Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of epilepsy with generalized tonic-clonic seizures alone, epilepsy with generalized tonic-clonic seizures on awakening, epilepsy with grand mal on awakening, idiopathic generalized epilepsy of adolescence and young adulthood with generalized tonic-clonic seizures, and genetic epilepsy with generalized tonic-clonic seizures alone. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Epilepsy with generalized tonic-clonic seizures (GTCS) alone is probably a syndrome of idiopathic/genetic generalized epilepsy of uncertain boundaries. Onset is usually in late adolescence, and genetic predisposition is common. Generalized onset tonic-clonic seizures occur at any time, but mainly on awakening and particularly after sleep deprivation and excessive alcohol consumption. By definition, other types of generalized seizure such as absences or myoclonic jerks (characteristic mainly of juvenile myoclonic epilepsy) are not part of this syndrome, though this is debated. The EEG usually shows asymptomatic 3 to 4 Hz generalized spike/polyspike discharges, but often video-EEG after partial sleep deprivation with recording in sleep and awakening is needed. Differential diagnosis is demanding for the exclusion of nonepileptic attacks and focal onset tonic-clonic seizures. Prognosis is markedly variable, from excellent in mild cases to severe with continuing GTCS becoming more frequent and less dependent on sleep-waking cycle and precipitating factors. Patients usually violate the precipitating factors and do not comply with medication because of certain personality traits. Prophylactic treatment, mainly with sodium valproate, levetiracetam, or lamotrigine, is effective.
• Epilepsy with generalized tonic-clonic seizures alone is probably a syndrome of idiopathic/genetic generalized epilepsy but of uncertain boundaries.
• Generalized onset tonic-clonic seizures may occur at any time though those happening after awakening are more characteristic and better studied.
• Precipitating factors such as sleep deprivation and over consumption of alcohol are significant; some patients may never have GTCS in the absence of these triggers.
• Other types of generalized seizures such absences or myoclonic jerks are not part of this syndrome, but this is debated.
• Differential diagnosis is often difficult without appropriately performed and assessed video-EEG.
• Prognosis varies from excellent to severe with lifelong continuing GTCS.
• Response to antiepileptic drugs, usually monotherapy with sodium valproate, levetiracetam, or lamotrigine, is commonly excellent.
• Avoidance of precipitating factors is the most significant part of management, but this is often violated because of certain personality traits.
The manifestations of generalized tonic-clonic seizures (GTCS) are so dramatic that their accurate descriptions can be found as early as 1050 BC in the twenty-fifth Babylonian cuneiform tablet devoted to miqtu (a disease in which the person loses consciousness and foams at the mouth) (09). A realistic depiction of GTCS, including marked cyanosis, can be seen in the painting of Saint Ignatius of Loyola exorcising (1617) by Peter Paul Rubens (1577-1640) (73).
That seizures can be related to sleep was already known to Aristotle:
Hence, also they are subject to epileptic seizures; for sleep is like epilepsy, and, in a sense, actually is a seizure of this sort. Accordingly, the beginning of this malady takes place with many during sleep, and their subsequent habitual seizures occur in sleep, not in waking hours. (Aristotle: On Sleep and Sleeplessness 350 BC; http://classics.mit.edu/Aristotle/sleep.html).
From the mid-nineteenth century, when all epilepsies were recognized as originating in the brain, the GTCS (grand mal) were considered the cardinal manifestation of genuine or idiopathic epilepsy due to a predisposition to have seizures. This predisposition was believed to be associated only with generalized convulsions (22).
Gowers first mentioned that in 5% of his patients attacks occurred only in the early morning (26). Langdon-Down and Brain divided their patients into those with diurnal, nocturnal, and diffused seizures. For the diurnal group, the most important peak was shortly after awakening (38). Hopkins found that seizures of 302 outpatients occurred in 2 main peaks, during sleep (about half of all patients) and in the period of awakening (defined as the first hour after arousal from sleep; about two third of all patients). The remaining patients had diurnal seizures any time “from the end of the awakening period to the resumption of sleep” (29). Griffiths and Fox found that of 104 institutionalized patients, 38.5% were “night-fitters,” 37.5% “day-fitters,” 10.5% “rising-fitters,” and 13.5% “diffused” (28; 30; 42; 47; 71; 72).
