This supplement has been supported through an unrestricted grant from UCB S.A., manufacturers of levetiracetam (Keppra®).
Address correspondence and reprint requests to Dr. C. P. Panayiotopoulos, Department of Clinical Neurophysiology and Epilepsies, St. Thomas' Hospital, SE1 7EH, London, U.K. E-mail: firstname.lastname@example.org
Summary: This chapter assesses probable epileptic syndromes within the idiopathic generalized epilepsies (IGE) that have not yet been recognized by the International League Against Epilepsy (ILAE). Jeavons syndrome, a purely reflex IGE that predominantly manifests with eyelid myoclonia and electroencephalogram (EEG) abnormalities on eye closure, is the most distinct and undisputed of the syndromes. Another is autosomal-dominant cortical tremor, myoclonus, and epilepsy, a purely monogenic disorder that has been documented in numerous reports, mainly from Japan and Italy. Perioral myclonia with absences is certainly a seizure type that may constitute an IGE syndrome when it is associated with a number of other clinical and EEG manifestations. Similarly, many patients suffer for years from phantom absences, a type of mild absence, before a first generalized tonic-clonic seizure that usually occurs in adulthood. Both perioral myoclonia with absences and phantom absences are clinically significant because they are probably lifelong and are associated with a very high incidence (around 50%) of absence status epilepticus that may escape diagnosis and appropriate treatment. The position of early childhood IGE, which manifests mainly with typical absence seizures that are distinctly different from childhood absence epilepsy and other recognized IGE syndromes, is less clear. The prevalence of these syndromes is significant. Their identification allows better clinical management and is important for genetic research and counselling. In addition, their recognition permits application of exclusion criteria for a more purified definition and a better understanding of the true boundaries of the other IGE syndromes already accepted by the ILAE.
The classification of idiopathic generalized epilepsy (IGE) is probably one of the most significant and debated issues (1). The two schools of thought, with diversely opposing views, are that IGE is one disease or a biological continuum, or that IGE comprises a large group of many distinct syndromes. The evidence so far is not conclusive in favor of one or the other, and any new classification should not take sides unreasonably.
In practical terms, the view that IGE is one disease would, overall, be an easy clinical diagnostic approach, but it would discourage the diagnostic precision required for genetic studies, prognosis, and management decisions. The view that IGE comprises a large group of many distinct syndromes would be more demanding diagnostically and occasionally require exhaustive clinical and video-electroencephalogram (EEG) data. However, this is often the price that we, as physicians, have to pay in pursuing an accurate diagnosis—the golden rule in medicine. This view also satisfies the requirement for maximum practical application to differential diagnosis, which is the main reason for reorganizing the classification of epileptic syndromes in the forthcoming International League Against Epilepsy (ILAE) revisions; it also takes advantage of significant advances in our understanding of IGE (2). Animal genetic studies have documented numerous syndromes of IGE, and this is likely to be the case in humans.
This chapter deals with probable syndromes of IGE that are not officially recognized by the ILAE; they include IGE with absences of early childhood, perioral myoclonia with absences (PMA), idiopathic generalized epilepsy with phantom absences, Jeavons syndrome (eyelid myoclonia with absences), and monogenic IGE syndromes (1). Their diagnosis in clinical practice is significant at least for genetic and prognostic reasons. Video-EEG documentation of most of them can be found in the CD companion to The Epilepsies: Seizures, Syndromes and Management (1). “Implicitly, one must be prepared to split before one can lump. Thus we must always be on guard against unwittingly lumping because we are unaware of certain characteristics on which we should have split.” (3)
IDIOPATHIC GENERALIZED EPILEPSY WITH ABSENCES OF EARLY CHILDHOOD
Typical absences starting from early childhood (between a few months and 4 years of age) (4,5) are not a specific expression of a distinct syndrome, but may be the first manifestation of other syndromes of IGE with absence seizures that are recognized, as well as those that are not recognized, by the ILAE. By excluding all these conditions, it is realistic to propose that there is a syndrome of IGE that starts in early childhood primarily manifesting with absences, often combined with generalized tonic-clonic seizures (GTCS) and possibly with myoclonic jerks.
