Clinical manifestations

Presentation and course

Focal onset generalized absence seizures may manifest as either typical (with > 2.5 Hz spike-wave discharges) or atypical (with < 2.5 Hz spike-wave discharges) absence seizures. The most classic focal onset generalized absence seizures are those manifested in patients with focal structural, mainly frontal, brain abnormalities as in case 1 of Clinical vignettes. They may be the most prominent seizure type in a patient, but more often, focal and focal to bilateral tonic clonic seizures predominate.

Frontal absences, that is, absence seizures of frontal lobe origin in patients with documented frontal lobe lesional foci, are probably the most common (32; 04; 03; 46; 34; 45; 26). Frontal absences “are characterized by speech and behavioral arrest, staring, reduced to complete loss of consciousness, (sometimes with minor head and eye turning), and simple automatisms. There does not appear to be a preceding aura. Absences can be as short as 10 s, typical of absence seizures in the idiopathic generalized epilepsies, but may continue for 30 s or more and may have a longer postictal period before complete recovery. Seizures may progress further into generalized convulsions, often with complex or asymmetric motor features” (46).

Grosso and associates described the characteristics of patients with typical absence seizures associated with focal epilepsy (Group 1) and compared them with patients having childhood absence epilepsy (Group 2) (22). Amongst consecutive patients with epilepsy, there were 14 in Group 1 and 53 in Group 2. In all patients of Group 1, onset was with focal seizures at a median age of 4.95±2.1 years (range 1.9 to 8.8). Ictal EEG and semiology features of typical absences of Group 1 did not show any distinctive features when compared to those of Group 2. However, in Group 1, more patients needed polytherapy, relapses were more frequent after drug discontinuation, and age at onset was significantly higher than in Group 2. None of the patients in Group 1 showed terminal remission.

Focal onset generalized absence seizures may progress to focal onset generalized tonic-clonic seizures as documented in a case report with video-EEG recording (45). This occurred after repeated bursts of 3 Hz spike-and-slow-wave complexes and manifested itself with conjugated deviation of the eyes and rotation of the head to the left before finally becoming a secondarily generalized tonic-clonic seizure. The patient was a 20-year-old man with seizure onset at 16 years of age. Seizures consisted of sudden loss of consciousness with quick recovery after each episode, at a frequency of more than 100 times a day; sudden arrested motions, with twitching at the left corner of the mouth, followed by clonic conjugated deviation of the eyes and head turning to the left (these occurred monthly); and secondarily generalized tonic-clonic seizures once or twice per month. Transient left hemiplegia remained after a cluster of seizures. MRI and SPECT were normal, but FDG-PET showed hypometabolism in the right frontal lobe. EEG showed 3 Hz (2.5 to 4 Hz) diffuse spike-and-slow-wave complexes predominantly in the frontal area. The diffuse spike-wave complexes were sometimes expressed in a burst form for between a few and dozens of seconds. The spike-and-slow-wave complexes were easily triggered by hyperventilation and sleep.

Another interesting case is of a 50-year-old woman who, from early childhood, had three types of seizures throughout her life: (1) focal motor seizures with right facial myoclonus involving the mouth, jaw, and periocular regions, and sometimes epilepsia partialis continua; (2) infrequent absence-like seizures with eye blinking, lasting up to 10 seconds; and (3) generalized tonic-clonic seizures occurring especially at night or early morning, sometimes beginning with head version to the right, but not followed by postictal paresis (13). High-resolution MRI with thin T1-weighted cuts and fluid-attenuated inversion recovery revealed a small area of focal cortical dysplasia in the depth of the left central sulcus. The authors compared the BOLD patterns related to both focal and generalized discharges and assessed the relationships between the underlying epileptogenic networks. BOLD activation was restricted, or almost restricted, to the dysplastic motor cortex in the case of focal events, whereas generalized spike-wave discharges induced activations slightly more anteriorly at the vicinity of the same area, but also in the homologous contralateral precentral cortex and bilaterally in remote cortical regions and thalamus. Although the central cortex was involved during both types of epileptic activity, EEG-fMRI revealed distinct neuronal networks at the time of the focal or generalized discharges, allowing a clear-cut differentiation of the generators; BOLD changes in the perilesional dysplastic area during focal or generalized discharges did not share a common pathophysiologic basis. The authors considered it debatable whether the patient had distinct epileptic syndromes or distinct electrographic patterns from the lesional trigger.

