPS). The photosensitivity, however, is reduced with age and suppressed by antiepileptic medication (Striano et al., 2002; Panayiotopoulos, 2005b). In contrast to other photosensitive epilepsies, JS patients are sensitive to both flickering and nonflickering bright light (Panayiotopoulos, 2005b).

According to the 2006 International League Against Epilepsy (ILAE) classification of epileptic syndromes, JS was not recognized as an epileptic syndrome, but eyelid myoclonia was classified as a unique type of generalized seizures (Engel, 2006). However, it has been proposed as a reflex IGE by Panayiotopoulos (2005a) because of the presence of normal posterior dominant background activity, paroxysmal generalized ictal EEG discharges, and photosensitivity. It has also been reported as a well-defined idiopathic generalized epilepsy (Striano et al., 2009). Occipital lobe or alpha generator malfunctions were postulated as a mechanism for the eye closure–induced seizures (Panayiotopoulos, 2005a).

This article describes interictal, ictal, and clinical findings on video-EEG in pediatric patients with JS. We analyze clinical and EEG findings to determine the specific occipital lobe relation to this “eye closure–induced” reflex idiopathic generalized epilepsy of JS.

Patients and Methods

We identified 12 children who met the diagnostic criteria of JS: (1) eyelid myoclonia; (2) eye closure–induced seizures/EEG paroxysms; and (3) photosensitivity from January 2004 to April 2009 at the Hospital for Sick Children, Toronto, Canada. All patients had eyelid myoclonia captured by video-EEG.

Video EEG equipments including photic stimulation

We recorded video-EEG telemetry (HARMONIE 5.4; Stellate, Montreal, PQ, Canada) using 19 scalp electrodes placed according to the International 10–20 system. A single reference was placed at Oz, Pz´ (located 1 cm behind Pz), or FCz, whichever was the most inactive electrode. The sampling rate was 200 or 500 Hz. We performed hyperventilation, photic stimulations (2–20 Hz), and passive or active eye closure and opening. Electromyography was placed at both deltoid muscles. Three physicians (AO, SV, and HO) reviewed EEG studies to analyze, select, and decide localizations of the interictal and ictal epileptiform discharges (EDs). We analyzed either generalized or focal EDs of interictal discharges during the sleep and awake stages. The EDs include sharp waves, spikes, spike and waves, and polyspike and wave complexes. We also analyzed the EEG findings when the patients showed EM on video-EEG. Prolonged video-EEG was performed in 10 patients, and 2 patients underwent routine video-EEG study. Ten of them (83%) were on antiepileptic drugs at the time of EEG study. All EEGs were performed in an illuminated room.

Magnetic resonance imaging

All patients underwent 1.5- or 3-Tesla magnetic resonance imaging (MRI). Our protocol consisted of sagittal T1-, axial T2-, and coronal T2-weighted images; axial and coronal fluid-attenuated inversion recovery (FLAIR) images; and axial three-dimensional (3D) T1-weighted images.

Results

Clinical features

Eleven (92%) of 12 children were female (Table 1). Age at seizure onset ranged from 1.5 to 9 years, with a mean age of 4.9 years. Six of the patients (50%) were previously diagnosed as having absence epilepsy. Other types of seizures such as generalized tonic seizures, generalized tonic–clonic seizures, or epileptic spasms were also seen in four patients. Five patients (42%) had documented developmental delay or learning disability at the time of their EEG monitoring. Four patients (33%) had family history of epilepsy. At the time of EEG monitoring, eight patients were on a single antiepileptic medication: valproic acid (three patients), lamotrigine (three patients), levetiracetam (one patient), and clobazam (one patient). Two patients were on two antiepileptic medications (valproic acid + lamotrigine or levetiracetam + topiramate) and the other two patients were not on any antiepileptic medication.

Table 1.   Video EEG findings of patients with Jeavons syndrome
No.GenderAge at seizure onset (years)Age at video- EEG (years)Interictal findingsIctal findings
Spiky posterior alpha activityFocal posterior epileptiform dischargesGeneralized epileptiform dischargesFocal posterior epileptiform dischargesGeneralized epileptiform dischargesPhotic stimulation provoking eyelid myoclonia/paroxysmal epileptiform dischargesHyperventilation provoking eyelid myoclonia/paroxysmal epileptiform discharges
  1. aThree patients had a history of photosensitivity.