Doose (4) studied 140 cases with onset of absences in early childhood and rightly concluded that “this is an heterogeneous subgroup within IGE. There is a distinct overlap with early childhood epilepsy with GTCS and myoclonic astatic epilepsy on the one side and with childhood absence epilepsy on the other. Thus it should not be regarded as a special syndrome.” I am in complete agreement with this statement. Age at onset of absence seizures alone cannot define an epileptic syndrome. However, with improved diagnostic skills, applying inclusion criteria (e.g., including absences and GTCS) and exclusion criteria (e.g., excluding childhood absence epilepsy and possibly symptomatic cases), it appears that there is such a rare IGE syndrome that needs precise clarification.
This is an IGE syndrome that occurs in otherwise normal children (4). Onset of absences occurs between ages 1 to 5 years, and absences are markedly different from those of childhood absence epilepsy (CAE). Clinically, they are less severe and less frequent. Ictal EEG 3–4-Hz spike/multiple spike-wave discharges are very irregular, and termination is not abrupt, but often fades with slow spike-wave complexes. GTCS are common, affecting two thirds of patients, and are often the first seizure type. Boys are more likely to suffer GTCS than are girls. Myoclonic jerks and myoclonic-astatic seizures occur in 40% of patients. Absence status epilepticus may lead to cognitive impairment. Background EEG shows a moderate excess of slow waves. Long-term prognosis is worse than that of CAE. There is a strong family history of IGE and generalized spike-wave discharge (GSWD) in the EEGs of unaffected members, particularly mothers.
PERIORAL MYOCLONIA WITH ABSENCES
Typical absences with ictal motor symptoms of perioral myoclonia is a discrete seizure type that has been unequivocally documented with video EEG (Fig. 1) (1,6–10). The symptom of perioral myoclonia may rarely occur in absence seizures of other IGEs and, as such, perioral myoclonia alone cannot be taken as sole evidence of the syndrome of PMA. However, this is often combined with a clustering of other clinical and EEG features probably constituting an interesting syndrome within IGE. Other manifestations of this syndrome include GTCS that often start early prior to or together with the absences, frequent occurrence of absence status epilepticus (ASE), resistance to treatment, and persistence in adult life.
Age at onset covers a wide range from 2 to 13 years (median age, 10 years). Girls are far more frequently affected than boys. The syndrome is uncommon in children (<1% with typical absences), but because it fails to remit, it is relatively common in adults (9.3%) with typical absence seizures.
Typical absence seizures with perioral myoclonia are the defining symptom. The characteristic feature is perioral myoclonia, which consists of rhythmic contractions of the orbicularis oris muscle that cause protrusion of the lips, contractions of the depressor anguli oris resulting in twitching of the corners of the mouth, or rarely more widespread involvement, including the muscles of mastication producing jaw jerking. Impairment of consciousness varies from severe to mild (Fig. 1). Most patients are usually aware of the perioral myoclonia. Duration is usually brief, lasting a mean of 4 s (range 2–9 s). Absences may be very frequent and occur many times per day or 1–2 times per week, or they are rare.
All patients suffer GTCS, which often start before or soon after the onset of clinically apparent absences. Exceptionally, GTCS may start many years after the onset of absences. GTCS are usually infrequent (ranging from once in a lifetime to 12 per year) and are often heralded by clusters of absences or ASE.
ASE in PMA is more common (57%) than in any other IGE and frequently ends with GTCS (Fig.1) (11,12). Perioral myoclonia may be more apparent than impairment of consciousness or vice versa.
One half of the patients with PMA have first-degree relatives, mainly siblings, with IGE and absences.
All tests apart from the EEG are normal. Interictal EEG frequently shows (a) abortive bursts or brief less than 1 s generalized discharges of spikes or multiple (3–4) spikes and slow waves (4–7 Hz), which are usually asymmetrical and may give the impression of a localized focus, and (b) focal abnormalities, including single spikes, spike-wave complexes and theta waves with variable side emphasis.
Ictal EEG consists of generalized discharges of spikes or multiple spikes and slow waves (3–4 Hz) with frequent irregularities of the GSWD in terms of the number of spikes in the spike-wave complex, the fluctuations in spike amplitude, and the occurrence of fragmentations. There is no photosensitivity.