Raymond and colleagues studied 100 adults with cortical dysgenesis and epileptic seizures (44; 43). Fourteen of these patients had 3 Hz spike-wave EEG paroxysms. Several reported “brief blank spells,” and the majority of them had subependymal heterotopia.

Thalamic lesions may be a rare cause of focal onset generalized absence seizures (12). Also, a case of Rasmussen syndrome developed clinico-EEG manifestations of typical absence seizures, which the authors attributed to oxcarbazepine (11). This was a girl with right hemiatrophy, mainly at the Sylvian fissure and interictal EEG with focal spikes and diffuse paroxysms in the right fronto-temporal regions. After initiating oxcarbazepine, the patient developed daily, brief absence seizures, lasting less than 20 seconds and associated with bilateral and synchronous 2.5-3-Hz spike-and-waves compatible with typical absences.

Approximately one-third of patients with Lennox-Gastaut syndrome manifest with atypical absence seizures due to secondary bilateral synchrony, and these seizures are probably no different than those of the other two-thirds of patients with this syndrome (21; 07; 37).

Focal onset generalized absence seizures due to secondary bilateral synchrony are detailed in the MedLink Neurology article on Lennox-Gastaut syndrome.

Prognosis and complications

Limited data exist for prognostic factors, specifically for focal onset generalized absence seizures. However, their prognosis appears to be less favorable than that for patients with typical absence seizures (22). Extremely severe is the prognosis of epileptic encephalopathies manifesting with this type of seizure.

Clinical vignette

Case 1. Focal onset generalized absence seizures originating in the right frontal lobe. A 33-year-old woman started having absences confirmed with EEG at the age of 28. They consisted of “losing control of thoughts,” mild eyelid flickering, repeating simple phrases, and, occasionally, mild jerking of the head to the right. They were brief, lasting for 4 to 5 seconds, but could also last up to 1 minute. Initially infrequent, they later occurred daily despite appropriate antiepileptic medication with valproate, lamotrigine, and, later, add-on clobazam and carbamazepine. She also had infrequent generalized tonic-clonic seizures and once had an episode of absence status epilepticus. Brain imaging demonstrated a right frontal lobe low-grade glioma.

Case 2. Hypermotor and focal onset generalized absence seizures originating from the left parietal lobe. A 28-year-old woman suffered from hypermotor seizures since she was 6 years old. Clinically, the seizures imitated those originating from the supplementary somatosensory area of the frontal lobe. They occurred in clusters and were mainly nocturnal. There was no ictal impairment of consciousness and no postictal symptomatology. She could be free of seizures for months, and sometimes for 1 or 2 years, for no apparent reason. However, when the seizures relapsed again, they were numerous, with 10 or more occurring every night. Various combinations of appropriate antiepileptic drug combinations failed to control the seizures.

Focal onset generalized absence seizures with 3 to 4 Hz spike-wave discharges were recognized only on video-EEG.

These would usually occur after the onset of her habitual hypermotor seizures or with no apparent focal onset. Clinical symptomatology during 3 to 4 Hz discharges consisted of rhythmic myoclonic jerking.

Brain MRI documented a small unilateral malformation of cortical development in the left parietal lobe.

Biological basis

Localization

Focal onset generalized absence seizures represent clinical manifestations of ictal electrical discharge beginning in a restricted focus and spreading to involve bilateral outputs from the brain, generating typical or atypical absence seizures. Focal onset generalized absence seizures and secondary bilateral synchrony more frequently originate from frontal lobe foci (48; 04; 09; 03; 46; 08). Frontal absences have been described with ictal onset sites in the medial frontal gyrus, the anterior cingulate gyrus, and orbitofrontal cortex. Frontal absences have not been seen in patients with seizures from the supplementary motor area, and seem to originate from the more anterior half of the mesial frontal cortex. One would hypothesize the areas maximally involved in the ictal discharge to have dense callosal connections, or projections to the thalamus, to account for the abrupt alteration of awareness and bilateral ictal EEG findings (46).