1Female37+++
2Female410++++++
3Female1.58+++++
4Female37++++++
5Female48++++++
6Female99+++++
7Female613++++
8Female2.54+++++
9Female39++++++
10Female68+++a
11Male917++++a
12Female7.510++++a

MRI findings

Magnetic resonance imaging (MRI) was performed in six patients. Three patients had abnormal findings on MRI. One patient had nonspecific increased signal intensity at bilateral frontal white matter. The other one had Chiari 1 malformation. A dysembryoplastic neuroepithelial tumor (DNET) at the right frontal region was shown in one patient. This patient (patient 11) has been having EM before and after surgical resection of DNET. None of the patients showed abnormality in the posterior regions of the cerebrum. Three patients showed unremarkable MRI.

Video-EEG findings

Age of video-EEG studies ranged from 4–17, years with a mean age of 9.2 years (Table 1). The video EEG was performed from the onset to 8 years after the seizure onset (mean 4.3 years).

Interictal EEG finding

All 12 children had normal posterior dominant alpha rhythm, which was reactive to eye opening. Frequent spiky posterior alpha activities were noted in six patients (Fig. 1). The spiky posterior alpha activities lasted 1–2 s in duration by the acts of sustained eye closure (Video S1). Spike components were superimposed to present irregularities; therefore, their frequency was higher than the alpha range. The amplitude of spiky posterior alpha activities was higher than the patients’ baseline background alpha rhythm during eye closure.

Figure 1.


Anteroposterior bipolar montage EEG shows, after first brief eye closure (asterisk), appearance of a brief posterior alpha rhythm in patient 2. After the second sustained eye closure, spiky alpha activities (arrow line) start from the occipital regions and spread diffusely. (Low frequency filter, 1 Hz; high frequency filter, 70 Hz; notch filter, 60 Hz.) At the end of eye closure, biphasic slow waves over the bilateral frontal regions indicate eyes rolling (corresponding to supplement Video S1).

Four patients had focal posterior interictal EDs consisting of right temporooccipital, bilateral temporooccipital, bilateral parietotemporal, and left centroparietal region, with each patient showing only one of the above findings. There were generalized EDs found in 10 (83%) of 12 patients, characterized by diffuse, high amplitude spike-waves and 3.5–5 Hz polyspikes or spike and wave complexes longer than 1 s without clinical signs. Brief generalized EDs <1-s were seen in 7 of 10 patients. Among the seven patients with brief fragments of the generalized EDs, frontal spikes were predominant in two patients and multiple independent spikes were seen in five patients. The other two patients had no interictal EDs by eye closure.

Ictal video-EEG finding

All 12 children presented with EM with or without absences lasting 1–4 s. Two patients (17%) showed brief eye rolling up with or without head jerking lasting 1–2 s. These seizures were induced by forced eye closure occurring within 0.5–3 s after closing the eyes.

Eleven patients (92%) showed focal posterior ictal EDs with predominant bilateral occipital regions triggered by eye closure. Nine patients had brief preceding posterior, occipital predominant EDs 0.2–1 s before generalized spike/polyspike-wave complexes (Fig. 2, Video S2). The remaining two patients (patients 2 and 11) had brief bilateral posterior spike-wave complexes without generalized EDs.

Figure 2.


Anteroposterior bipolar montage EEG shows, after eye closure (arrow), brief (0.2 s) bilateral occipital spikes (dotted line) preceding generalized spike and waves associated with eyelid myoclonia in patient 9. (Low frequency filter, 1 Hz; high frequency filter, 70 Hz; notch filter 60 Hz.) Supplement Video S2 is submitted to present clinical semiology and electrographic finding of this figure in this article (corresponding to supplement Video S2).

Ten patients (83%) showed generalized ictal EDs. Nine patients had both focal and generalized ictal EDs during the same video-EEG recording (Fig. 3). Isolated generalized ictal EDs were seen in only one patient (patient 5). When the patients presented with both EM and absences, EEG showed rhythmic generalized spike and wave complexes lasting 4–6 s. In the same patients, during only brief EM or eyes rolling up without absence, EEG showed brief generalized spikes or polyspikes.