Patients with PMA are frequently erroneously diagnosed as having focal motor seizures because the prominent motor features of the absences, which are often reported, are sometimes recorded as unilateral and interictal focal EEG abnormalities are present. However, this error is unlikely to happen if the EEG is properly recorded and interpreted (Fig. 1). Also, patients with focal motor seizures are unlikely to suffer nonconvulsive status epilepticus, which is common in PMA.
The main differential diagnosis is from CAE, juvenile absence epilepsy (JAE), myoclonic absence epilepsy (MAE), or IGE with phantom absences, depending on the age at onset. Video EEG invariably reveals perioral myoclonia that sometimes, particularly in treated patients, may be subtle. Onset of GTCS before or at the same age as typical absences, the relatively brief duration of the absence seizures and perioral myoclonia, and the frequent occurrence of ASE are useful clinical indicators in favor of PMA and against childhood, juvenile, or other forms of IGE. Perioral myoclonia with absences may be difficult to differentiate from epilepsy with myoclonic absences, particularly if the latter presents with mild myoclonic jerks localized in the face (9). However, MAE is often symptomatic and is rarely associated with generalized nonconvulsive status epilepticus (13).
Absences and GTCS may be resistant to medication, unremitting, and possibly lifelong (6,8).
Treatment is with valproate alone or combined with ethosuximide, small doses of lamotrigine, or clonazepam. Levetiracetam may be effective because of the myoclonic elements of the absences. ASE, of which most patients are aware, should be terminated with immediate self-administered medication of oral midazolam or rectal diazepines.
IDIOPATHIC GENERALIZED EPILEPSY WITH PHANTOM ABSENCES
Phantom absences denote typical absence seizures, which are so mild that they are inconspicuous to the patient and imperceptible to the observer (1,14). The absences are simple and brief (usually 2–4 s) causing only mild impairment of cognition, as demonstrated by errors and discontinuation during breath counting on video EEG (Fig. 2). They are not clinically disturbing to the patient. Although not classic, they fulfil the criteria of typical absences with more than 2.5-Hz generalized discharges of spike waves (14). It should also be emphasized that the phantom absences in these adults do not represent aborted past childhood or juvenile absences modified by age or medical treatment (14).
There is reasonable evidence to suggest that phantom absences are not only discrete seizures, but may also constitute the main symptom of a syndrome within the broad spectrum of IGE. There is nonfortuitous clustering of other symptoms such as GTCS of usually late-onset, frequent occurrence of ASE, and persistence in adult life (1,12,14,15).
The first overt clinical manifestations of GTCS appear in adult life, although absences may have started much earlier. ASE as the first overt symptom in childhood is rare (16). Men and women are equally affected. The prevalence was estimated to be 15% of IGE with typical absences, 10% of IGE, and 3% of 410 consecutive patients over 16 years of age with epileptic seizures (14).
The syndrome is characterized by the triad of (14):
• phantom absences that are inconspicuous and never appreciated prior to the onset of GTCS
• GTCS, which are commonly the first overt clinical manifestations, usually starting in adulthood and infrequent
• absence status epilepticus, which occurs in 50% of patients
Phantom absences are the defining and consistent symptom in these patients (Fig. 2). Patients are not usually aware, even retrospectively, that absences interfere with their daily life, even when driving or in demanding professions. Patients may retrospectively admit to momentary lack of concentration and forgetfulness, which in their opinion was of no practical significance (14).
GTCS are usually the first overt clinical manifestation (14). They are of late onset, infrequent, and without consistent circadian distribution or specific precipitating factors.
Absence status epilepticus occurs in 50% of patients (Fig. 2) (11,12,14). This often lasts for many hours alone or prior to GTCS. Ictal cognitive impairment is usually of mild or moderate severity. Patients in ASE often communicate poorly and slowly, feel strange and confused, make errors at work, and look depressed, but do not become unresponsive. Frequently, they have a good recollection of the ictal events (14). Experiential, mental, and sensational symptoms are more common than is usually appreciated (14,17). Neuropsychological examination under video-EEG monitoring during ASE revealed only mild attentional and executive disturbances, with selective impairment in the initiation of response and self-generated action, whereas short-term storage of external information was intact (15).