Using scalp EEG recording, Tükel and Jasper reported that in some cases, a generalized 3 Hz spike-wave complex appeared in paramedian lesions. They coined the term “secondary bilateral synchrony” to describe the spike-wave complex that was focused in focal lesions and became secondarily generalized: “The wave and spike of petit mal is a primary bilateral synchronous discharge . . . ; it appears not to be related to a unilateral cortical focus, but may be of subcortical origin. . . . On the other hand, a bilateral synchronous discharge which can be shown to arise from a unilateral cortical focus we shall call secondary bilateral synchrony” (48).

However, Penfield and Jasper had previously remarked: “An epileptogenic lesion of the mesial or inferior aspect of a frontal lobe, although it is one-sided, may produce bifrontal synchronous discharges” (40).

With stereoelectroencephalography recordings, Bancaud and Talairach reported 161 seizures in 39 patients, in whom discharges initially affected the medial surface of the intermediate frontal region, producing two types of paroxysmal clinical manifestations: (1) “frontal absences,” as they termed them, and (2) complex motor seizures (04; 03).The clinical patterns of frontal absences were very close to those of typical absence seizures: arrest of speech and gestures, opening of the eyes, and brisk recovery of consciousness.

Relevant to the above is the knowledge that patients with idiopathic generalized epilepsy and generalized 3 to 4 Hz spike-wave discharges may also have focal clinical or EEG signs, and reports from animal models indicate that absence seizures arise from the somatosensory cortex, thus, providing support of a "focal hypothesis" of typical absence seizures (33; 36; 35; 41; 42; 31; 29). From this focus, seizure activity generalizes rapidly over the cortex. During the first cycles of the seizure the cortex drives the thalamus, whereas thereafter the cortex and thalamus drive each other, thus, amplifying and maintaining the rhythmic discharge. In this way the "cortical focus" theory for generalized absence epilepsy bridges cortical and thalamic theories. For more information on localization and pathophysiology, see the article on Typical absences.

Secondary bilateral synchrony from cortical, mainly frontal, foci has been implicated in atypical absence seizures and other “generalized” epileptic seizures in epileptic encephalopathies (21; 07; 27; 37; 38; 08). Secondary bilateral synchrony refers to bilateral and synchronous EEG discharges generated by a unilateral cortical focus. Contrary to secondary bilateral synchrony, primary bilateral synchrony manifests with more rapid symmetrical and synchronous generalized spike-wave discharges caused by a generalized epileptic process independent of any focal hemispheric lesion. Secondary bilateral synchrony has been considered the main pathophysiological mechanism in a third of cases of typical Lennox-Gastaut syndrome (37).

Like the typical absences, the atypical absences with an irregular diffuse sharp and slow-wave discharge appear to include a diffuse cerebral discharge affecting, above all, the nonspecific thalamocortical system, perhaps as a secondarily generalized discharge from a cortical focus often hidden (mesial frontal, orbital frontal, etc.). The irregularity of the discharges may be related to the diffuse cortical damage and the partial breakdown of thalamocortical connections by the atrophic encephalopathy (20).

Differential diagnosis

Confusing conditions

The diagnosis of absence seizures relies critically on history and EEG documentation. Usually it is not difficult to distinguish focal onset generalized absence seizures from typical absence seizures of idiopathic generalized epilepsy, such as childhood or juvenile absence epilepsy. However, these are more difficult to differentiate from atypical absences of syndromes such as Lennox-Gastaut or Dravet syndrome.

