Episodes of IGE-AS/IGE-MSE appear to be rare in JME. Three studies on JME patients examined status and included about half of the total published cases of status in this syndrome [5, 49, 50]; the rest were presented as case reports, while larger series have focused on the effect of treatment with ASDs inappropriate for IGE [6, 52].

Agathonikou et al. [5] reported IGE-AS/IGE-MSE in 2 of their 30 JME patients over 5 years (6.7%); Dziewas et al. [49] in 4 of their 69 patients (5.8%) over a similar period; and Larch et al. [50] in 7 of their 247 patients over 37 years (3%).

Clinically, a dominant myoclonic component characterizes the majority of the reported cases. Clinical descriptions are available for 25 patients, indicating 3 clinical forms, IGE-MSE, IGE-AS, and mixed IGE-AS/IGE-MSE. Pure IGE-MSE has been clearly described in 8 patients. It is characterized by arrhythmic bilateral myoclonic jerks of the head, limbs, or both, either continuous every few seconds, or in clusters every 10–15 s, in the absence of clear impairment of consciousness, or other symptoms. A notable exception was the patient reported by Badhwar et al. [53], who reported an overwhelming feeling of needing to void. In two patients with a diagnosis of JME, myoclonus was restricted to the ocular muscles, preventing eye opening [52, 54]. Mixed episodes were described in 13 patients, typically as states of confusion with superimposed bilateral jerks, mainly of the upper limbs. Boundaries between these two types are not always clear, and in some patients periods of lapses of attention or staring spells may alternate with periods with predominant myoclonic jerks [67]. IGE-AS associated with mild infrequent eyelid blinking, but not with limb jerking, is the rarest type, reported only in four patients. The age at the first status episode ranges from 10 to 69 years and was between 20 and 35 in half. An episode of status was never the first presentation of the JME in any of the patients. Even in patients with apparently de novo IGE-AS status, careful history taking after the resolution of the state reveals earlier myoclonic jerks that had passed unnoticed, or had never been appreciated as “abnormal” by the patients [68]. Women outnumber men (ratio 4:1 in patients with known gender).

Myoclonic and absence-myoclonic status episodes can occur spontaneously during the course of the disease in drug-naïve patients [68] (Fig. 15.5), often precipitated by sleep deprivation, tiredness, stress. The same factors, and in addition ASD withdrawal or poor compliance, can precipitate absence / myoclonic status in already treated patients. Further, the literature contains ample evidence that inappropriate for IGE anti-seizure drugs, either in chronic therapy or after dose increment or add-on treatment, can facilitate or trigger episodes of absence / myoclonic status [4, 6, 52–54, 56, 67]; IGE-GCSE induced by inappropriate ASDs appears sparse [6]. A more complete picture emerges from the three large series [5, 49, 50] with 13 patients with absence / myoclonic status among them: 2 had spontaneous episodes, 4 had episodes after ASD withdrawal, 6 had been on chronic treatment with inappropriate ASDs, and one had a single episode induced by vigabatrin. It is also noted that in a minority of JME patients recurrent unprovoked episodes of status may occur despite appropriate treatment, possibly suggesting a rare spontaneous adverse evolution of an earlier-benign course [5, 7].

Differentiation of IGE-MSE from non-epileptic myoclonic states mimicking JME requires emergency EEG to confirm the absence of any GSWD in association with the myoclonic jerks. It is emphasized that interictal EEGs may be normal in some patients with active JME. Non-epileptic MSE can be clinically suspected when adequate appropriate treatment has been ineffective and there is evidence of a psychiatric disorder [69].

The reported frequency of IGE-AS in JAE is higher than that in JME, but it varies widely among different studies (3.2% [70], 20% [5], 27.4% [71], and 38% [72]), presumably owing to different diagnostic criteria. Concurrent myoclonic jerks occur infrequently and do not dominate the clinical picture. Episodes may occur spontaneously, facilitated by sleep deprivation and menstruation [5] but can also be induced by inappropriate ASDs for IGE [55] or be related to chronic treatment with CBZ and PHT, including during dose increments [52]; 7 of the 8 patients with inappropriate ASD-induced ASE were women.

IGE-AS episodes are characterized by sub-continuous eyelid myoclonia with upward eye deviation and mild to moderately severe impairment of consciousness. Patients with intense eyelid myoclonia may appear unable to open their eyes to command (see EEG section above). Agathonikou et al. [5] reported absence status in 2 of their 11 patients (18.2%) over 5 years, while Smith [73] reported absence status in 3 of the 5 patients seen at the Chalfont epilepsy center over 3 years. The age at first episode of absence status has ranged from 8 to 27 years. Liability to absence status is maximal in the morning after awakening. All reports indicate that episodes are typically precipitated by eye closure in bright sunlight, but exceptionally they can also occur in total darkness after clinical photosensitivity has been controlled by medication [47]. Episodes have also occurred during severe infections [7, 73] and after withdrawal of ASDs [5]. They primarily affect women (10:1) and show a strong tendency to recur. In two patients, absence episodes were associated with headache, resulting in a misdiagnosis of migraine attacks [7, 74].

