Address correspondence to Ingrid E. Scheffer, Melbourne Brain Centre, 245 Burgundy Street, Heidelberg, Vic. 3084, Australia. E-mail: firstname.lastname@example.org
The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes; a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging (MRI). Electroencephalography (EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants.
The benign occipital epilepsies of childhood include two well-recognized epilepsy syndromes: Panayiotopoulos syndrome (PS) and Gastaut syndrome (GS) (Berg et al., 2010). Although they have an overlapping age of onset (1–15 years), PS occurs predominantly in younger children and GS occurs more often in older children. These syndromes are differentiated by prominent autonomic features (vomiting, pallor), head version, tonic eye deviation, and prolonged seizures in PS, in contrast with frequent brief seizures with visual aura in GS (Panayiotopoulos, 2000; Covanis et al., 2005; Taylor et al., 2008).
Both syndromes share the electroencephalography (EEG) signature of occipital spikes with fixation off sensitivity, although a wide variety of EEG manifestations have been described including generalized spike-wave activity (Gastaut, 1982; Gastaut & Zifkin, 1987; Panayiotopoulos et al., 2008). Occipital spikes and generalized spike-wave are also seen in idiopathic photosensitive occipital epilepsy (IPOE), a third occipital epilepsy syndrome, beginning in late childhood to adolescence in which photosensitivity is an essential feature. In IPOE, patients experience brief occipital seizures with conscious head and eye version and visual hallucinations (Guerrini et al., 1995). The disorder may occur in individuals and families with the genetic generalized epilepsies (previously called idiopathic generalized epilepsies; Taylor et al., 2004).
The etiology of the occipital epilepsies is unclear, but genetic mechanisms are postulated (Taylor et al., 2004, 2008; Panayiotopoulos et al., 2008). Twin and family studies suggest the presence of shared genetic determinants and environmental influences, with complex inheritance being most likely (Taylor et al., 2004, 2008).
We present adolescent siblings with unusual refractory occipital epilepsy characterized by frequent visual seizures. We studied the networks involved in seizure generation using EEG-fMRI (functional magnetic resonance imaging) to explore whether the siblings have a localized or a bilateral epilepsy network.
A sister and brother with refractory occipital lobe seizures were referred to our epilepsy genetics program. Detailed electroclinical information including video-EEG monitoring was obtained. This project was approved by the Austin Health Human Research Ethics Committee. Written informed consent was obtained.
EEG with fMRI
EEG with fMRI was performed in each patient as described previously (Carney et al., 2010). Epileptiform activity was identified during in-scanner EEG following comparison with the subjects' routine EEGs. fMRI data were obtained using a 3-T GE Signa LX whole-body scanner (General Electric, Milwaukee, WI, U.S.A.) with continuous acquisition of gradient-recalled echo planar image (EPI) volumes (repetition time = 3,200 msec, echo time = 40 msec, flip angle = 80 degrees with axial oblique slices 3.2 mm thick + 0.2 mm gap, 22 cm field of view (FOV); 64 × 64 matrix). The first four image acquisitions were discarded to ensure steady-state tissue magnetization. One hour EEG-fMRI recordings were performed.
fMRI data were preprocessed and analyzed using SPM8 (Statistical Parametric Mapping, Welcome Department of Imaging Neuroscience, London, United Kingdom). Data preprocessing was performed including slice timing and motion correction. Spatial smoothing was performed using an isotropic Gaussian kernel with full-width-at-half-maximum of 6 mm. A standard event-related analysis was performed using the canonical hemodynamic response function (HRF; Carney et al., 2010). Anatomic localization was performed using xjview (www.alivelearn.net/xjview8/).
This 18-year-old female began having seizures at 10 years. She was the elder of two children to unrelated parents without a family history of epilepsy. Initially she experienced elementary visual phenomena such as seeing stars. She went on to develop seizures characterized by visual loss followed by head and eye deviation to the right, pallor, and prominent postictal headache. This led to an early misdiagnosis of migraine (Data S1). Seizures became increasingly frequent and were refractory to multiple antiepileptic drugs (AEDs), culminating in up to three seizures daily. Lamotrigine and the ketogenic diet had been the most effective antiepileptic therapies.
Investigations and neuroimaging were unremarkable (Table 1). Neuropsychological assessment showed normal intellect with weakness in working memory, processing speed, and attention.
Table 1. Electroclinical features of the sister and brother
PPR, photoparoxysmal response; FOS, fixation off sensitivity; anti-TGA, anti-tissue transglutaminase IgA; POLG, polymerase gamma; N/A, not administered.
Mutations screened in blood p.A467T. p.W748S, p.G848S.
Mutations screened in blood m.1555a>G, m.3271T>C, m.8356T>C, m.9176T>C, m.13513G>A, m.14459G>A).