The focal localization is usually recognized on EEG and brain imaging. However, spread of the seizure can be extremely rapid, making it difficult to appreciate clinically or with EEG. Further, generalized 2 to 4 Hz EEG discharges and absence seizures without evidence of focal onset in patients having a brain lesion raise the question of the inter-independency of the two phenomena and whether the brain lesion should be considered incidental. Furthermore, idiopathic generalized epilepsies with typical absence seizures frequently show focal, mainly multifocal, spikes (33; 39; 31; 29; 28). The difficulty in differentiating “truly focal onset generalized absence seizures” from typical absence seizures of idiopathic generalized epilepsy is illustrated in the spatiotemporal profiles of focal and generalized spikes in children with childhood absence epilepsy (29). Spatiotemporal analysis demonstrated a variety of mainly frontal and occipital locations for pre-generalization focal spike-wave discharges with propagation along the longitudinal axis in either direction and across homologous sites. Interictal focal spike and wave discharges demonstrated similar spatiotemporal characteristics. In contrast, the topography and propagation patterns of the first generalized spike of the spike-wave discharge showed less variability, mainly involved the frontotemporal/temporal areas, and correlated poorly (less than 10%) with that of the pre-generalization focal spike-wave discharge. In one report, the same group of investigators studied the spatial distribution in time of generalized ictal spikes in 12 children with childhood absence epilepsy who had more than two typical absences during their routine video-EEG (28). Seizures were identified, and ictal spikes were marked over the maximum electronegative peak, clustered, waveform-averaged, and spatio-temporally analyzed in 2D electrode space. It was found that consistency of spatiotemporal patterns of ictal spikes was high between the absences of the same child, but low between children. Three main discharge patterns were identified: of anterio-posterior propagation, of posterio-anterior propagation, and confined to the frontal/prefrontal regions. In four patients, the propagation patterns transformed during the seizure into either a lateralized diminished or a non-lateralized reverse direction form. Most spikes originated fronto-temporaly, all maximized over the frontal or prefrontal electrodes and mostly decayed prefrontaly. In four patients, lateralized propagation patterns were identified. It was concluded that ictal spike propagation patterns suggest that epileptogenic childhood absence epilepsy networks are personalized, interconnect distal areas in the brain—not the entire cortex—with a tendency to generate bilateral symmetrical discharges, sometimes unsuccessfully. The transformation of propagation patterns during the seizure indicates the existence of dynamic interplay within epileptogenic networks (28).

Associated and underlying disorders

Although typical absences are considered the paradigm seizure type of idiopathic generalized epilepsies, they may occasionally be symptomatic, arising as a consequence of a known disorder of the CNS (16; 12). The latter may be focal or diffuse, traumatic, metabolic, or inflammatory (16). In most cases an etiological link is not proved, and it is likely that some of them are coincidental.

Structural frontal lobe epilepsy is the main focal epilepsy in which focal onset generalized absence seizures occur. Lennox-Gastaut and Dravet syndromes are severe forms of epilepsy manifesting with this type of epileptic seizure.

Diagnostic workup

A detailed medical history of the semiology of the seizure, coexistence of other types of seizure, neurologic and cognitive state of the patient, and family history is essential. EEG and MRI are the most important diagnostic tools.

The EEG abnormalities that can be observed in focal onset generalized absence seizures include interictal and ictal patterns. The interictal pattern may show focal abnormalities of slow waves or focal spikes-polyspikes and sharp waves, or a combination. These are usually consistently localized around the same brain area (mainly frontal). Conversely, focal spikes in idiopathic generalized epilepsies with typical absence seizures are usually multifocal and in various localizations (31; 29; 28). The ictal pattern usually consists of irregular 2 to 4 Hz generalized spike/multi-spike and slow wave.

The coexistence of focal and generalized EEG discharges in the same patient is not infrequent, particularly in children, although overt epileptic seizures of both types are rare (30; 22; 23; 24).

Brain MRI is recommended as the standard of care for patients with suspicion of focal-onset epilepsy, including focal onset generalized absence seizures.

Management

Prophylactic treatment with antiepileptic drugs is the mainstay of the management of focal onset generalized absence seizures, though surgery may also be appropriate in selective cases with clear cut focal abnormalities.

The antiepileptic drug selection is based on consideration of underlying cause, other types of coexistent seizures, comorbidities, and drug interactions. Patients probably respond best to broad spectrum antiepileptic drugs, which are efficacious in all or most focal and generalized epileptic seizures. These include valproate, levetiracetam, lamotrigine, and topiramate, alone or in combination. More specifically, levetiracetam was found useful in reducing both secondary bilateral synchrony on EEG and seizure frequency (25). Lamotrigine also had a good efficacy as an add-on therapy in severe focal epilepsy in adults with drop seizures and secondary bilateral synchrony on EEG (06).

Perampanel, lacosamide, and brivaracetam are the newest antiepileptic drugs to consider (02; 01). For more information, please see pharmacological treatment of epilepsy in adolescents and adults.

Surgery may be appropriate in selective cases with clear cut focal abnormalities, but the results are not encouraging (47).