POMA is a rare form of IGE, in which typical absences are characterized by rhythmic contractions of the perioral musculature. GTCS occur in all patients and episodes of IGE-AS in more than 50% of them, starting at any age and with a strong tendency to recur [5]. As the typical absences in this syndrome, IGE-AS is frequently characterized by oral or bulbar myoclonus that can be intense enough to cause marked dysarthria [46] or impede drinking and eating [75]. POMA appears to be rare, but as all reports have pointed out, it is frequently misdiagnosed as focal epilepsy [46, 75–77], including epilepsia partialis continua in one patient with lateralized oral twitching [78]. Correct diagnosis requires demonstration of the characteristic IGE features, including typical absences (found most readily by video-EEG with hyperventilation [HV] on awakening) after the resolution of the AS.

As the term indicates, ASE is characterized by recurrent, unprovoked episodes of IGE-AS, which is the predominant and defining seizure type for this syndrome (Figs. 15.3 and 15.6). Most patients have infrequent GTCS, while a few have a history of (also infrequent) absences but cannot be classified into childhood or JAE. Phantom absences and MS are not part of this syndrome, and photosensitivity has not been reported (Table 15.1]. As in the epilepsy with phantom absences, episodes of IGE-AS occur without provocation and are not merely due to the aggravating effects of inappropriate ASDs used in IGE [8, 79].

The typical presentation of E-PA is the adult with the first GTCS or with an episode of IGE-AS, usually culminating in a GTCS. There is no earlier history of absences or myoclonic jerks, including in childhood or early adolescence. Diagnostic video-EEG after the IGE-AS shows brief 3–4 Hz GSWD associated with brief hesitations, omissions or repetitions of a reciting number during HV with breath counting, or a fleeting motor arrest reflecting impaired concentration, motor execution, or both (PA) (see Fig. 15.1) [80]. PA is the defining seizure type; conventional TA and MS are not part of E-PA. Because of the clinical imperceptiveness, the age of onset of PA cannot be ascertained, so the onset of E-PA is defined by the first overt clinical manifestation, either a GTCS or an episode of IGE-AS.

All patients have GTCS, and half may have one or more episodes of IGE-AS (see Fig. 15.1), but the latter does not dominate the clinical presentation as in the syndrome of ASE. Episodes of IGE-AS were associated with inappropriate use of particular ASDs in the treatment of 6 of 16 patients in three reports [5, 7, 9, 44], but a clear precipitating ASD effect was seen in only one patient.

Fixation-off sensitivity (FOS) is the occurrence of epileptic EEG discharges upon elimination of visual fixation [81]. FOS is infrequently associated with seizures, but there is a handful of well-documented cases of women with periodic episodes of IGE-AS associated with eyelid myoclonus and sometimes with GTCS [51, 82–84]. EEG during status showed attenuation or elimination of GSWD by visual fixation, and interictal EEG confirmed FOS without photosensitivity. Episodes were catamenial in three patients and periodic, every 2 weeks, in the fourth [82]. The threshold of FOS is expected to fluctuate in the same patient and, although the clinical picture may develop over time, these cases may constitute a pure form of FOS IGE [84].

Reports of patients with episodes of IGE-AS triggered by eye closure outside the syndrome of ELMA are sparse. A 44-year-old woman was described recently with catamenial IGE-AS, characterized by inability to maintain her eyes open, distractibility and macropsia, and associated with eye closure sensitivity but not with photosensitivity or FOS [85]. Her IGE-AS episodes started in childhood, and there were striking similarities to the case of a girl with JME reported by Kimura and Kobayashi [54]. The mechanism of discharge generation is similar to that in ELMA but without the added effect of photosensitivity (see ELMA and EEG section).

IGE-AS and IGE-MSE must be differentiated from non-epileptic conditions that include toxic and metabolic states, post-traumatic or transient amnestic states, psychiatric disorders (depression, schizophrenia, or conversion), and migraine aura. As they may also follow a GTCS [16, 51], any prolonged “postictal confusion” should arouse suspicion and prompt EEG recording [59].

Differentiation from focal and other forms of NCSE is extremely important, particularly for patients without a known history of epilepsy at the time of the status, as acute treatment (but also management after the resolution of the episode) is different in IGE. Not infrequently, classification of the epilepsy type and syndrome diagnosis is achieved by obtaining a full clinical history, an EEG and imaging, and other laboratory studies after the resolution of the status. The main epileptic states that present with clinical and EEG features that may overlap with those of IGE-SE include:

Rarely, however, the child may be in a state of confusion lasting for hours, which the electroencephalograph proves is a petit mal status. If there is any rigidity of muscles, if the person does automatic purposeless things or if he mumbles, groans or makes chewing motions the attack is probably a short psychomotor seizure and not a petit mal. Involuntary muscle movements, if present, are clonic in petit mal and tonic in psychomotor seizures. Lennox, 1945 [86]

Impairment of consciousness is more frequently mild in IGE-AS, but can range between mild and severe in both conditions. The characteristic for CPSE cycling changes between periods of unresponsiveness and partial responsiveness [57] may be confused with the fluctuations of behavior and mental state that occur in IGE-AS due to varying clustering of discharges and the brief interspersed periods of a normal state.