Figure 3.


(A) Anteroposterior bipolar montage EEG shows a generalized spike and wave complex. (Low frequency filter, 3 Hz; high frequency filter, 70 Hz; notch filter, 60 Hz.) (B) Anteroposterior bipolar montage EEG shows runs of spikes over bilateral posterior head regions (dotted line) followed by a generalized spike and wave complex. Prior to the dotted line, normal background alpha rhythm exists over the bilateral occipital regions. (Low frequency filter, 3 Hz; high frequency filter, 70 Hz; notch filter, 60 Hz.) Both epileptiform discharges in A and B are associated with eyelid myoclonia in patient 8.

Intermittent photic stimulation (IPS) provoked EM and/or paroxysmal EDs in nine patients (75%) during video-EEG recording. The other three patients had a history of seizures induced by light or IPS. Hyperventilation provoked EM and/or paroxysmal EDs in seven patients (58%).

Discussion

Spiky posterior alpha activity and posterior EDs in JS

Spiky posterior alpha activities appeared at eye closure and during sustained eye closure in half of children with JS. The spiky posterior alpha activities consisted of superimposed spike components, associated with sustained eye closure. The frequency of alpha rhythm, which is often higher than the baseline frequency by 2 Hz at 1–2 s immediately following eye closure, was reported “squeak” activity in normal subjects (Storm van Leeuwen & Bekkering, 1958). The spiky posterior alpha activity in JS may be differentiated from the “squeak” activity with its spike components, irregularities, higher amplitudes spreading to the frontal region, and association with sustained eye closure. These spiky posterior alpha activities in JS may support the hypothesis of alpha rhythm generator malfunction in the occipital lobe (Panayiotopoulos, 2005a).

Interictal generalized EDs were seen frequently in children with JS. Interictal focal EDs in addition to generalized EDs were also seen over the posterior head regions in the subset of JS patients. In idiopathic generalized epilepsy, Lombroso found that 32 (56%) of 58 patients had consistent focal interictal EDs for decades (Lombroso, 1997). Focal spikes preceded generalized spike and wave discharges in quite a few patients with absence seizures. In childhood absence epilepsy, Caraballo et al. (2008) found that 15% (30 of 203) had evidence of focal negative spike and slow wave as seen in benign focal epilepsy. Matur et al. (2009) studied 50 adult patients with absence seizures, in whom 34% had evidence of focal interictal EDs, mainly in frontotemporal region. Focal interictal EDs in generalized epilepsies have indications of focal brain abnormalities. Their focal discharges have been localized over the frontal, Rolandic, and temporal regions in patients with idiopathic generalized epilepsy (Lombroso, 1997). There was nonspecific cortex initiating the generalized epilepsy with absence seizures. However, in our patients with JS, the consistent interictal EDs over the focal posterior head region with occipital dominance and spiky posterior alpha activities suggested the specific epileptic occipital cortex including alpha generator malfunction in JS network. There were no definite “eye-closed” abnormalities in this study. The eye-closed abnormality contains continuous or intermittent, generalized or focal, and unilateral or bilateral EDs persisting as long as the eyes remain closed (Duncan & Panayiotopoulos, 1996). The spiky posterior alpha activity might resemble the eye-closed abnormalities, although not completely sustained as long as eyes are closed. Further systematic studies in complete darkness and using Frenzel glasses will be performed to differentiate photosensitivity and fixation-off sensitivity.

Focal posterior ictal EDs preceding generalized EDs in JS

In our study of ictal EEG findings of 12 children with JS, we found that 11 patients (92%) had focal posterior ictal EDs. All focal ictal EDs were described as either posterior EDs leading by 200 ms to 1 s before generalized EDs (nine patients) or posterior EDs alone (two patients) predominantly over the occipital region. Mourente-Diaz et al. (2007) described unusual focal ictal EEG findings in two patients with EM and mild developmental delay. Both of them had normal background activity. Bilateral occipital polyspikes or spike-wave complexes were noted during EM immediately after eye closure in both patients. Ogura et al. also described a 14-year-old girl with EM with absences. Ictally, generalized spike and wave discharges were always preceded by paroxysmal burst activity in the occipital region (Ogura et al., 2005). Their findings indicated that the elimination of fixation on visual cues in the light could trigger the occipital spikes. In our cases, two patients showed only focal posterior EDs on scalp EEG producing EM. Although the occipital cortex alone cannot produce EM, the possible epileptic neural network of the brainstem initiated by the occipital cortex might produce EM after eye closure and during IPS. The ictal occipital EDs, both alone and together with generalized EDs during EM, highly suggested the occipital epileptic cortex initiating the JS epileptic network.