Patients with recurrent ASE are often aware of the impeding GTCS, and try to find a safe place to have it.
IGE with phantom absences is probably genetically determined (14).
All tests apart from the EEG are normal. The background activity is normal; 50% of patients have EEG focal paroxysmal abnormalities consisting of short transients of localized slow, sharp waves or spikes, or both, occurring either independently or in association with the generalized discharges (14). EEG photosensitivity is exceptional.
Ictal EEG consists of spikes/multiple spikes and slow waves at 3–4 Hz with occasional fragmentations. They are typically brief (2–4 s), lasting usually no more than 5 s. Mild cognitive impairment manifested with hesitation, discontinuation, and errors in breath counting is the only clinical ictal symptom during GSWDs (Fig. 2). A few may also have mild ictal eyelid fluttering (14). Hyperventilation is a major provocative factor.
During ASE, the EEG shows continuous, generalized, mainly 3-Hz spike/multiple spike slow wave activity (Fig. 2).
The diagnostic and management errors involving adult patients with IGE and typical absence seizures have been well reported (14,18). The magnitude of the problem is worse in IGE with phantom absences, in which the absences are very mild, ASE is confused with nonepileptic events or temporal lobe epilepsy, and GTCS are of late onset. This is compounded by frequent EEG focal abnormalities, and the current practice of most EEG departments to not test cognition appropriately during brief generalized discharges of spike waves.
The main problems to consider in IGE with phantom absences are that the first overt unprovoked GTCS appears in adult life, absence status epilepticus, and differentiation from other syndromes of IGE. It is essential to take a careful clinical history and to interpret correctly symptoms that may be suggestive of typical absences and ASE. A history of altered consciousness preceding GTCS should not be taken as evidence of complex focal seizures, depression, or an unspecified seizure prodrome
Other forms of the so-called adult-onset IGE may be otherwise typical examples of juvenile myoclonic epilepsy (JME), JAE, or other IGE syndromes that start or become clinically identifiable after the age of 20 years (19,20). Some of the patients described may suffer from IGE with phantom absences.
IGE with phantom absences may be a lifelong propensity to seizures of undetermined onset and remission. Patients are of normal intelligence, which does not show any signs of deterioration. Furthermore, phantom absences, although frequent, do not appear to affect daily activity.
It is questionable whether patients with phantom absences need treatment. All reported patients had a normal life without medication until their first GTCS, probably many years after the onset of frequent daily mild absence seizures. We do not know how many people there are in the general population with the same problem but without GTCS or conspicuous ASE. If treatment is considered necessary (driving a car is a significant factor), the choice is probably between valproate, lamotrigine, and levetiracetam (in this order).
JEAVONS SYNDROME (EYELID MYOCLONIA WITH ABSENCES)
Jeavons syndrome is one of the most distinctive reflex IGE syndromes with well-defined clinical and EEG manifestations (1,21,22). It has been vividly described by Jeavons (23) and documented in numerous reports (1,21,22,24,25). Jeavons syndrome is characterized by the triad of eyelid myoclonia with and without absences, eye-closure–induced seizures, EEG paroxysms, or both, and photosensitivity. Jeavons syndrome has not been recognized by the ILAE (2). Instead, a new seizure type, eyelid myoclonia with and without absences, has been accepted (2,26). These seizures occur in many epileptic conditions of idiopathic, symptomatic, or probable symptomatic causes (26,27).
Onset is typically in childhood, with a peak at 6–8 years of age (range 2–14 years). There is a twofold preponderance among girls. The prevalence of Jeavons syndrome is around 3% among adult patients with epileptic disorders and 13% among IGEs with absences (21).
Eyelid myoclonia, not the absences, is the hallmark of Jeavons syndrome (21,26). Eyelid myoclonia consists of marked jerking of the eyelids often associated with jerky upward deviation of the eyeballs and retropulsion of the head (eyelid myoclonia without absences). This may be associated with or followed by mild impairment of consciousness (eyelid myoclonia with absences). The seizures are brief (3–6 s) and occur mainly after eye closure and consistently many times per day (Fig. 3). All patients are photosensitive.