The most thorough and systematic study of the relation of GTCS to sleep-waking cycle is by Janz (Janz 1953; 30). In his classical report, he makes an exhaustive review of the literature and masterly analyzes his own data concluding that:
Under this aspect, three types of course may be described: (1) grand mal epilepsies with attacks predominantly following waking and during the period of relaxation following work ("Feierabend"), the so-called awakening epilepsies; (2) grand mal epilepsies with attacks mainly after falling asleep or before waking, the so-called sleep epilepsies; (3) grand mal epilepsies with irregular dispersed attacks, the so-called diffuse epilepsies. As a rule these types remain constant even in cases of considerable duration. Transitions occur from awakening epilepsy to sleep epilepsy or to diffuse epilepsy and from sleep epilepsy to diffuse epilepsy, but not vice versa” (30).
Of 1051 patients with “pure grand mal seizures only (no other types of seizure),” 30% occurred on awakening, 50% occurred in sleep, and 20% were random (30). His report examines all types of GTCS in their relation to awakening, sleep, or no particular circadian distribution, though it is better known and cited for “epilepsy with grand mal on awakening” to which he also devoted subsequent papers (Janz 1994; 33). The most elaborate sleep investigations were made on this syndrome by Billiard (08).
Classification and nomenclature. The 1989 ILAE proposal recognized an epileptic syndrome of “Epilepsy with generalized tonic-clonic seizures on awakening” (or “epilepsy with grand mal on awakening”); they classified it amongst the idiopathic generalized epilepsies and defined it as follows:
Epilepsy with generalized tonic-clonic seizures on awakening is a syndrome with onset occurring mostly in the second decade of life. The GTCS occur exclusively or predominantly (more than 90% of the time) shortly after awakening regardless of the time of day or in a second seizure peak in the evening period of relaxation. If other seizures occur, they are mostly absence or myoclonic, as in juvenile myoclonic epilepsy. Seizures may be precipitated by sleep deprivation and other external factors. Genetic predisposition is relatively frequent. The EEG shows one of the patterns of idiopathic generalized epilepsy. There is a significant correlation with photosensitivity (13).
The ILAE Task Force in 2001, based on a review by Andermann and Berkovic (04), abandoned the term “epilepsy with GTCS on awakening” and instead proposed a syndrome of “epilepsy with generalized tonic-clonic seizures only” (with GTCS only irrespective of circadian distribution) and classified it amongst “idiopathic generalized epilepsies with variable phenotypes”:
• Juvenile absence epilepsy
“Epilepsy with GTCS only” included:
- Seizures on awakening
Later, the ILAE Core Group revised its position and did not recognize it as a separate syndrome:
Epilepsy with GTCS only is not a syndrome, and the Core Group was unable to agree on any syndrome with this feature; the consistent diurnal pattern of seizures in some patients needs further investigation. Whether epilepsy with GTCS on awakening exists as a distinct entity is unclear (19).
“Epilepsy with generalized tonic-clonic seizures alone” is the new modified name used by the latest reports of the ILAE Commission, and it is listed amongst electroclinical syndromes of “adolescence – adult onset” together with juvenile absence epilepsy, juvenile myoclonic epilepsy, progressive myoclonus epilepsies, autosomal dominant epilepsy with auditory features, and other familial temporal lobe epilepsies (07). The current epilepsy manual of the ILAE Commission clarifies that “epilepsy with GTCS alone” means that seizures other than GTCS types of seizure are not allowed in this syndrome. If seizures other than GTCS types of seizure are allowed to be present, then the “epilepsy with GTCS alone” should probably be renamed to “epilepsy with predominant GTCS” (37) Such broadening of seizure types would cause significant overlapping with other syndromes of idiopathic generalized epilepsies and mainly with juvenile myoclonic epilepsy or idiopathic epilepsy with phantom absences (50). However, it is not clarified whether the proposal of Janz that 6 GTCS are required for making the diagnosis of epilepsy with GTCS on awakening (Janz 1994) is practical considering that most patients may have fewer than 6 seizures (sometime in life time) with appropriate treatment and avoidance of triggering factors (04) (see clinical vignette). Furthermore, there are some reports indicating that epilepsy with GTCS on awakening may be different from that with GTCS occurring randomly (27; 17; 64). Thus, the recognition and boundaries of epilepsy with GTCS alone may still be far from final dissolution.