Clearly “focal” symptoms and signs, such as persistent oro-alimentary automatisms, strongly lateralized motor phenomena (such as dystonic posturing), or dysphasia, suggest CPSE, in which memory is usually severely affected. However, automatic behavior and experiential phenomena, such as déjà vu, may occur in both forms. On the other hand, regional bilateral (eyelid, perioral, or upper limb) myoclonus would suggest IGE-ASE, although they may appear lateralized, particularly in some inappropriately treated IGE patients [52]. Historical evidence may suggest prior focal seizures, but clinical differentiation between limbic temporal lobe seizures and absences can be exceptionally difficult. Emergency EEG will show focal discharges in the majority of patients with CPSE [65]. In contrast to IGE-AS, in which prompt clinical recovery coincides with normalization of the EEG, clinical response (and recovery of normal cerebral electrical activity) to acute IV treatment is usually gradual and delayed in CPSE, due to the ensuing postictal state [65].

Transient epileptic amnesia (TEA) is a rare but increasingly recognized distinctive clinical phenotype of temporal lobe epilepsy. Pure, frequently incomplete, acute amnesia may be the sole ictal symptom [87]; variable retrograde amnesia during the seizure also occurs. Amnesic seizures can last for more than 30 min in about half of patients. A tendency for the attacks to occur on waking may suggest IGE-AS, but in the latter, amnesia is never so selectively (and seldom so severely) affected. Additional ictal symptoms, such as a rising epigastic sensation, déjà vu or dysphasia, provide important diagnostic clues when present, but other symptoms like fear and anxiety and myoclonic jerks [87] may also occur in IGE-AS. Interictal, preferably sleep-deprived EEG shows temporal abnormalities.

Convulsive and nonconvulsive frontal lobe status is the commonest extra-temporal focal epileptic state [23–25], and evidence suggests that FL-NCSE may be more frequent than CPSE of temporal lobe onset [28, 88, 89]. FL-NCSE can manifest either as simple focal SE, associated with mild impairment of consciousness and focal symptoms and ictal EEG changes (FL-NCSE type 1), or as complex partial SE, usually with severe impairment of consciousness and bilateral ictal EEG discharges, known as FL-NCSE type 2 [66]. The latter may sometimes mimic IGE-AS from both the clinical and EEG standpoints leading to misdiagnosis, particularly in patients without known epilepsy. Secondary bilateral synchrony (SBS) from strategically positioned foci in the frontal midline is considered as the principal underlying mechanism [90, 91], perhaps in association with a genetic predisposition. However, the reason for which SBS evolves in self-perpetuating thalamocortical oscillations into status is unknown. Employing strict spatial and temporal constraints, Blume and Pillay [92] showed that SBS-GSWD were slower than 3 Hz in 3/4 of the patients, most of whom had frontal lobe foci.

Focal clinical features suggesting FL-NCSE type 2 rather than IGE-AS include lateralized twitching or dystonia, head version, or clear dysphasia, either at seizure onset or during the course of the epileptic state; typically, and at variance with IGE-AS, consciousness is severely affected and there is amnesia for the episode. On the EEG front, in FL-NCSE type 2, bilateral frontally predominant and apparently synchronous discharges frequently follow a lateralized frontal onset; they are usually “slow” at 1–2 Hz [93, 94], and may show “lateralization” [66, 93, 95, 96] or be accompanied by “embedded” focal discharges [93]. In addition, FL-NCSE type 2 (as type 1) is usually unresponsive to IV BDZ and VPA, frequently requiring IV PHT or phenobarbital for full seizure control [66, 94].

Notwithstanding the validity of the above diagnostic criteria for most cases of FL-NCSE type 2, electroclinical boundaries with IGE-AS may overlap, making differential diagnosis very difficult—or sometimes, even impossible—at least in the acute phase of the status. Deceptively, episodes of FL-NCSE type 2 can be activated by HV [93, 95, 96], as in IGE, although clear (but frequently forgotten) evidence that focal seizures can also be activated by HV dates to the late 1970s [97]. Incomplete frontally predominant GSWD also occur in IGE, associated with milder loss of consciousness in both TA [98] and even in prolonged subclinical IGE-AS [99]. In some patients, the frequency of the GSWD in FL-NCSE type 2 is fast, well within the IGE spectrum [91, 95, 96] implying secondary activation and sustained involvement of the thalamocortical system. On the other hand, in later stages of IGE-AS, discharge frequency may drop below 2.5 Hz.