Spots and visual loss
Occasional to right
Infrequent clonic leg movement
8–9 Hz PDR
9–10 Hz PDR
Posterior quadrant low voltage fast activity and spike wave in sleep
Left and rare independent right posterior quadrant sharp and slow discharges
5–10 s, visual loss without objective changes, awareness maintained right posterior quadrant fast activity evolves into theta slowing
5–10 s, no clinical change, awareness maintained bilateral (L > R) posterior quadrant low voltage fast activity evolves to delta slowing
Low average with strengths in verbal and visual areas and weakness in working memory, processing speed and attention
Average intellectual function
Diminished attentional processing slower gains in single-word reading, written arithmetic and spelling
Video-EEG monitoring (VEM) demonstrated interictal bursts of low-voltage fast activity, and independent and bilaterally synchronous spike and wave activity in the posterior quadrants maximal in the occipital leads. Fixation off sensitivity was not seen. Seizures were brief (<10 s) and characterized by visual loss with retained awareness. Ictal EEG showed low-voltage fast activity emanating from the right or bilateral occipital and posterior temporal regions (Fig. 1).
Her 12-year-old brother, with a past history of a febrile generalized tonic–clonic seizure at 2 years, also developed seizures at 10 years. Initially seizures comprised brief episodes of visual blurring and loss with retained awareness and pallor or flushing. AEDs were commenced 12 months after onset when he experienced daily attacks of visual loss, loss of awareness, and head and eye deviation to the right followed by headache. AEDs were ineffective until the ketogenic diet was introduced. Investigations were unremarkable (Table 1).
Interictal EEG showed frequent left and occasional right occipital sharp-slow and poly-spike and wave discharges and intermittent posterior quadrant delta on an otherwise normal background. During seizures, the patient was unable to see but remained fully responsive without automatisms. Ictal EEG demonstrated low-voltage fast activity over the posterior quadrants (more prominent on the right) followed by intermittent rhythmic delta activity (Fig. 1).
In the proband, 29 interictal bursts (70 s, range 1–5 s) of fast activity in the right or bilateral posterior quadrants were recorded during EEG-fMRI. Significant decreases in blood oxygen level–dependent (BOLD) were seen in the lingual gyrus with increases in the anterior corpus callosum and the bilateral ventral regions of the thalamus (Fig. 1).
The brother had 24 bursts of left occipital fast activity (35 s, range 0.5–2 s). Positive BOLD change was seen in the left middle occipital gyrus, with negative BOLD in the same region on the right (Fig. 1).
These siblings have an occipital epilepsy syndrome characterized by frequent brief occipital seizures with visual loss or elementary visual phenomena and eye deviation beginning at 10 years. Seizures were refractory to AEDs but responded partially to the ketogenic diet and continued to occur frequently in late adolescence.
Their epilepsy syndrome can be easily distinguished from PS by their later onset, multiple daily seizures, and the absence of prolonged attacks with ictal vomiting (Panayiotopoulos et al., 2008). IPOE is excluded, as neither child is clinically or electrically photosensitive.
The siblings' epilepsy is most similar to GS given the visual aura of ictal blindness, and the brief duration and frequency of the seizures (Gastaut, 1982; Panayiotopoulos et al., 2008). Their EEG does not show the characteristic occipital paroxysms or fixation off sensitivity seen in GS; however, the EEG may be normal in GS (Panayiotopoulos et al., 2008). The refractoriness of the disorder is also atypical for GS with ongoing seizures into young adult life. GS usually remits by late adolescence, although one study noted a poorer prognosis in the setting of atypical features such as mental retardation or abnormalities on computed tomography (CT) imaging (Gastaut & Zifkin, 1987). Three of their 63 patients had ongoing seizures with different semiology in adult life; their occipital seizures had remitted. The clinical history and investigations did not suggest a more sinister cause of occipital epilepsy such as a mitochondrial disorder or Lafora disease (Table 1). There was no evidence of a structural cause or acquired cause, which more commonly results in refractory occipital epilepsy.
In our siblings, significant BOLD changes in the occipital cortex were observed in association with interictal epileptiform discharges, supporting the presumption that the siblings' epilepsy arises from a focal cortical network. In the proband, negative BOLD was seen in the primary visual cortex (lingual gyrus), whereas in her brother, BOLD change was seen in the middle occipital gyri, increased on the left and decreased on the right (Fig. 1). This supports the EEG and clinical findings of a focal occipital generator of epileptiform activity. These observations show similar localization to a study of three children with GS (Leal et al., 2006).
The striking electroclinical concordance in the siblings provides strong evidence for a genetic basis for their epilepsy syndrome, but it is unclear if the etiology is monogenic or polygenic. If monogenic, an autosomal recessive inheritance pattern is most likely, but mitochondrial inheritance or a de novo dominant germline mutation in one parent may also be possible. With the advent of new molecular techniques such as whole exome and whole genome sequencing, identification of the causative genetic variant(s) may provide insights into the neurobiology of seizure disorders emanating from the occipital lobe.
We thank patients and their family for participating; Dr. Danny Flanagan for assistance with EEG recording reporting and analysis; Shawna Farquharson, Renee Mineo, and Saba Ansary for radiography; Dr. David Abbott and Dr. Richard Masterton for development of analysis methodology. National Health and Medical Research Council program Grant in Epilepsy. Pfizer Neuroscience Research Grant. PC was supported by a Dowd Foundation Scholarship. The Operational Infrastructure Support Program of the State Government of Victoria, Australia.
Funding bodies provided financial assistance without contributing to the direction or interpretation of research. GDJ receives royalties from the publication of Magnetic Resonance in Epilepsy, 2nd ed. (Elsevier, 2005). The remaining authors have nothing 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.