Role of occipital cortex in JS

Based on the clinical semiology and EEG findings observed in our patients, the occipital visual cortex may play an important role in eye closure–induced seizures and photosensitivity seen in JS. Striano et al. (2009) proposed the epileptic neural network for EM with absences. The intensity of light alters the volume of the occipital cortex, thereby activating the epileptic cortex and/or the level of excitability. Eye closure and IPS activate the epileptic occipital cortex and the excitabilities spread to the brainstem to produce EM. When the occipital excitability reaches the next level, EDs spread to the frontocentral cortex via either transcortical or thalamocortical pathways to project generalized spike and waves associated EM with absences.

Our findings of both focal interictal and ictal posterior and generalized EDs in children could be explained by the proposed mechanism (Fig. 4). We speculate the specific JS epileptic neural network to explain EEG and clinical findings. The normal alpha generator exists beside the epileptic occipital cortex to produce posterior alpha rhythm reactive to eye opening and closure (blinking). The alpha generator malfunction possibly within the epileptic occipital cortex may produce the spiky posterior alpha activities during sustained eye closure. If the photic stimuli including limitation of light by eye closure and IPS are not of sufficient strength to trigger the brainstem, we may see focal posterior EDs with and without generalized EDs but not producing EM. The generalized EDs at times can be projected via various transcortical pathways including U fibers, and superior and inferior longitudinal fasciculi from the occipital cortex without EM. If the stimuli are strong enough to activate the occipital cortex and further to trigger the brainstem such as superior colliculus and pretectal regions, the patient presents EM. Two EEG findings can be seen during EM. EM is produced by the epileptic occipital cortex and the brainstem without generalized EDs. When the posterior EDs are large enough or the transcortical pathway is synchronized, generalized EDs can occur with EM. The thalamocortical network is probably the last station of the JS epileptic network to present absence seizures with generalized spike and waves. EEG-fMRI (functional MRI) revealed thalamic blood oxygen level-dependent (BOLD) changes during ictal and interictal generalized spike and waves in four patients with EMA (Liu et al., 2008). The BOLD changes corresponding with generalized spike and waves lasting up to 6 s were extensive, yet major activation was seen in the thalami. The brainstem and thalamocortical network may have reciprocal ways because hyperventilation can provoke not only absences but also EM in JS. The scalp EEG is not complete enough to disclose the activated sections of the JS epileptic network. The well-defined visual and photic stimuli projecting EEG and clinical findings of JS can propose the specific JS epileptic neural network. The epileptic occipital visual cortex plays a key role in causing EDs and EM. JS is classified under idiopathic generalized epilepsy because of normal posterior dominant background activity and paroxysmal generalized ictal EDs, yet the specific occipital cortex must initiate the JS epileptic network. A number of pathways can be contributory to the mechanism underlying JS; therefore, a systematic study of relative importance of clinical and EEG findings could be useful in understanding this syndrome.

Figure 4.


Speculative model of the epileptic neural network involved in Jeavons syndrome, explaining EEG and clinical findings (see Discussion for further explanation).

Conclusion

We observed two pieces of neurophysiologic evidence of focal interictal EEG findings from the posterior head region, and predominant focal posterior ictal EEG findings preceding generalized EDs in JS. Further clinical observations of seizures induced by eye closure, IPS, and hyperventilation along with EEG paroxysms would raise the possibility of the occipital cortex initiating the generalized epilepsy network including the brainstem, and thalamocortical and transcortical pathways in JS.

Acknowledgment

We wish to thank Ms. Momoko Sugiyama and Dr. Hiroshi Okamoto for their checking of references and submitting the paper for which they received compensation.

Disclosure

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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