In the 2014 ILAE epilepsy diagnosis manual, epilepsy with generalized tonic-clonic seizures alone is classified as a genetic epilepsy syndrome of adolescents/adults (Commission on Classification and Terminology of the International League Against Epilepsy 2014). The complete description of epilepsy with generalized tonic-clonic seizures alone is as follows:
This syndrome (previously known as epilepsy with grand mal seizures on awakening) is a common genetic generalized epilepsy. Individuals have infrequent generalized convulsive seizures from the second decade of life, typically provoked by sleep deprivation.
Note. A genetic generalized epilepsy is an epilepsy with generalized seizures associated with generalized epileptiform EEG patterns, such as generalized spike wave activity.
Clinical context. This syndrome is characterized by onset of generalized convulsive seizures between the ages of 5 to 40 years of age (peak 11 to 23 years, 80% of cases have their first convulsion in the second decade). Seizures may be frequent, with one fifth of cases having more than 1 seizure per month prior to treatment. Treatment is required for life. Sleep deprivation, fatigue, and alcohol lower threshold for seizures. Antecedent and birth history is normal, although there are patients with a previous history of childhood absence epilepsy. Neurologic examination and head size are normal. Development and cognition are typically normal.
Mandatory seizures. Generalized convulsive seizures are mandatory for this epilepsy syndrome, predominantly/exclusively occurring on awakening (within 1 to 2 hours, although also seen from awake or sleep states).
Exclusionary. All other seizure types.
EEG Background. The EEG background is normal.
Caution. Generalized slowing is not seen.
Caution. If focal slowing is seen consistently over 1 area, consider structural brain abnormality.
Interictal. Generalized spike-and-wave or polyspike-and-wave is seen in the interictal EEG. Half of the patients have these abnormalities only in sleep.
Caution. Although focal spike-and-wave can occur, if seen consistently in 1 area, consider structural brain abnormality.
Caution. If slow spike-and-wave (< 2.5 Hz) is not seen, consider other epilepsy syndromes.
Activation. An intermittent photoparoxysmal response to photic stimulation may be seen.
EEG abnormality is enhanced by sleep deprivation and in sleep. Generalized spike-and-wave often becomes fragmented with sleep deprivation or in sleep. Fragmented generalized spike-and-wave can appear focal or multi-focal but usually is not consistently seen in 1 area. The morphology of the focal spike-and-wave typically appears similar to the generalized spike-and-wave.
Ictal. With generalized convulsive seizures, the ictal EEG is often obscured by artifact. Generalized fast rhythmic spikes are seen in the tonic stage. Bursts of spikes and after-coming slow waves are synchronous with clonic jerks. A postictal period of irregular slow activity follows.
Imaging. Neuroimaging is normal.
Genetics. It has a complex inheritance. Known genes linked to this syndrome include CLCN2 and others.
Family history of seizures/epilepsy. A family history of epilepsy is common (in 20%, commonly the same epilepsy syndrome). A family history of febrile seizures is reported in around 10% of cases.
• Genetic epilepsy with febrile seizures plus
Note on nomenclature. The 2010 ILAE report has recommended that some terms used in this article, such as idiopathic, symptomatic, and cryptogenic be replaced with the terms genetic, structural-metabolic, and unknown (07). However, healthcare professionals are still more familiar with the “older” terms. Furthermore, the new terminologies have not been widely accepted, idiopathic is not equated with genetic, and cryptogenic is more specific than unknown (50). A striking example of these difficulties is “idiopathic generalized epilepsies,” which cannot be replaced with the term “genetic generalized epilepsies.” It is for this reason that the newest position paper of the ILAE Commission for Classification and Terminology (57) stated that:
There has been, however, considerable desire to retain the term idiopathic generalized epilepsy. The Task Force has therefore decided that the term idiopathic generalized epilepsy will be acceptable specifically for the group of four epilepsy syndromes: Childhood Absence Epilepsy, Juvenile Absence Epilepsy, Juvenile Myoclonic Epilepsy, and Generalized Tonic-Clonic Seizures Alone. In individual cases, the term Genetic Generalized Epilepsy may be used where the clinician is comfortable with invoking a genetic etiology.
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