GTCS, either induced by lights or spontaneous, are probably inevitable in the long term and are particularly provoked by precipitating factors (sleep deprivation, alcohol) and inappropriate antiepileptic drug modifications. Typically, GTCS are sparse and avoidable. Myoclonic jerks of the limbs may occur, but are infrequent and random.
Eyelid myoclonic status epilepticus either spontaneous, mainly on awakening, or photically induced occurs in one fifth of patients. It consists of repetitive and discontinuous episodes of eyelid myoclonia with mild absence, rather than continuous nonconvulsive absence status epilepticus (Fig. 3) (11,26).
The most potent precipitating factor is eye closure, whether it is voluntary, involuntary, or reflex. The majority, and in some patients all, of the seizures are induced immediately after closure of the eyes in the presence of uninterrupted light. Eye closure in total darkness is ineffective (Fig. 3).
Contrary to other forms of photosensitive epilepsies that are sensitive only to flickering lights, patients with Jeavons syndrome are also sensitive to bright, nonflickering lights. This is probably due to the enhancing effect of bright light on eye-closure sensitivity.
Self-induction in Jeavons syndrome
Most relevant reports and most epileptologists unquestionably consider the eyelid myoclonia of Jeavons syndrome as a manoeuvre used by patients to self-induce IPS and elicit seizures. Our view, based on numerous video-EEG recordings and interviews with 17 patients, is that eyelid myoclonia is an ictal event (15 patients) and that self-induced seizures in Jeavons syndrome are rare (possibly two patients) (26). However, patients may not be deliberate self-inducers, but may suffer from compulsive self-induction similar to the phenomenology described in Tourettes syndrome (24).
Jeavons syndrome is a genetically determined homogeneous syndrome (28,29). Of 18 patients with Jeavons syndrome, 14 had a family history of epilepsy and 4 patients had other family members affected by the same syndrome (29).
All tests apart from the EEG are normal. Video EEG is the single most important procedure for the diagnosis of eyelid myoclonia with or without absences. It shows frequent high-amplitude generalized discharges of 3–6-Hz spike/usually, polyspike waves. These typically are related to eye closure, that is, they occur immediately (within 0.5 to 2 s) after closing the eyes in an illuminated recording room and brief (1–6 s, commonly 2–3 s). The discharges are eliminated in total darkness (Fig. 3). Eyelid myoclonia of varying severity often occurs with these discharges. In addition, photoparoxysmal discharges are recorded from all untreated young patients, but may be absent in older patients or those on medication.
EEG discharges are also enhanced by hyperventilation. In sleep, the discharges are shorter and devoid of discernible clinical manifestations of any type, even in those patients who have numerous seizures during alert states. The EEG and clinical manifestations deteriorate consistently after awakening. A normal EEG is rare, even in well-controlled patients.
The diagnosis of Jeavons syndrome is simple, because the characteristic eyelid myoclonia, if seen once, will never be forgotten or confused with other conditions (26). Furthermore, the EEG with the characteristic eye-closure–related discharges and photosensitivity leaves no room for diagnostic error.
As a simple rule of thumb, eyelid myoclonia is highly suggestive of Jeavons syndrome. This becomes more likely when eyelid myoclonia is combined with photosensitivity, and it is pathognomonic of the syndrome when it also occurs after eye closure. Nevertheless, eyelid myoclonia is often misdiagnosed as facial tics, sometimes for many years. Also, eyelid myoclonia should not be confused with the rhythmic or random closing of the eyes, often seen in other forms of IGE with absences or the eyelid jerking that may occur at the opening or the initial stage of the discharges in typical absence seizures of childhood or juvenile myoclonic epilepsy.
A main misconception in Jeavons syndrome is that eyelid myoclonia (the seizure) is a self-induced attempt to induce seizures. This belief is so strong that the patient described by Radovici et al (1932) (30) is erroneously cited as the first reported case of self-induced seizures even by hand waving in nearly all relevant publications. No such evidence or mention of self-induced seizures can be found in the original report. “AA…age de 20 ans, presente des troubles moteurs sous forme de mouvements involontaires de la tete et des yeux sous l' influence des rayons solaires” (AA… aged 20 years old presents motor disturbances in the form of inviluntary movements of the head and eyes under the influence of sunlight)(30).
The symptom/seizure of eyelid myoclonia alone is not sufficient to characterize Jeavons syndrome, because it may also occur in cryptogenic and symptomatic epilepsies (27,31), which are betrayed by developmental delay, learning difficulties, neurological deficits, abnormal MRI, and abnormal background EEG (27,31).
Jeavons syndrome is a lifelong disorder, even if seizures are well controlled with antiepileptic drugs. Men may have a better prognosis than women. There is a tendency for photosensitivity to disappear in middle age. Eyelid myoclonia persists, is highly resistant to treatment, and occurs many times per day, often without apparent absences and even without demonstrable photosensitivity (21).
According to anecdotal evidence, the drugs of choice are valproate, ethosuximide, and clonazepam. Of the newer antiepileptic drugs, levetiracetam may prove the most effective because of its antimyoclonic and antiphotosensitive properties. Lamotrigine may exaggerate myoclonic jerks. Lifestyle and avoidance of seizure precipitants are important. Nonpharmacological treatments used for photosensitive patients (such as wearing special glasses) often have a beneficial effect and should also be employed (32).
IGE syndromes with Mendelian (monogenic) inheritance have been described in the last decade. Among those with autosomal-dominant inheritance, autosomal-dominant cortical tremor, myoclonus, and epilepsy (ADCME) is more common (33,34). Familial infantile myoclonic epilepsy is of autosomal-recessive inheritance (35,36).
Autosomal-dominant cortical tremor, myoclonus, and epilepsy
This term has been used recently to include a number of familial autosomal disorders manifesting with cortical tremor, myoclonus, and epilepsy, such as benign familial adult myoclonic epilepsy, familial adult myoclonic epilepsy, familial essential myoclonus and epilepsy, familial cortical tremor and epilepsy, and autosomal-dominant cortical myoclonus and epilepsy. It has been described mainly in Japanese and Italian families. They all have a similar phenotype and may be a single relatively benign nonprogressive autosomal-dominant IGE syndrome with high penetrance and genetic heterogeneity (33,34).
Age at onset of cortical tremor and myoclonus varies from 11 to 50 years. ADCME is probably the most common of all autosomal IGE syndromes.
Adult-onset cortical tremor and myoclonus are the defining symptoms. Most patients (80%) also have infrequent GTCS in periods of worsening myoclonus. Cortical tremor looks like fine shivering of the fingers and hands intensified by posture, fine movement, emotional, and physical stress (33,34,37,38). The majority of patients also suffer from cortical myoclonus manifesting with distal, arrhythmic, and erratic jerks of mainly hands and fingers. These are also exaggerated by posture, fine movement, emotional, and physical stress. Most patients (80%) also have infrequent GTCS in periods of worsening myoclonus. GTCS are usually precipitated by sleep deprivation and photic stimulation. Rarely, in some families, additional complex focal seizures may occur. Mental and neurological states are normal, but some patients may show mild cognitive impairment. Families with members having concurrent migraine or blindness have been reported.
The genes for ADCME have been mapped to 8q24 in Japanese (39–42) and 2p11.1-q12.2 in European families (33,34).
The EEG shows generalized polyspikes and waves and photoparoxysmal responses. Photomyogenic responses may also be present. Somatosensory and visually evoked potentials were of very high amplitude. Consistent with cortical myoclonus, long-loop C-reflexes are enhanced and cortical spikes precede the rhythmic jerk on jerk-locked back EEG averaging. Surface EMG shows irregular, arrhythmic, or semirhythmic and myoclonic jerks at around 10 Hz. EMG bursts last about 50 ms, and are usually synchronous between agonist and antagonist muscles, without the regular agonist/antagonist alternation of the essential tremor (33).
Cortical tremor may be misinterpreted as essential tremor, from which it is clinically and electrophysiologically different.
These are nonprogressive disorders. Epileptic seizures are usually infrequent but cortical tremor and myoclonus may sometimes be severe. Occasionally, mental decline is reported in old age.
This is with antiepileptic drugs that have antimyoclonic activity such as valproate, phenobarbital, clonazepam, and levetiracetam (33,43). Piracetam in high doses is often beneficial for the cortical tremor. Lamotirigine, gabapentin, tiagabine, and pregabalin because of some pro-myoclonic action are probably contraindicated.